CHANGING TRENDS IN LUNG CANCER EPIDEMIOLOGY

 CHANGING TRENDS IN LUNG CANCER EPIDEMIOLOGY

Dr Shilpa Chandran¹, Dr Ravindran Chetambath²

¹Resident Trainee, ²Senior Consultant & Chief of Medical Services

Dept. of Pulmonology, Baby Memorial Hospital, Calicut, Kerala

 

Abstract

Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths. Lung cancer is mostly attributed to smoking even though exposure to environmental pollutants and occupational agents also contributes to its causation. For the last 2 decades there is a change in epidemiology and histopathological types of lung cancer. More and more women are affected that too at a younger age when compared to their male counterparts. Another important change noticed is the increase in number of adenocarcinoma surpassing previously predominant squamous cell carcinoma. This article reviews the changes in the epidemiological and histopathological trends in lung cancer.

Key Words

Lung Cancer, trends, cigarette smoking

Introduction

Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths. In the last century carcinoma of the lung has progressed from an uncommon and obscure disease to one of the most common cancers in the world. In the late 1840s there were only 22 ever published cases of lung cancer. In 1912 Adler identified only 374 published cases.¹ According to GLOBOCAN data 2.21 million lung cancer cases were diagnosed in the year of 2020 worldwide.

 

Figure-1: Estimated age standardized incidence rates in 2020 (World), both sexes, all ages

(Data source GLOBOCAN 2020)

Comprehensive data on lung cancer in India are lacking. According to GLOBOCAN 2020 data lung cancer was ranked the fourth leading cause of cancer in India in all ages and sexes. Furthermore 66,279 of all cancer related deaths were attributed to lung cancer. In India, lung cancer constitutes 6.9 per cent of all new cancer cases and 9.3 per cent of all cancer related deaths in both sexes.

Notable changes in lung cancer epidemiology have occurred over the past decade owing to the changes in smoking patterns, advances in our understanding of the genetics of lung cancer, role of immune systems in the control of lung cancer and options available for lung cancer treatment. Several studies, including a ten year study conducted at  All India Institute of Medical Sciences (AIIMS) Delhi² have reported that adenocarcinoma (ADC) has surpassed squamous cell carcinoma (SCC) as the most common histological subtype of lung cancer. This shift seems to be attributable partly to the changed smoking pattern and the increasing incidence of lung cancer in females and non-smokers. In contrast, Jindal et al in 1990 after a  10 year follow up study reported that SCC is the most common subtype in India.³

Figure-2: Estimated number of new cases in 2020 (India), both sexes, all ages

(Data source GLOBOCAN 2020)

Change in Incidence Among Males and Females

Incidence trends and geographical patterns are different for men and women and primarily reflect historical, cultural and regional differences in tobacco smoking. Risch et al⁴. has proposed a hypothesis that women smokers are at higher risk of lung cancer than men. It was found that the odds ratio for women was almost three times greater than that for men (27.9 vs. 9.6), when smokers with a 40 pack-year smoking history were compared to non-smokers^5, 6. In addition, Zang and Wynder have shown that the odds ratios for major lung cancer types are consistently higher in women than in men at every level of exposure to cigarette smoke and that these gender differences are likely due to the higher susceptibility to tobacco carcinogens in women⁷.

Over the past decade, due to intensive smoking cessation programs and subsequent reductions in tobacco consumption, incidence rates and deaths attributable to lung cancer declined. However, lung cancer incidence rates have not decreased as much as expected. There are increasing evidence showing variations in rates of decline in lung cancer by sex and race/ethnicity. In a study conducted in California by Manali Patel et al in 2017 it is reported that there is an increase in lung cancer incidence among low socioeconomic class females and for adenocarcinoma⁸.

The reasons behind higher female lung cancer rates in recent years have been attributed to smoking. However, others have refuted smoking as the sole reason for the higher incidence rates among females⁷ and suggest that non-smoking related risk factors may be contributing to the higher rates of lung cancer incidence among females as compared with males.

In a recent study, Jemal and colleagues showed continued sex-based incidence differences and presented compelling evidence that these discrepancies may not be attributed to smoking behaviours in the United States¹⁰. The investigators ascertained incidence trends from 1995 to 2014 using the North American Association of Central Cancer Registries and smoking prevalence trends from 1970 to 2016 by race/ethnicity, age, and sex, using the National Health Interview Study. The authors found an overall decrease in the rate of new lung cancer diagnoses, this trend was driven primarily by a decrease in incidence among non-Hispanic white and Hispanic males. The authors noted increased lung cancer incidence rate ratios (IRR) among females as compared with males from the mid-1990s to 2010-2014 [IRR among persons 40–44 increased from 0.82 (95% CI, 0.79–0.85) to 1.13 (95% CI, 1.08–1.18)]. The authors concluded that the patterns of historically higher incidence rates of lung cancer among men than among women have reversed among non-Hispanic whites and Hispanics born since the mid-1960s, and they are not fully explained by sex differences in smoking behaviours. The rate of new cases (incidence) increased 14% among men from 1975 until peaking in 1984, and has since decreased 46%. The rate of new cases increased 120% among women from 1975 until peaking in 1998, and has since decreased 16%.

Few studies reported that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles.

Studies from East Asia have also shown an increased risk of lung cancer in women with shorter menstrual cycles (threefold higher risk) implying a higher number of hormone influences during the reproductive period¹¹.  Death rates increased for both men and women from 1930 until peaking in 1990 at 91.1 per 100,000 for men and in 2002 at 41.6 per 100,000 for women. Over the last 10 years, rates have decreased by 31% for men and 24% for women.

Age Group

Older age is associated with cancer development due to biologic factors that include DNA damage over time and shortening telomeres. According to the American Cancer Society, most people diagnosed with lung cancer are 65 years or older, with the average age at diagnosis being 70 years.

Laura Guarga et. al. studied trends in lung cancer incidence by age and the data suggest a decrease in the absolute number of new cases in men under the age of 70 years and an increase in women aged 60 years or older¹².  Three quarters of lung cancer deaths in 2019 occurred among those aged 65 years of age and older, and 95% among those aged 55 years of age and older.

In a recent study conducted by Anand Mohan et al, majority of the patients were males (82.9%), in the age bracket of 46–70 years, with mean (SD) age of 58 (11.1) years. The mean age remained relatively unchanged over the study time‑period. The proportion of females showed an increasing trend, from 7.9% in 2008 to 27.2% in 2018.²

Histology and Smoking Pattern

In recent years, there has been a great interest in the histological characterization and genomic classification of lung carcinoma due to the availability of several new targeted therapeutic modalities. The use of generic terms such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are being questioned.

The cause–effect relationship between cigarette smoking and lung cancer is undisputed. Lung cancers that develop as a result of cigarette smoking present in a wide variety of histological phenotypes. This likely reflects the complexity of cigarette smoke, which contains large numbers of different carcinogens. The most common histological variants of lung cancer related to smoking are squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma and small cell carcinoma, but less common variants of neuroendocrine neoplasms of varying degrees of malignancy are also associated with cigarette smoking. The relationship between cigarette smoking and adenocarcinoma of the lung was previously thought to be less than that between smoking and squamous cell carcinoma and small cell carcinoma, but data over the past few decades convincingly point to a cause–effect relationship for tobacco and adenocarcinoma^13,14. Another major diagnostic category of lung cancer, large cell carcinoma, might represent poorly differentiated squamous cell cancers or adenocarcinomas, and these cancers are also closely related to tobacco use¹³. Major shifts have been recorded for frequencies of the various histological types of lung cancer in many countries, with significant increases in the relative incidence of adenocarcinoma

Devasa et. al. reported that Squamous cell carcinoma rates among males declined 30% or more in North America and some European countries, while changing less dramatically in other areas; small cell carcinoma rates decreased less rapidly. Squamous and small cell carcinoma rates among females generally rose, with the increases especially pronounced in the Netherlands and Norway. In contrast, adenocarcinoma rates rose among males and females in virtually all areas, with the increases among males exceeding 50% in many areas of Europe; among females, rates also rose rapidly and more than doubled in Norway, Italy and France. Rates of all lung cancer types among women and adenocarcinoma among men continue to rise despite declining cigarette use in many Western countries and shifts to filtered/low-tar cigarettes¹⁵.  In the Western countries and most of the Asian countries, adenocarcinoma has surpassed squamous cell carcinoma.

It is widely accepted that the changes in cigarette design are responsible for the shifts in lung cancer pathology. Most notably, with emerging evidence that cigarettes are the major cause of lung cancer, and recognition of cigarette tar as a reservoir of carcinogens, consumers demand for filtered cigarettes. Cigarette filters are designed to trap tars, and filters typically also have small perforations, which are intended to dilute mainstream smoke. In 1950, less than 1% of all cigarettes sold in the USA had filter tips, but by the late 1990s filter cigarettes constituted more than 97% of the US market.

Another important change in cigarette composition over past decades is in the tobacco blends used in cigarette manufacturing, with a general increase in the amounts of stems and ribs used in the cigarette blends. The stems and ribs of burley tobacco have particularly high levels of nitrates. This later trend is of particular significance, because NNK [4- (methyl-nitrosamino)-1-(3-pyridyl)-1-butanone] appears to be a carcinogen highly specific for pulmonary adenocarcinomas in animal studies¹⁶.

In principle, the use of filter cigarettes reduces the levels of both tar and nitrosamines in the mainstream smoke. Although current smokers generally have decreased exposure to tars and the carcinogens in tars (such as polycyclic aromatic hydrocarbons (PAH)), compared with smokers of the past, craving for nicotine (the major addictive substance of cigarette smoke) appears to cause smokers to cover ventilation holes along the sides of the filters, and also inhale more intensely to satisfy the nicotine crave. For example, studies have shown that smokers of filtered cigarettes take more frequent puffs, and increased volume with each puff, resulting in the peripheral lung being exposed to a proportionally higher level of carcinogens¹⁷. The net result of these changes in cigarette design and pattern of smoke inhalation is a transformation in the anatomic distribution of carcinogen exposure as well as significant alterations in the levels of different carcinogens. These changes are commonly attributed for the shifts in lung cancer histology by increasing incidence of peripheral adenocarcinoma and decreasing incidence of central squamous cell carcinoma.

Although the longitudinal and histology-specific lung cancer data are not as extensive for Asian, African, or South American countries, it appears that similar trends pervade worldwide. Lam et. al. studied the lung cancer patterns in Asian population.

To a large extent, overall increases in lung cancer in these countries parallel the increasing consumption of cigarettes, particularly among men and it appears that the same general histological patterns are seen for these cancers as for the smoking-related cancers in North America and Europe. However, lung cancer in Asian women also appears to be increasing in incidence, and in general, these cancers appear to be predominantly adenocarcinoma. This trend appears to involve rural as well as urban women, and although there is no reliable data for cigarette consumption among women in Asia, there is a general impression that this in relatively independent of cigarette smoking¹⁷.

In the initial years of  a 10 year  study conducted by Anand Mohan et al SCC dominated the morphological type of NSCLC but was overtaken by ADC in 2012, and this trend continued till 2018.¹⁶ It should be noted, however, that the distribution of SCC and SCLC remained largely unchanged, while the frequency of NSCLC- NOS declined. This occurred most likely due to the changing practices of pathological reporting keeping in tune with the advancement in immunohistochemical techniques and based on the revision of guidelines for pathological reporting for lung cancer. Another contributory factor may be an increase in the proportion of females over the 10-year period.

Conclusion

In reviewing the available literature, it is evident that lung cancer incidence is increasing among females, that too at a younger age when compared to their male counter parts. Apart from smoking female hormonal influences are also attributed to this higher incidence. The predominant histopathological type now is adenocarcinoma in all age group and in both sexes.

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