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The International Epidemiology of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics

Open ArchivePublished:June 27, 2016DOI:https://doi.org/10.1016/j.jtho.2016.05.021

      Abstract

      Introduction

      Our aim was to update global lung cancer epidemiology and describe changing trends and disparities.

      Methods

      We presented country-specific incidence and mortality from GLOBOCAN 2012 by region and socioeconomic factors via the Human Development Index (HDI). Between- and within-country incidence by histological type was analyzed by using International Agency for Research on Cancer data on cancer incidence on five continents. Trend analyses including data from the International Agency for Research on Cancer, cancer registries, and the WHO mortality database were conducted using joinpoint regression. Survival was compared between and within countries and by histological type.

      Results

      In 2012, there were 1.82 and 1.59 million new lung cancer cases and deaths worldwide, respectively. Incidence was highest in countries with a very high HDI and lowest in countries with a low HDI (42.2 versus 7.9 in 100,000 for males and 21.8 versus 3.1 in 100,000 for females, respectively). In most countries with a very high HDI, as incidence in males decreased gradually (ranging from –0.3% in Spain to –2.5% in the United States each year), incidence in females continued to increase (with the increase ranging from 1.4% each year in Australia to 6.1% in recent years in Spain). Although histological type varied between countries, adenocarcinoma was more common than squamous cell carcinoma, particularly among females (e.g., in Chinese females, the adenocarcinoma-to–squamous cell carcinoma ratio was 6.6). Five-year relative survival varied from 2% (Libya) to 30% (Japan), with substantial within-country differences.

      Conclusions

      Lung cancer will continue to be a major health problem well through the first half of this century. Preventive strategies, particularly tobacco control, tailored to populations at highest risk are key to reducing the global burden of lung cancer.

      Keywords

      Introduction

      Lung cancer imposes a major disease burden on the world. Worldwide, lung cancer remains the most common cancer diagnosed (excluding keratinocyte carcinoma) and the greatest cause of cancer-related death. Lung cancer accounts for 17% and 9% of all cancers in men and women, respectively, and represents 19% of all cancer-related deaths.
      • Torre L.A.
      • Bray F.
      • Siegel R.L.
      • Ferlay J.
      • Lortet-Tieulent J.
      • Jemal A.
      Global cancer statistics, 2012.
      Because of its extraordinary disease burden and the international variability in trends for population growth, aging, and smoking behavior, the global epidemiology of lung cancer requires continual monitoring.
      The epidemiology of lung cancer in major developed countries such as the United States and countries in the European Union has consistently been reported.
      • Henley S.J.
      • Richards T.B.
      • Underwood J.M.
      • Eheman C.R.
      • Plescia M.
      • McAfee T.A.
      Lung cancer incidence trends among men and women—United States, 2005-2009.
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      • Bosetti C.
      • Malvezzi M.
      • Rosso T.
      • et al.
      Lung cancer mortality in European women: trends and predictions.
      • Ferlay J.
      • Steliarova-Foucher E.
      • Lortet-Tieulent J.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.
      However, potential differences in lung cancer rates by levels of socioeconomic development between countries have been less well described. This is important because almost half (49%) of all lung cancer cases now occur in countries ranked as medium to low on the Human Development Index (HDI),

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      a composite measure encompassing population health, knowledge, and living standards to indicate the development of a country.

      United Nations Development Programme. Human Development Report 2013. The rise of the South: human progress in a diverse world. New York, NY: United Nations Development Programme; 2013.

      In addition, although some studies have reported within-country differences in lung cancer incidence across defined subpopulations,
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
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      • Sheppard A.J.
      • Withrow D.R.
      • Marrett L.D.
      Cancer survival among First Nations people of Ontario, Canada (1968-2007).
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      • Brewster D.
      The epidemiology of lung cancer in Scotland: a review of trends in incidence, survival and mortality and prospects for prevention.
      • Funatogawa I.
      • Funatogawa T.
      • Yano E.
      Trends in smoking and lung cancer mortality in Japan, by birth cohort, 1949-2010.
      there is limited understanding of the overall extent of these geographical disparities from a global perspective.
      The histology and molecular markers of lung cancer, such as genetic mutations, are important when classifying lung cancers for treatment and preventive strategies.
      • Ettinger D.S.
      • Akerley W.
      • Borghaei H.
      • et al.
      Non-small cell lung cancer.
      For example, widespread temporal increases in rates of adenocarcinoma may be explained by changes in cigarette components and delivery systems,
      • Thun M.J.
      • Lally C.A.
      • Flannery J.T.
      • Calle E.E.
      • Flanders W.D.
      • Heath Jr., C.W.
      Cigarette smoking and changes in the histopathology of lung cancer.
      as well as by non–tobacco-related risk factors.
      • Samet J.M.
      • Avila-Tang E.
      • Boffetta P.
      • et al.
      Lung cancer in never smokers: clinical epidemiology and environmental risk factors.
      Overall, the global epidemiology of these characteristics in relation to lung cancer incidence and mortality has yet to be extensively documented.
      The objectives of this study are to (1) describe the most recent patterns at the country level by region and HDI and trends in lung cancer epidemiology worldwide as an update of a previous article in this journal presenting GLOBOCAN 2002 data
      • Youlden D.R.
      • Cramb S.M.
      • Baade P.D.
      The international epidemiology of lung cancer: geographical distribution and secular trends.
      ; (2) review and discuss the global perspectives of the histological and molecular features of lung cancer; (3) report region- and country-specific profiles, emphasizing disparities and changing trends; and (4) outline opportunities to reduce the burden of lung cancer through prevention, early diagnosis, and new therapies, as Discussion. In objective 3, we present specific results for African countries, Central and South American countries, Australia, China, and the United States to elucidate different strategies for preventing and controlling lung cancer in these populations.

      Methods

      Data

      Lung cancer was defined as International Classification of Diseases (ICD), 10th Revision/ICD-O3 codes C33 and C34 and ICD-9 code 162, which include malignant neoplasms of the trachea, bronchus, and lung. Data on lung cancer incidence and mortality were extracted from GLOBOCAN 2012, an International Agency for Research on Cancer (IARC) project providing contemporary national estimates of cancer statistics for 184 countries.

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      We present regional incidence and mortality data according to geographic area and level of socioeconomic development, and we provide estimates for specific countries selected to be broadly representative of the various regions and development levels. Countries are classified into four levels of development (very high, high, medium, or low) according to the 2012 HDI, a composite index developed by the United Nations Development Program.

      United Nations Development Programme. Human Development Report 2013. The rise of the South: human progress in a diverse world. New York, NY: United Nations Development Programme; 2013.

      A higher HDI indicates that on average, a country's people live longer, are healthier, are more knowledgeable, and have a better standard of living than those in countries with a lower HDI.

      United Nations Development Programme. Human Development Report 2013. The rise of the South: human progress in a diverse world. New York, NY: United Nations Development Programme; 2013.

      Histological type–specific incidence rates were extracted from the online detailed version of Cancer Incidence in Five Continents Volume X.

      Forman D, Bray F, Brewster DH, et al., eds. Cancer incidence in five continents, Vol. X. http://www.iarc.fr/en/publications/pdfs-online/epi/sp164/. Accessed April 7, 2014.

      Lung cancer was classified into two major cell types according to its histological features, NSCLC (which includes the subtypes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) and SCLC, on the basis of the WHO 2004 guidelines.
      A new guideline on histological classification based on genetic as well as clinical and histological features was recently released by WHO.
      As the new guideline is yet to be implemented by cancer registries, the classifications used here were based on the 2004 definitions.
      Registries were included only if at least 60% of cases had been microscopically verified.
      To examine incidence trends over time, longitudinal lung cancer data were obtained from IARC

      Ferlay J, Bray F, Steliarova-Foucher E, Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9. http://ci5.iarc.fr/CI5plus/Default.aspx. Accessed September 24, 2014.

      and individual cancer registries.

      Australian Institute of Health and Welfare. Australian Cancer Incidence and Mortality. (ACIM) Books. http://www.aihw.gov.au/acim-books/. Accessed November 24, 2014.

      National Cancer Registry Ireland. The National Cancer Registry Ireland: incidence, mortality, treatment and survival. http://www.ncri.ie/. Accessed July 23, 2014.

      Center for Cancer Control and Information Services, National Cancer Center Japan. Cancer incidence 1975-2010. Center for Cancer Control and Information Services, National Cancer Center. http://ganjoho.jp/en/professional/statistics/table_download.html; Accessed April 17, 2014.

      Netherlands Comprehensive Cancer Organisation (IKNL). Dutch cancer figures using Netherlands Cancer Registry data. http://www.cijfersoverkanker.nl/?language=en. Accessed December 3, 2014.

      National Board of Health and Welfare (Socialstyrelsen). Cancer statistical database. http://www.socialstyrelsen.se/statistics/statisticaldatabase/cancer. Accessed April 9, 2013.

      Hong Kong Cancer Registry. Cancer Statistics Query System by ICD-10. http://www3.ha.org.hk/cancereg/e_a1b.asp. Accessed December 11, 2013.

      Surveillance, Epidemiology, and End Results (SEER) Program. National Cancer Institute, DCCPS, Surveillance Research Program. Surveillance Systems Branch Research data (1973-2011). http://www.seer.cancer.gov. Released April 2014, based on the November 2013 submission; 2014.

      Countries were included if at least 15 years of data were readily available and if, for IARC data, at least 60% of lung cancer cases were microscopically verified and less than 30% were diagnosed by death certificate. All included countries had more than 100 lung cancers diagnosed in males and females (separately) each year.
      Mortality trends over time utilized the WHO Mortality Database.

      World Health Organization. WHO Mortality Database (released 25 February 2014). http://www.who.int/healthinfo/statistics/mortality_rawdata/en/. Accessed November 12, 2014.

      This database contains medically certified deaths only, so completeness can vary between countries. Countries were selected on the basis of data availability (at least 12 years of data), the number of deaths each year (>100 for each sex), and data completeness (>85%). China was additionally included as it represents almost one-fifth of the world’s population, even though the available mortality data covered less than 10% of China’s population and provided an estimated data completeness across the whole country of only 4%.
      In addition, we presented data from the literature on lung cancer epidemiology for China and for African and Central and South American countries because of inadequate coverage of the national population by the available registries in many of these countries.
      • Ferlay J.
      • Soerjomataram I.
      • Dikshit R.
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      • Mathers C.D.
      • Fat D.M.
      • Inoue M.
      • Rao C.
      • Lopez A.D.
      Counting the dead and what they died from: an assessment of the global status of cause of death data.

      Statistical Analysis

      Incidence and mortality rates were directly age-standardized to the World Standard Population as specified by Segi

      Segi M. Cancer mortality for selected sites in 24 countries (1950-57). Sendai, Japan: Department of Public Health, Tohoku University of Medicine; 1960.

      and modified by Doll et al.
      and were expressed per 100,000 population. Calculations were performed in Stata, version 13.1 (StataCorp, College Station, TX), and trend graphs were created using SAS 9.4 (SAS Institute, Inc., Cary, NC).
      Trend analyses were conducted using the Joinpoint Regression Program, version 4.0.4 (National Cancer Institute, Bethesda, MD). The program is designed to evaluate changing linear trends over time by inserting a joinpoint when the linear trend changes significantly in either direction or magnitude. All models used the same specifications and required a minimum of six data points between a joinpoint and either end of the data series and at least 5 years of data between joinpoints. A maximum of three joinpoints were allowed. The annual percent change was used to report trends.
      Age-standardized net survival estimates for lung cancers diagnosed in 2005–2009 and followed up to 31 December 2009 were obtained from the CONCORD-2 study,
      • Allemani C.
      • Weir H.K.
      • Carreira H.
      • et al.
      Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).
      using lung cancer data from 240 registries in 60 countries for persons aged 15 to 99 years at diagnosis. The Pohar Perme method of estimation was used in this study to estimate net survival. More recent relative survival estimates were also available by sex for selected countries, including Australia (at-risk in 2006–2010, ages 0–89 years at diagnosis),

      Australian Institute of Health and Welfare. Cancer Survival and Prevalence in Australia: Period Estimates from 1982 to 2010 (Supplementary Material). Canberra, Australia: AIHW; 2012.

      the United States (at-risk in 2010, ages 0–99 years at diagnosis)

      Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Survival—SEER 18 Registries Research Data: National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2014 (updated May 7, 2014), based on the November 2013 submission. http://seer.cancer.gov/data/seerstat/nov2013/. Accessed July 22, 2014.

      and the Nordic countries (diagnosis in 2009–2011, with follow-up to 2012, ages 0–89 years at diagnosis).

      Association of the Nordic Cancer Registries. Danish Cancer Society. NORDCAN: cancer incidence, mortality, prevalence and survival in the nordic countries, version 7.2 (16.12.2015). http://www.ancr.nu. Accessed January 23, 2016.

      All survival estimates were calculated under the period method, apart from NORDCAN, which used the cohort method. Relative survival estimates by histological features were readily obtainable from the Surveillance, Epidemiology, and End Results-18 database (the United States)

      Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Survival—SEER 18 Registries Research Data: National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2014 (updated May 7, 2014), based on the November 2013 submission. http://seer.cancer.gov/data/seerstat/nov2013/. Accessed July 22, 2014.

      and the Australian Cancer Database (Australia).

      Australian Institute of Health and Welfare. Cancer Survival and Prevalence in Australia: Period Estimates from 1982 to 2010 (Supplementary Material). Canberra, Australia: AIHW; 2012.

      Results are presented in four sections according to the four stated objectives of this study, with each section incorporating a discussion of their implications for the global burden of lung cancer.

      Results and Discussion

      Recent Patterns and Trends in Lung Cancer Epidemiology

      Incidence

      In 2012, the world age-adjusted incidence rate of lung cancer was 34.2 in 100,000 for men and 13.6 in 100,000 for women (Table 1). This translated into 1.82 million new lung cancer cases (in 1.24 million men and 0.58 million women), which was an increase from the 2002 estimates (1.35 million for both sexes).
      • Youlden D.R.
      • Cramb S.M.
      • Baade P.D.
      The international epidemiology of lung cancer: geographical distribution and secular trends.
      The incidence rate was generally highest in socioeconomically developed countries (very high HDI) and lowest in socioeconomically undeveloped countries (low HDI) for both males and females. However, this effect did not have a consistent gradient, with some countries ranked as high on the HDI having higher incidence rates than those ranked as very high. With regard to the geographic regions, males in Central and Eastern Europe had the highest incidence rate (53.5 in 100,000), followed by males in Eastern Asia (50.4 in 100,000). The highest incidence rates among females were in North America (33.8 in 100,000) and Northern Europe (23.7 in 100,000).
      Table 1Lung Cancer Incidence and Mortality by Region and Selected Countries, 2012
      Data from GLOBOCAN 2012.

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      Region/CountryMalesFemalesQuality of Country Data on

      Incidence and Mortality
      IncidenceMortalityIncidenceMortality
      CountsRatesCountsRatesCountsRatesCountsRates
      World1,241,60134.21,098,70230.0583,10013.6491,22311.1
      Data quality is unavailable for regions.
       Very high HDI440,52042.2371,19234.1265,90521.8206,33015.6
       High HDI166,11832.1148,38328.654,6578.147,2846.9
       Medium HDI607,57835.6554,79232.6250,19213.1226,60211.7
       Low HDI26,8707.923,8817.112,0393.110,7382.8
      Northern Africa11,86515.610,56914.026413.123712.8
      Eastern Africa31023.828093.520492.218482.0
      Middle Africa5842.05251.82880.82580.7
      Western Africa13841.712251.59921.18601.0
      Southern Africa482126.1430223.8258810.223169.1
      Northern America125,53644.0102,41534.8114,24533.885,29723.5
      Caribbean599925.8560723.7354213.5325912.1
      Central America687410.261809.039094.934824.3
      South America39,45220.835,26018.424,74410.720,8148.9
      Eastern Asia556,08950.4501,65444.8240,44619.2211,14116.2
      Southeastern Asia74,03129.665,76326.630,98710.527,7729.4
      South and Central Asia80,90111.972,96910.724,8433.422,5193.1
      Western Asia31,69737.628,37934.067017.158546.2
      Western Europe80,55244.068,06335.339,18720.031,69014.8
      Central and Eastern Europe106,96153.595,69247.631,65410.426,2998.3
      Southern Europe69,93346.461,34539.121,77212.818,28810.0
      Northern Europe33,45834.629,60629.726,70323.722,86519.1
      Australia/New Zealand781132.7583823.5554721.7405315.0
      Melanesia33114.330313.31635.81395.0
      Micronesia/Polynesia22042.719838.49917.59817.3
      Very high HDI
       Argentina769032.5742230.9355411.8310910.0Medium and medium
       Australia671533.3496423.6461621.5326814.1High and high
       Canada13,44442.510,69032.512,03734.4941825.1High and high
       Germany34,15938.828,70231.316,65417.914,71814.5High and medium
       Hungary589376.6523866.6339533.2283226.6Medium and high
       Italy26,93138.524,68633.610,30713.2884510.4Medium and medium
       Japan66,01638.853,75228.928,83912.921,3678.3Medium and high
       Spain21,78052.517,43040.3493511.336888.0Medium and medium
       Sweden192819.4183317.0196319.1186216.1High and medium
       United Kingdom21,84534.919,39530.218,53725.816,18621.4High and high
       United States of America112,05444.291,69335.1102,17233.775,85223.4High and high
      High HDI
       Brazil20,23521.317,19817.914,04512.211,0879.5Medium and medium
       China459,49552.8421,69548.3193,34720.4175,48718.0Medium and medium
       Iran330710.329509.115815.014114.5Medium and medium
       Mexico547110.549459.429684.926634.3Medium and medium
       Russia45,59951.441,89247.110,2066.889965.6Medium and medium
       Thailand13,09430.711,85427.9641112.6581511.6Medium and medium
      Medium HDI
       Congo, Republic of191.8181.750.450.4Medium and medium
       Egypt363411.2324510.113833.812433.4Medium and medium
       Guatemala3697.93337.22785.22514.7Medium and medium
       India53,72811.048,6979.916,5473.115,0622.9Medium and medium
       Indonesia25,32225.822,52523.293748.183797.3Medium and medium
       Mongolia22827.721326.1645.8595.5Medium and medium
       Nicaragua1799.21628.31165.21064.6Medium and medium
       Philippines882231.3766728.232529.527028.0Medium and medium
       South Africa469428.7418726.1254811.2227810.0Medium and medium
      Low HDI
       Cameroon1122.0991.7661.0570.9Medium and medium
       Kenya3103.42783.02142.01851.8Medium and medium
       Zimbabwe2407.22146.31383.21222.8Medium and medium
      Note: Rates are age-standardized to the World Standard Population.

      Segi M. Cancer mortality for selected sites in 24 countries (1950-57). Sendai, Japan: Department of Public Health, Tohoku University of Medicine; 1960.

      Data quality definitions are classified as follows: high-quality incidence refers to projecting rates to 2012 or applying current rates to the 2012 population AND high-quality national or regional incidence data; medium-quality incidence means estimated by modeling using either national or regional mortality data, or as the weighted average of local incidence rates OR whenever the data quality and methods clashed; high-quality mortality refers to projecting rates to 2012 or applying current rates to the 2012 population AND high-quality complete vital registration data; and medium-quality mortality means estimation of rates AND medium-quality complete vital registration data.
      HDI, Human Development Index.
      a Data quality is unavailable for regions.
      There have been substantial temporal changes in incidence rates (Fig. 1). The incidence rates for males and females in most of the countries classified as having a high or very high HDI (Australia, Canada, Denmark, Germany, the Netherlands, Russia, Sweden, the United Kingdom, and the United States) gradually converged over time. This was due to the significant downward trends among men and the sustained increase in lung cancer rates in females, although in the United States incidence has also begun to show signs of a decreasing trend among females since 2010.
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      • Lewis D.R.
      • Chen H.S.
      • Midthune D.N.
      • Cronin K.A.
      • Krapcho M.F.
      • Feuer E.J.
      Early estimates of SEER cancer incidence for 2012: approaches, opportunities, and cautions for obtaining preliminary estimates of cancer incidence.
      In contrast, incidence rates are increasing in parallel for both sexes in Brazil and Japan and decreasing among both sexes in Hong Kong. Trends in lung cancer incidence rates for the selected countries by sex are listed in Supplementary Table 1.
      Figure thumbnail gr1
      Figure 1Trends in lung cancer incidence rate by country, 1980–2011. (A) Increasing trend in both sexes. (B) Rates in males increase but rates in females are relatively stable. (C) A stable trend in both sexes. (D) Rates in males are relatively stable but those in females are decreasing. (E) Rates in males decrease whereas rates in females increase. (F) A decreasing trend in both sexes. The y axis represents incidence rate per 100,000 population per year and is on the log scale; the x axis represents year. Incidence rates have been age-standardized to the World Standard Population.

      Segi M. Cancer mortality for selected sites in 24 countries (1950-57). Sendai, Japan: Department of Public Health, Tohoku University of Medicine; 1960.

      Trends have been calculated using Joinpoint software, version 4.0.4 (National Cancer Institute). Countries are grouped by their most recent trend.
      Data from Australian Institute of Health and Welfare (Australia),

      Australian Institute of Health and Welfare. Australian Cancer Incidence and Mortality. (ACIM) Books. http://www.aihw.gov.au/acim-books/. Accessed November 24, 2014.

      Hong Kong Cancer Registry (Hong Kong),

      Hong Kong Cancer Registry. Cancer Statistics Query System by ICD-10. http://www3.ha.org.hk/cancereg/e_a1b.asp. Accessed December 11, 2013.

      National Cancer Registry Ireland (Ireland),

      National Cancer Registry Ireland. The National Cancer Registry Ireland: incidence, mortality, treatment and survival. http://www.ncri.ie/. Accessed July 23, 2014.

      National Cancer Center (Japan),

      Center for Cancer Control and Information Services, National Cancer Center Japan. Cancer incidence 1975-2010. Center for Cancer Control and Information Services, National Cancer Center. http://ganjoho.jp/en/professional/statistics/table_download.html; Accessed April 17, 2014.

      Netherlands Comprehensive Cancer Organisation (Netherlands),

      Netherlands Comprehensive Cancer Organisation (IKNL). Dutch cancer figures using Netherlands Cancer Registry data. http://www.cijfersoverkanker.nl/?language=en. Accessed December 3, 2014.

      National Board of Health and Welfare (Sweden),

      National Board of Health and Welfare (Socialstyrelsen). Cancer statistical database. http://www.socialstyrelsen.se/statistics/statisticaldatabase/cancer. Accessed April 9, 2013.

      Surveillance, Epidemiology, and End Results-9 (United States),

      Surveillance, Epidemiology, and End Results (SEER) Program. National Cancer Institute, DCCPS, Surveillance Research Program. Surveillance Systems Branch Research data (1973-2011). http://www.seer.cancer.gov. Released April 2014, based on the November 2013 submission; 2014.

      and International Agency for Research on Cancer (all other countries).

      Ferlay J, Bray F, Steliarova-Foucher E, Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9. http://ci5.iarc.fr/CI5plus/Default.aspx. Accessed September 24, 2014.

      Cigarette smoking or tobacco use is the most important causal risk factor for development of lung cancer. For males and females, smoking causes more than 90% and 70% of lung cancer deaths, respectively, in countries with a very high HDI, whereas in countries with a high, median, or low HDI, the respective rates are approximately 65% among males and 25% among females.
      US Dept. of Health and Human Services
      The Health Consequences of Smoking: A Report of the Surgeon General.
      • Jha P.
      • Ramasundarahettige C.
      • Landsman V.
      • et al.
      21st-century hazards of smoking and benefits of cessation in the United States.
      • Ezzati M.
      • Lopez A.D.
      Estimates of global mortality attributable to smoking in 2000.
      With the lower smoking prevalence among women, particularly Asian women (2% in China),
      • Li Q.
      • Hsia J.
      • Yang G.
      Prevalence of smoking in China in 2010.
      it is estimated that approximately half of lung cancers in females worldwide are not attributable to primary consumption of combustible tobacco for the years 2000 and 2012.
      • Parkin D.M.
      • Bray F.
      • Ferlay J.
      • Pisani P.
      • Parkin D.M.
      Global cancer statistics, 2002.
      • Saika K.
      • Machii R.
      Cancer mortality attributable to tobacco by region based on the WHO Global Report.
      The long latency of 30 years between exposure to tobacco smoke and lung cancer development most likely explains the delay between lung cancer incidence rates reflecting preceding smoking prevalence changes.
      • Thun M.
      • Peto R.
      • Boreham J.
      • Lopez A.D.
      Stages of the cigarette epidemic on entering its second century.
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      For example, Hungarian men had the highest lung cancer incidence in Europe in 2012 (76.6 of 100,000), reflecting their high smoking prevalence in the late twentieth century onward (42.7% in 1980).
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      • Bray F.I.
      • Weiderpass E.
      Lung cancer mortality trends in 36 European countries: secular trends and birth cohort patterns by sex and region 1970-2007.
      In addition, secondhand smoke increases risk for lung cancer in nonsmokers,
      • Hackshaw A.K.
      • Law M.R.
      • Wald N.J.
      The accumulated evidence on lung cancer and environmental tobacco smoke.
      US Dept. of Health and Human Services
      The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General.
      although its impact on global lung cancer epidemiology is unclear.

      Mortality

      In 2012, the world age-adjusted mortality rate of lung cancer was 30.0 in 100,000 for men and 11.1 in 100,000 for women (see Table 1). There were 1.59 million deaths attributable to lung cancer, and the number has increased from 1.18 million deaths in 2002.
      • Youlden D.R.
      • Cramb S.M.
      • Baade P.D.
      The international epidemiology of lung cancer: geographical distribution and secular trends.
      By socioeconomic groupings, the mortality rate followed a pattern similar to that of the incidence rates, with the highest mortality rate among the countries with a very high HDI, followed by countries with a medium HDI, then a high HDI, and finally a low HDI. Among the geographic regions, males in Central and Eastern Europe had the highest mortality rate (47.6 in 100,000), followed by males in Eastern Asia (44.8 in 100,000). The highest mortality rates among females were in North America (23.5 in 100,000) and Northern Europe (19.1 in 100,000).
      As with incidence, lung cancer mortality rates have changed substantially over time (Fig. 2). For most of the included countries (e.g., Australia, Denmark, France, Germany, Sweden, and the United States), the trends in lung cancer mortality closely mirrored those for incidence, with reductions in mortality among males and increasing or stable trends among females and male-to-female mortality rates converging over time. Parallel and increasing sex-specific mortality trends were observed in Romania; mortality rates were stable for both sexes in Japan; and parallel decreasing trends by sex were reported in Hong Kong and the Russian Federation. Trends in lung cancer mortality rates for selected countries by sex are listed in Supplementary Table 2.
      Figure thumbnail gr2
      Figure 2Trends in lung cancer mortality rate by country, 1980–2012. (A) An increasing trend in both sexes. (B) Rates in males are relatively stable but rates in females are increasing. (C) Rates in males decrease whereas those in females increase. (D) Rates in males decrease whereas those in females are relatively stable. (E) A decreasing trend in both sexes. The y axis represents mortality rate per 100,000 population per year and is on the log scale; the x axis represents year. Mortality rates have been age-standardized to the World Standard Population.

      Segi M. Cancer mortality for selected sites in 24 countries (1950-57). Sendai, Japan: Department of Public Health, Tohoku University of Medicine; 1960.

      Trends have been calculated using Joinpoint software, version 4.0.4 (National Cancer Institute, Bethesda, MD). Countries are grouped by their most recent trend.
      Data from WHO.

      World Health Organization. WHO Mortality Database (released 25 February 2014). http://www.who.int/healthinfo/statistics/mortality_rawdata/en/. Accessed November 12, 2014.

      Survival

      Despite the generally poor prognosis, there is substantial international variation in recently published 5-year relative survival estimates (Table 2). Women tend to have higher survival of lung cancer than men across all countries for which estimates by sex are available. These estimates show that Japan had among the highest 5-year relative survival worldwide at 30%, whereas Libya, Mongolia, Chile, Bulgaria, and Thailand had among the lowest survival rates (<10%). The difference is not solely related to country-specific levels of socioeconomic development, because there is also variation even between highly developed countries; for example, the 5-year relative survival rate in the United Kingdom is approximately 10%, which is much less than that reported for several other countries with a high HDI.
      Table 2Five-Year Net Survival (%) Estimates of Lung Cancer in Selected Countries and Groups
      Data from Australian Institute of Health and Welfare (Australia),

      Australian Institute of Health and Welfare. Cancer Survival and Prevalence in Australia: Period Estimates from 1982 to 2010 (Supplementary Material). Canberra, Australia: AIHW; 2012.

      NORDCAN (Nordic countries),

      Association of the Nordic Cancer Registries. Danish Cancer Society. NORDCAN: cancer incidence, mortality, prevalence and survival in the nordic countries, version 7.2 (16.12.2015). http://www.ancr.nu. Accessed January 23, 2016.

      Surveillance, Epidemiology, and End Results-18 (the United States),

      Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Survival—SEER 18 Registries Research Data: National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2014 (updated May 7, 2014), based on the November 2013 submission. http://seer.cancer.gov/data/seerstat/nov2013/. Accessed July 22, 2014.

      and the CONCORD-2 study (all others).
      • Allemani C.
      • Weir H.K.
      • Carreira H.
      • et al.
      Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).
      CountryPeriod5-Year Net Survival (%) (95% CI)
      TotalMalesFemales
      Algeria2005–200915 (11–18)
      Data were unavailable.
      Argentina2005–200912 (10–14)
      Australia2006–201014 (14–14)13 (12–13)17 (16–17)
      Brazil2005–200918 (13–23)
       Aracaju2005–200919 (12–25)
       Jahu2005–20099 (4–14)
      Bulgaria2005–20096 (6–7)
      Chile2005–20096 (2–10)
      China2005–200918 (17–18)
       Beijing2005–200918 (18–19)
       Cixian2005–200919 (14–24)
       Haining2005–200923 (20–25)
       Jianhu2005–20095 (2–8)
       Qidong2005–20098 (6–10)
      Colombia2005–20099 (7–11)
      Denmark2009–201311 (11–12)16 (15–17)
      Finland2009–201310 (10–11)16 (15–17)
      Germany2005–200916 (16–17)
      Iceland2009–201314 (11–18)20 (17–24)
      India2005–200910 (5–15)
      Indonesia2005–200912 (1–23)
      Italy2005–200915 (14–15)
       Biella2005–20098 (5–11)
       Milano2005–200917 (15–19)
       Romagna2005–200919 (17–20)
      Japan2005–200930 (29–31)
      Libya (Benghazi)
      For Libya and Mongolia, estimates were not available for 2005–2009.
      1995–20092 (1–4)
      Mongolia
      For Libya and Mongolia, estimates were not available for 2005–2009.
      1995–20097 (4–9)
      Norway2009–201315 (14–15)19 (18–20)
      Saudi Arabia2005–200913 (7–19)
      Sweden2009–201314 (13–15)19 (18–19 )
      Thailand2005–20098 (7–9)
       Khon Kaen2005–200914 (10–17)
       Lampang2005–20096 (5–8)
       Songkhla2005–20097 (5–9)
      Tunisia2005–200910 (0–21)
      Turkey2005–200910 (9–11)
      United Kingdom2005–200910 (9–10)
      United States201015 (15–15)13 (13–13)18 (18–18)
       White201015 (15–16)13 (13–13)18 (18–18)
       Black201013 (13–13)11 (11–11)15 (15–16)
       Other
      American Indian/Alaska Native or Asian/Pacific Islander.
      201016 (16–16)14 (14–14)19 (19–20)
      Note: No total estimates were available from NORDCAN. Italic means that estimates are of lower quality.
      CI, confidence interval.
      a Data were unavailable.
      b For Libya and Mongolia, estimates were not available for 2005–2009.
      c American Indian/Alaska Native or Asian/Pacific Islander.
      The low survival rate of patients with lung cancer is related to the stage of lung cancer at diagnosis. In the United States during 2005–2011, patients in whom lung cancer was diagnosed when localized and regional had moderate 5-year survival rates (55% and 27%, respectively); however, this rate decreased to 4% for those with distant cancer.

      National Cancer Institute. SEER stat fact sheets: lung and bronchus cancer. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed November 25, 2015.

      Because of the nonspecific nature of lung cancer symptoms, most lung cancers are typically diagnosed after they have advanced (57% of lung cancers in the United States are detected with metastases).

      National Cancer Institute. SEER stat fact sheets: lung and bronchus cancer. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed November 25, 2015.

      In England in 2012 almost half (49%) were stage IV when diagnosed, two-thirds (69%) were considered advanced (stages III or IV), and only 20% were diagnosed when localized (10% were unstaged).
      • McPhail S.
      • Johnson S.
      • Greenberg D.
      • Peake M.
      • Rous B.
      Stage at diagnosis and early mortality from cancer in England.
      Stage proportions can differ by histological type. In the United States during 2005–2011, SCLCs tended to have the highest proportions of advanced cancers diagnosed (almost 90% detected at stages III and IV), with squamous cell cancer having the lowest (approximately 60%).
      • Meza R.
      • Meernik C.
      • Jeon J.
      • Cote M.L.
      Lung cancer incidence trends by gender, race and histology in the United States, 1973–2010.
      In addition, variation in the treatment of lung cancer (e.g., time to curative treatment and adherence to guidelines) is likely an important determinant of the differences in survival between countries, even when the stage distribution of lung cancer is similar.
      • Stevens W.
      • Stevens G.
      • Kolbe J.
      • Cox B.
      Lung cancer in New Zealand: patterns of secondary care and implications for survival.
      • Nadpara P.
      • Madhavan S.S.
      • Tworek C.
      Guideline-concordant timely lung cancer care and prognosis among elderly patients in the United States: a population-based study.
      There have, however, been slight improvements in lung cancer survival among more socioeconomically developed countries such as Sweden, Japan, the United States, Canada, and Australia during recent decades.
      • Allemani C.
      • Weir H.K.
      • Carreira H.
      • et al.
      Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).
      The survival rates in Japan are substantially better than in other countries, even in the same region. The explanation for this likely lies in several factors, including a high relative proportion of EGFR mutation–positive lung tumors for targeted therapies, the standardized long-term surveillance of lung cancer survivors, and the coordinated efforts on a national level to monitor and improve cancer care in Japan.
      • Higashi T.
      • Nakamura F.
      • Saruki N.
      • Sobue T.
      Establishing a quality measurement system for cancer care in Japan.
      • Takenaka T.
      • Inamasu E.
      • Yoshida T.
      • et al.
      Post-recurrence survival of elderly patients 75 years of age or older with surgically resected non-small cell lung cancer.
      Survival estimates also differ within countries. In China during 2005–2009, the 5-year relative survival estimates for lung cancer were considerably higher in cities such as Beijing (18%) and Haining (23%) than in some rural areas such as Qidong (8%) and Jianhu (5%) (see Table 2). Brazil, Thailand, and Italy also showed at least a twofold difference in lung cancer survival rates between different geographical regions. The reasons for these differences are unclear but may include diagnostic patterns, because these estimates are not adjusted for tumor stage.

      Histological and Molecular Features of Lung Cancer

      The distribution of the histological types/subtypes of microscopically verified lung cancer varies widely between countries (Table 3). Generally among males, the incidence of adenocarcinoma was higher than that for squamous cell carcinoma (adenocarcinoma-to-squamous cell carcinoma ratio >1). In some countries such as Belarus, India, the Netherlands, and the Russian Federation, however, squamous cell carcinoma had the higher incidence. The pattern of higher incidence of adenocarcinoma compared with squamous cell carcinoma was even more evident among females, with a more than fivefold difference reported for women in China, Japan, and Saudi Arabia. Globally, the incidence of adenocarcinoma has stabilized in males but continues to increase in females.
      • Lortet-Tieulent J.
      • Soerjomataram I.
      • Ferlay J.
      • Rutherford M.
      • Weiderpass E.
      • Bray F.
      International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women.
      The increase in adenocarcinoma in smokers has been linked to design changes in cigarettes that have promoted deeper inhalation since the late 1950s.
      • Thun M.J.
      • Lally C.A.
      • Flannery J.T.
      • Calle E.E.
      • Flanders W.D.
      • Heath Jr., C.W.
      Cigarette smoking and changes in the histopathology of lung cancer.
      • Thun M.J.
      • Carter B.D.
      • Feskanich D.
      • et al.
      50-year trends in smoking-related mortality in the United States.
      Studies in Southeast Asia, where prevalence of smoking among females is low, have suggested that the rise of adenocarcinoma in females can be attributed to secondhand smoke and cooking fumes.
      • Tse L.A.
      • Yu I.T.
      • Au J.S.
      • et al.
      Environmental tobacco smoke and lung cancer among Chinese nonsmoking males: might adenocarcinoma be the culprit?.
      • Yu I.T.
      • Chiu Y.L.
      • Au J.S.
      • Wong T.W.
      • Tang J.L.
      Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women.
      • Wang X.R.
      • Chiu Y.L.
      • Qiu H.
      • Au J.S.
      • Yu I.T.
      The roles of smoking and cooking emissions in lung cancer risk among Chinese women in Hong Kong.
      Table 3Incidence Rates (per 100,000) of Microscopically Verified Lung Cancer by Histological Type
      Data from Cancer Incidence in Five Continents Volume X (2003–2007).

      Forman D, Bray F, Brewster DH, et al., eds. Cancer incidence in five continents, Vol. X. http://www.iarc.fr/en/publications/pdfs-online/epi/sp164/. Accessed April 7, 2014.

      Country or Area of Registry/EthnicityMalesFemales
      SCCACLCCSCLCAC/SCC RatioSCCACLCCSCLCAC/SCC Ratio
      Australia6.79.54.73.81.40.60.40.30.00.7
      Belgium19.218.43.89.01.02.88.01.03.02.9
      Belarus26.95.81.76.40.21.11.40.10.31.3
      Brazil4.15.93.91.41.41.23.11.60.82.8
      Canada9.511.93.75.01.33.911.82.54.03.0
      China
      Exact percentages of microscopically verified cases were 59.1%, 55.4% and 54.7% for China, Russia, and Thailand, respectively.
      ,
      China includes data from the 14 available cancer registries in China.
      6.59.31.32.61.41.17.10.60.66.6
       China, Beijing City8.39.42.23.81.11.78.61.21.25.1
      China, Nangang District, Harbin City2.21.21.20.50.40.80.32.0
      China, Shanghai City6.38.20.21.41.30.77.10.10.210.1
       China, Cixian County15.420.73.51.37.19.51.11.3
       China, Hong Kong9.919.11.54.51.91.312.60.50.69.7
      Egypt, Gharbiah2.22.93.01.41.30.31.50.70.25.0
      India
      India includes data from the 12 available cancer registries in India.
      1.61.42.11.00.90.40.80.70.32.1
       India, Bangalore0.91.82.00.72.00.20.80.80.24.0
       India, Chennai2.21.92.40.50.90.30.80.70.12.7
       India, Mumbai1.42.20.71.31.60.31.10.20.43.7
       India, New Delhi1.80.84.41.10.40.30.41.10.21.3
      Japan9.114.91.84.31.61.08.70.30.78.7
      The Netherlands13.311.88.37.30.93.58.14.34.82.3
      Russia
      Exact percentages of microscopically verified cases were 59.1%, 55.4% and 54.7% for China, Russia, and Thailand, respectively.
      15.64.01.64.70.31.31.40.20.61.1
      Saudi Arabia1.12.20.70.62.10.21.30.00.06.2
      Sweden5.17.14.52.51.42.57.63.42.23.0
      Tunisia, North7.84.98.23.80.60.40.60.80.21.5
      Thailand
      Exact percentages of microscopically verified cases were 59.1%, 55.4% and 54.7% for China, Russia, and Thailand, respectively.
      3.68.12.11.52.21.14.40.90.54.0
      Uruguay8.68.55.83.41.01.12.51.00.82.3
      United States
       United States, American Indian8.97.91.94.80.94.67.61.24.91.7
       United States, Asian and Pacific Islander4.310.31.52.32.41.38.40.80.96.5
       United States, black15.818.44.26.01.25.811.81.93.92.0
       United States, white11.614.32.97.01.25.412.61.86.02.3
      Note: Rates are age-standardized to the World Standard Population.

      Segi M. Cancer mortality for selected sites in 24 countries (1950-57). Sendai, Japan: Department of Public Health, Tohoku University of Medicine; 1960.

      Italicized names indicate that less than 60% of cases were microscopically verified.
      SCC, squamous cell carcinoma; AC, adenocarcinoma; LCC, large cell carcinoma.
      a Exact percentages of microscopically verified cases were 59.1%, 55.4% and 54.7% for China, Russia, and Thailand, respectively.
      b China includes data from the 14 available cancer registries in China.
      c India includes data from the 12 available cancer registries in India.
      For those countries for which histology-specific survival data were available (Australia and the United States [Table 4]), the 5-year relative survival was higher for adenocarcinoma and squamous cell carcinoma than for either large cell carcinoma or SCLC. In the United States, blacks, primarily males,
      • Ries L.A.
      Influence of extent of disease, histology, and demographic factors on lung cancer survival in the SEER population-based data.
      • Jemal A.
      • Clegg L.X.
      • Ward E.
      • et al.
      Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival.
      have lower survival rates for adenocarcinoma and squamous cell carcinoma than do whites and other racial/ethnic groups.
      Table 4Five-Year Relative Survival by Histological Subtype in Australia and the United States
      Data from the Australian Institute of Health and Welfare (Australia, 2006–2010)

      Australian Institute of Health and Welfare. Cancer Survival and Prevalence in Australia: Period Estimates from 1982 to 2010 (Supplementary Material). Canberra, Australia: AIHW; 2012.

      and Surveillance, Epidemiology, and End Results-18 (the United States, 2010).

      Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Survival—SEER 18 Registries Research Data: National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2014 (updated May 7, 2014), based on the November 2013 submission. http://seer.cancer.gov/data/seerstat/nov2013/. Accessed July 22, 2014.

      CountryHistological Subtype
      Squamous Cell CarcinomaAdenocarcinomaLarge Cell CarcinomaSCLC
      RS (%)(95% CI)RS (%)(95% CI)RS (%)(95% CI)RS (%)(95% CI)
      Australia18.2(17.2–19.3)19.7(18.8–20.5)8.3(7.6–9.1)6.6(5.9–7.4)
      United States17.2(17.0–17.4)21.4(21.2–21.5)8.0(7.9–8.2)6.3(6.2–6.5)
      United States by race
       White17.9(17.6–18.1)21.8(21.6–22.1)7.9(7.8–8.1)6.3(6.2–6.5)
       Black13.2(12.7–13.8)16.9(16.4–17.4)8.1(7.6–8.6)5.8(5.3–6.4)
       Other15.5(14.5–16.4)21.9(21.2–22.6)8.7(7.9–9.4)6.9(6.1–7.7)
      RS, relative survival; CI, confidence interval.
      At the molecular level, identifying somatic mutations in the lung is important, as current treatment strategies rely heavily on these markers to identify the patients who would benefit the most from targeted therapies.
      • Pirker R.
      • Herth F.J.
      • Kerr K.M.
      • et al.
      Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop.
      Currently, the genes for which standard genetic aberrations are evaluated and for which there are approved therapeutic agents or drugs under investigational include the following: AKT/serine threonine kinase 1 (AKT1), AKT/serine threonine kinase 2 gene (AKT2), BRAF, cyclin-dependent kinase 4 gene (CDK4), echinoderm microtubule associated protein like 4 gene–anaplastic lymphoma receptor tyrosine kinase gene (EML4-ALK), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), dicoidin domain receptor tyrosine kinase 2 gene (DDR2), fibroblast growth factor receptor 1 gene (FGFR1), fibroblast growth factor receptor 3 gene (FGFR3), Harvey rat sarcoma viral oncogene homolog gene (HRAS), KRAS, KIT proto-oncogene receptor tyrosine kinase gene (KIT), MNNG HOS Transforming gene (MET), neuroblastoma RAS viral oncogene homolog (NRAS), neurotrophic tyrosine kinase, receptor, type 1 gene (NTRK1),
      • Passiglia F.
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      The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer.
      • Farago A.F.
      • Le L.P.
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      • et al.
      Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer.
      phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), platelet derived growth factor receptor alpha gene (PDGFRA), ret proto-oncogene (RET), MEK, phosphatase and tensin homolog gene (PTEN), ROS1, RAS like without CAAX 1 gene (RIT1), and CREB regulated transcription coactivator 1 gene (TORC1).
      • Li T.
      • Kung H.J.
      • Mack P.C.
      • Gandara D.R.
      Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies.
      The proportions of the genetic events (mutations, amplifications, or translocations) vary considerably across published studies and by histologic subtype,
      • Devarakonda S.
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      • Govindan R.
      Genomic alterations in lung adenocarcinoma.
      • Chang J.T.
      • Lee Y.M.
      • Huang R.S.
      The impact of The Cancer Genome Atlas on lung cancer.
      leading to both frequent pathway alterations (cell cycle regulation and DNA repair) and divergent effects (RAS/RAf, mammalian target of rapamycin, and Jak-STAT in adenocarcinoma versus squamous differentiation, oxidative stress and PIK3CA in squamous cell carcinoma). Supplementary Figure 1 summarizes the difference in the distribution of mutations in adenocarcinoma in a Chinese population
      • Wang R.
      • Pan Y.
      • Li C.
      • et al.
      Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas.
      and in the U.S. and European populations.
      • Pao W.
      • Girard N.
      New driver mutations in non-small-cell lung cancer.
      • Saber A.
      • van der Wekkenb A.
      • Hiltermannb T.J.N.
      • Kokc K.
      • van den Berga A.
      • Groen H.J.M.
      Genomic aberrations guiding treatment of non-small cell lung cancer patients.
      • Kohno T.
      • Nakaoku T.
      • Tsuta K.
      • et al.
      Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer.
      In East Asia, where the burden of EGFR mutations is much higher in adenocarcinoma than in the United States and Europe, the frequencies of other mutations are also different. In comparisons described by Kohno et al.
      • Kohno T.
      • Nakaoku T.
      • Tsuta K.
      • et al.
      Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer.
      and Li et al.,
      • Li T.
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      • Mack P.C.
      • Gandara D.R.
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      ERBB2, RET, BRAF and ROS1 mutations frequencies in adenocarcinoma are essentially the same in East Asian and white populations whereas there are significantly more KRAS mutations in the white population (20%–30% versus 8%–10%, respectively). In a pooled analysis to describe the spectrum of somatic mutations in African Americans, although the frequencies of EGFR and KRAS mutations are comparable, African Americans have a mutational pattern distinct from that of white Americans, with a significantly higher proportion of unknown driver mutations that are not yet fully characterized (77% of NSCLCs and 70% of non–squamous cell lung cancers).
      • Araujo L.H.
      • Lammers P.E.
      • Matthews-Smith V.
      • et al.
      Somatic mutation spectrum of non-small-cell lung cancer in African Americans: A Pooled Analysis.
      The frequency of mutations in squamous cell carcinoma, without mixed histologic features, is summarized in Supplemental Figure 2.
      • Heist R.S.
      • Sequist L.V.
      • Engelman J.A.
      Genetic changes in squamous cell lung cancer: a review.
      In addition to these distinct mutations, as with adenocarcinoma, there are other frequently amplified genes that are also actionable, either directly or indirectly, including FGFR1 (20%), SRY (sex determining region Y)-box 2 (SOX2) (20%), MDM2 proto-oncogene, E3 ubiquitin protein ligase gene (MDM2) (10%), MET (6%), and PDGFRA (8%–10%). The difference in mutational spectrum seen between adenocarcinoma and squamous cell carcinoma illustrates how the treatment for NSCLC treatment has evolved into a histology-based subtyping approach targeting the mutations in adenocarcinoma versus in squamous cell carcinoma.
      • Li T.
      • Kung H.J.
      • Mack P.C.
      • Gandara D.R.
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      • Shames D.S.
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      Region- and Country-Specific Profiles

      Africa

      Incidence rates of lung cancer remain low across most of Africa, which has the lowest incidence rates in males of all the continents (7.7 in 100,000), with lung cancer mortality rates of 7.0 in 100,000.

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      Because the risk of lung cancer increases exponentially in late-middle and older age, the low incidence rate may in part result from the generally lower life expectancy in Africa compared with on other continents.
      • McCormack V.A.
      • Schuz J.
      Africa's growing cancer burden: environmental and occupational contributions.
      In general, the lowest incidence rates for lung cancer are reported for western, middle, and eastern Africa, whereas the highest rates are found in southern and northern Africa (see Table 1). Within Africa, Réunion (32.3 in 100,000) and Tunisia (31.1 in 100,000) had the highest lung cancer incidence rates in males, whereas Niger (0.4 in 100,000) had the lowest.

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      The average rates of incidence and mortality from lung cancer are substantially lower among women, at 2.6 and 2.4 in 100,000, respectively; however, the rate varies across countries, with females in South Africa having much higher incidence rates (11.2 in 100,000) than in other African countries. This observation is potentially due to the higher prevalence of smoking among females in South Africa (10.4% in 1980 and 9.1% in 2012) compared with in other African countries in general.
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      • Winkler V.
      • Mangolo N.J.
      • Becher H.
      Lung cancer in South Africa: a forecast to 2025 based on smoking prevalence data.
      Many African countries have poor data coverage and quality, and it has been suggested that incidence and mortality rates may be higher than these estimates.
      • Ng N.
      • Winkler V.
      • Van Minh H.
      • Tesfaye F.
      • Wall S.
      • Becher H.
      Predicting lung cancer death in Africa and Asia: differences with WHO estimates.
      Nonetheless, despite the high mortality-to–incidence rate ratios, lung cancer continues to carry a comparatively small burden of overall mortality in most of this region, especially compared with communicable diseases such as human immunodeficiency virus/acquired immunodeficiency syndrome.

      World Health Organization. The global burden of disease: 2004 update. 2008 http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/. Accessed July 13, 2015.

      • Chokunonga E.
      • Levy L.M.
      • Bassett M.T.
      • Mauchaza B.G.
      • Thomas D.B.
      • Parkin D.M.
      Cancer incidence in the African population of Harare, Zimbabwe: second results from the cancer registry 1993-1995.
      • Newton R.
      • Ngilimana P.J.
      • Grulich A.
      • et al.
      Cancer in Rwanda.
      • Wabinga H.R.
      • Parkin D.M.
      • Wabwire-Mangen F.
      • Nambooze S.
      Trends in cancer incidence in Kyadondo County, Uganda, 1960-1997.
      The prevalence of smoking among African men is fivefold to 10-fold higher than among African women. In 2012, approximately half (45%) of men in Tunisia were identified as smokers (compared with 4.5% of women), and in Nigeria the percentages were 7.5% in men and 1.4% in women.
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      In countries of the Sub-Saharan region (Benin, Malawi, Mozambique, Niger, Sierra Leone, and Swaziland), the prevalence of current smoking in males ranged from 8.7% to 34.6% during 2003–2009, which is expected to drive an increase in lung cancer mortality in the next decade.
      • Winkler V.
      • Ott J.J.
      • Cowan M.
      • Becher H.
      Smoking prevalence and its impacts on lung cancer mortality in Sub-Saharan Africa: an epidemiological study.

      Central and South America

      In most countries, mortality rates in males have been decreasing since the 1980s or 1990s, but among females, the rates have been steadily increasing.
      • Chatenoud L.
      • Bertuccio P.
      • Bosetti C.
      • et al.
      Trends in mortality from major cancers in the Americas: 1980-2010.
      • Politis M.
      • Higuera G.
      • Chang L.R.
      • Gomez B.
      • Bares J.
      • Motta J.
      Trend analysis of cancer mortality and incidence in Panama, using joinpoint regression analysis.
      • Chatenoud L.
      • Bertuccio P.
      • Bosetti C.
      • et al.
      Trends in cancer mortality in Brazil, 1980-2004.
      In 2012, although most countries had incidence rates less than 25.0 in 100,000 and mortality rates less than 20.0 in 100,000 among males, there were some notable exceptions, including the estimated incidence in Uruguay (50.6 in 100,000), Cuba (42.8 in 100,000), and Argentina (32.5 in 100,000).

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      Of these, Cuba had incidence and mortality rates approaching those in North America for both men (42.8 and 39.6 in 100,000, respectively) and women (23.8 and 21.6 in 100,000, respectively).

      Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide. IARC CancerBase No. 11.. http://globocan.iarc.fr. Accessed December 16, 2013.

      The incidence of lung cancer in these countries may be largely attributable to their previously high smoking rates—38.7% and 23.7% in Uruguay, 30.8% and 15.3% in Cuba, and 30.8% and 22.5% in Argentina for men and women, respectively, in 1980.
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      Since then, the smoking prevalence rates in these countries, as well as in several South American countries, including Chile, Bolivia, and Brazil, have been progressively decreasing for both sexes.
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      In females, the impact of decreasing smoking prevalence may not yet have been manifested in trends in lung cancer incidence.

      Australia

      Projected estimates of cancer incidence in 2014 in Australia indicate that lung cancer was the fourth most frequently diagnosed cancer (excluding keratinocyte carcinoma) among males (10% of all cancers) and females (8% of all cancers), but the number 1 cause of cancer death for both men and women.
      Australian Institute of Health and Welfare
      Cancer in Australia: An Overview, 2014.
      Lung cancer mortality accounts for approximately one-fifth of all cancer deaths (20% in men and 18% in women). Incidence and mortality rates of lung cancer have steadily decreased among Australian men since 1982, with the mortality reduction more pronounced since 1989. Among women, incidence rates have increased since 1982, whereas mortality rates increased sharply to 1991, after which the rate of increase leveled off to the 2011 rate (see Figs. 1 and 2 and Supplementary Tables 1 and 2).
      Approximately three-quarters of Australian men were reported to be smokers at the end of World War II, along with approximately one-fourth of Australian women. The prevalence of male adult smokers decreased from then onward, down to 43% in 1976 and 22% in 2010.
      • Woodward S.D.
      Trends in cigarette consumption in Australia.
      • Scollo M.M.
      • Winstanley M.H.
      Tobacco in Australia: Facts and Issues.
      • Gray N.J.
      • Hill D.J.
      Patterns of tobacco smoking in Australia. 2.
      Among female adults, however, smoking prevalence increased to 33% in 1976 and then decreased steadily to 18% in 2010.
      • Woodward S.D.
      Trends in cigarette consumption in Australia.
      • Scollo M.M.
      • Winstanley M.H.
      Tobacco in Australia: Facts and Issues.
      • Gray N.J.
      • Hill D.J.
      Patterns of tobacco smoking in Australia. 2.
      Several authors
      • Hill D.J.
      • White V.M.
      • Scollo M.M.
      Smoking behaviours of Australian adults in 1995: trends and concerns.
      • White V.
      • Hill D.
      • Siahpush M.
      • Bobevski I.
      How has the prevalence of cigarette smoking changed among Australian adults? Trends in smoking prevalence between 1980 and 2001.
      have suggested that the decline in smoking prevalence during the 1980s and 1990s in Australia was correlated with the level of Australian tobacco control activities during that time. After the release of the Surgeon General's report in 1964,

      US Department of Health, Education, and Welfare. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DC: US Department of Health, Education, and Welfare, Public Health Service; 1964. Public Health Service Publication No. 1103.

      there was a gradually increasing awareness in Australia of the harm caused by smoking. Since then, Australia has become a world leader in tobacco control, with some of the strongest legislation in the world, including being the first to introduce tobacco plain packaging in 2012.
      • Smith C.N.
      • Kraemer J.D.
      • Johnson A.C.
      • Mays D.
      Plain packaging of cigarettes: do we have sufficient evidence?.
      After the WHO Framework Convention on Tobacco Control,

      World Health Organization. WHO Framework Convention on Tobacco Control. A56/8. Geneva, Switzerland: WHO; 2003.

      Australia has progressively raised the tax on cigarettes; made public spaces, eating and drinking areas, and other enclosed areas smoke free; subsidized methods to quit smoking; and consistently run education and prevention campaigns.
      • Scollo M.M.
      • Winstanley M.H.
      Tobacco in Australia: Facts and Issues.
      Indigenous Australians were reported to have nearly a twofold higher risk of receiving a diagnosis of lung cancer than nonindigenous Australians between 2005 and 2009, making lung cancer the most frequent cancer diagnosed among Indigenous Australians, with a similar differential for lung cancer mortality.
      Australian Institute of Health and Welfare
      Cancer in Australia: An Overview, 2014.
      In addition, Australians living in the most disadvantaged areas of the country had significantly higher lung cancer incidence and mortality rates than did those living in more affluent areas.
      Australian Institute of Health and Welfare
      Cancer in Australia: An Overview, 2014.
      The inequalities by indigenous status and area disadvantage are both consistent with the higher reported smoking prevalence in these subgroups.
      Australian Institute of Health and Welfare
      Cancer in Australia: An Overview, 2014.

      China

      It is estimated that more than one of every three lung cancers occurs in China (36% of the world total [see Table 1]). In the past four decades in China, lung cancer has surpassed other major cancers to become the leading cause of cancer deaths for both men and women.
      • Chen W.
      • Zheng R.
      • Zhang S.
      • et al.
      Annual report on status of cancer in China, 2010.
      Lung cancer incidence has steadily increased from 1988 to 2011.
      • Chen W.
      • Zheng R.
      • Zhang S.
      • et al.
      Annual report on status of cancer in China, 2010.
      • Chen W.Q.
      • Zheng R.S.
      • Zhang S.W.
      • et al.
      Report of incidence and mortality in china cancer registries, 2008.
      • Chen W.
      • Zheng R.
      • Zhang S.
      • et al.
      Report of incidence and mortality in China cancer registries, 2009.
      • Chen W.
      • Zheng R.
      • Zeng H.
      • Zhang S.
      • He J.
      Annual report on status of cancer in China, 2011.
      • Chen W.
      • Zheng R.
      • Zeng H.
      • Zhang S.
      Epidemiology of lung cancer in China.
      • She J.
      • Yang P.
      • Hong Q.
      • Bai C.
      Lung cancer in China: challenges and interventions.
      Cancer registry coverage in China has been improving and is now coordinated by the National Center Cancer Registry. In 2011, the data from 177 cancer registries covering more than 175 million (13%) of the total Chinese population showed that the incidence of lung cancer was 48 in 100,000 in men and 22 in 100,000 in women,
      • Chen W.
      • Zheng R.
      • Zeng H.
      • Zhang S.
      • He J.
      Annual report on status of cancer in China, 2011.
      and these numbers are similar to the GLOBOCAN estimates (see Table 1). Incidence of lung cancer and mortality were generally higher in urban areas and eastern China than in rural areas and western China.
      • Chen W.
      • Zheng R.
      • Zeng H.
      • Zhang S.
      Epidemiology of lung cancer in China.
      • She J.
      • Yang P.
      • Hong Q.
      • Bai C.
      Lung cancer in China: challenges and interventions.
      Similarly to in Western countries, the proportion of adenocarcinoma among male patients with lung cancer has increased to a level similar to or higher than that of squamous cell carcinoma (see Table 3).
      • Zou X.N.
      • Lin D.M.
      • Wan X.
      • et al.
      Histological subtypes of lung cancer in Chinese males from 2000 to 2012.
      Lung cancers in females are predominately adenocarcinoma.
      • Zhang L.
      • Li M.
      • Wu N.
      • Chen Y.
      Time trends in epidemiologic characteristics and imaging features of lung adenocarcinoma: a population study of 21,113 cases in China.
      The rise of tobacco use among Chinese males (average consumption of one cigarette per day in 1952 and 10 cigarettes per day in 1992) has been the major determinant of male lung cancer incidence.
      • Liu B.Q.
      • Peto R.
      • Chen Z.M.
      • et al.
      Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths.
      • Yang L.
      • Parkin D.M.
      • Li L.
      • Chen Y.
      Time trends in cancer mortality in China: 1987-1999.
      One-third of the world’s tobacco is grown and consumed in China.
      • Hu T.W.
      • Mao Z.
      • Shi J.
      • Chen W.
      The role of taxation in tobacco control and its potential economic impact in China.
      Cigarette smoking has a unique role in Chinese politics and culture, with the tobacco industry in China being nationally monopolized and an important source of tax revenue.
      • Hu T.W.
      • Mao Z.
      • Shi J.
      • Chen W.
      The role of taxation in tobacco control and its potential economic impact in China.
      For example, as etiquette, cigarettes are commonly offered to guests, even by nonsmokers.
      • Wang C.P.
      • Ma S.J.
      • Xu X.F.
      • Wang J.F.
      • Mei C.Z.
      • Yang G.H.
      The prevalence of household second-hand smoke exposure and its correlated factors in six counties of China.
      The prevalence of smoking among physicians remains substantial (>50% of male physicians in many cities and provinces).
      • Abdullah A.S.
      • Qiming F.
      • Pun V.
      • Stillman F.A.
      • Samet J.M.
      A review of tobacco smoking and smoking cessation practices among physicians in China: 1987-2010.
      • Smith D.R.
      • Zhao I.
      • Wang L.
      Tobacco smoking among doctors in mainland China: a study from Shandong province and review of the literature.
      Thus, awareness of the health hazards of smoking remains poor and tobacco control policies face many barriers and challenges in China.
      • Yang Y.
      • Wang J.J.
      • Wang C.X.
      • Li Q.
      • Yang G.H.
      Awareness of tobacco-related health hazards among adults in China.
      • Hu T.W.
      • Lee A.H.
      • Mao Z.
      WHO Framework Convention on Tobacco Control in China: barriers, challenges and recommendations.
      Given that the prevalence of smoking among women in China has historically been very low (and is decreasing) (5% in 1980 and 2% in 2012),
      • Ng M.
      • Freeman M.K.
      • Fleming T.D.
      • et al.
      Smoking prevalence and cigarette consumption in 187 countries, 1980-2012.
      • Giovino G.A.
      • Mirza S.A.
      • Samet J.M.
      • et al.
      Tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys.
      exposure to risk factors other than active smoking may play an important role in the incidence of lung cancer in females. Exposure to secondhand smoke and indoor and outdoor air pollution remain common in China.
      • She J.
      • Yang P.
      • Hong Q.
      • Bai C.
      Lung cancer in China: challenges and interventions.
      Large-scale surveys showed that 83% to 95% of adults reported secondhand smoke in restaurants; 53% to 84% reported exposure at their workplace; and 40% of those who lived with smokers reported exposure at home.
      • Feng G.
      • Jiang Y.
      • Zhao L.
      • et al.
      [Degree of exposure to secondhand smoking and related knowledge, attitude among adults in urban China].
      • Ye X.
      • Yao Z.
      • Gao Y.
      • et al.
      Second-hand smoke exposure in different types of venues: before and after the implementation of smoke-free legislation in Guangzhou, China.
      The smoking ban or tobacco-free policy in public places often fails to protect nonsmokers from exposure because of lack of enforcement.
      • Ye X.
      • Yao Z.
      • Gao Y.
      • et al.
      Second-hand smoke exposure in different types of venues: before and after the implementation of smoke-free legislation in Guangzhou, China.
      In addition, women in rural areas in particular are exposed to fumes and smoke produced while cooking with biomass fuels such as coal and wood,
      • Zhang J.J.
      • Smith K.R.
      Household air pollution from coal and biomass fuels in China: measurements, health impacts, and interventions.
      and people in major cities often face hazardous levels of air pollution.
      • Zhang J.
      • Mauzerall D.L.
      • Zhu T.
      • Liang S.
      • Ezzati M.
      • Remais J.V.
      Environmental health in China: progress towards clean air and safe water.
      Although it has been suggested that cigarette smoking may cause more lung cancer in urban versus rural areas in China,
      • Niu S.R.
      • Yang G.H.
      • Chen Z.M.
      • et al.
      Emerging tobacco hazards in China: 2. Early mortality results from a prospective study.
      the extent to which these different sources and levels of exposure contribute to the observed urban-rural differential in lung cancer incidence and histological features warrants further study.

      United States

      Lung cancer is the second most frequent cancer (accounting for 14% of cancers diagnosed among both males and females), and it is the number 1 cause of cancer deaths for both sexes. Lung cancer mortality accounts for more than a quarter of all cancer deaths (29% in men and 26% in women).
      • Siegel R.
      • Naishadham D.
      • Jemal A.
      Cancer statistics, 2012.
      Chronologically, the epidemic of lung cancer in the United States aligns with historical patterns of tobacco use. The annual cigarette consumption per capita for persons aged 18 years or older increased by more than 70 times (from 54 to 4,000) from 1880 to the 1970s.
      • Burns D.M.
      • Lee L.
      • Shen L.Z.
      • Gilpin E.
      • Tolley H.D.
      • Vaughn J.
      • et al.
      Cigarette smoking behavior in the United States.
      Lung cancer mortality in men increased 18-fold (from five to 90 in 100,000) between 1930 and 1990.
      • Siegel R.
      • Naishadham D.
      • Jemal A.
      Cancer statistics, 2012.
      On the basis of our trend analysis, incidence and mortality rates have started to decline for men since the 1990s and women’s rates have also leveled off since early 2000 and started to show signs of decrease since 2010,
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      • Lewis D.R.
      • Chen H.S.
      • Midthune D.N.
      • Cronin K.A.
      • Krapcho M.F.
      • Feuer E.J.
      Early estimates of SEER cancer incidence for 2012: approaches, opportunities, and cautions for obtaining preliminary estimates of cancer incidence.
      mainly thanks to a decrease in smoking prevalence.
      US Centers for Disease Control and Prevention
      Great American Smokeout—November 18, 1999.
      US Centers for Disease Control and Prevention
      Current cigarette smoking among adults—United States, 2011.
      • Moolgavkar S.H.
      • Holford T.R.
      • Levy D.T.
      • et al.
      Impact of reduced tobacco smoking on lung cancer mortality in the United States during 1975-2000.
      Geographically, lung cancer incidence is also highly associated with smoking prevalence (lung cancer incidence 60.4 and 44.4 in 100,000 for males and females, respectively, in California versus 125.9 and 80.3 in 100,000 for males and females, respectively, in Kentucky; adult smoking prevalence 14% in California versus 30% in Kentucky).
      • Siegel R.
      • Ma J.
      • Zou Z.
      • Jemal A.
      Cancer statistics, 2014.

      US Centers for Disease Contro and Prevention. Tobacco control state highlights 2012. http://www.cdc.gov/tobacco/data_statistics/state_data/state_highlights/2012/. Accessed December 11, 2015.

      For lung cancer mortality, the rate declined continuously from 1973 to 2007 among white women in California, but not among those in several southern and midwestern states.
      • Jemal A.
      • Ma J.
      • Rosenberg P.S.
      • Siegel R.
      • Anderson W.F.
      Increasing lung cancer death rates among young women in southern and midwestern States.
      The geographical variation results mainly from different degrees of tobacco control measures between these states.
      In addition to the sex and geographical differences, lung cancer incidence varies by histological and racial groups. Whereas squamous cell carcinoma and SCLC rates are declining, the incidence of adenocarcinoma continues to increase among every racial and sex group.
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      What is more alarming is that in younger cohorts, the incidence of adenocarcinoma in females has surpassed that in males.
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      African American males have a higher incidence of both adenocarcinoma and squamous cell carcinoma than do white males. The difference remains given the same amount of smoking exposure.
      • Haiman C.A.
      • Stram D.O.
      • Wilkens L.R.
      • et al.
      Ethnic and racial differences in the smoking-related risk of lung cancer.
      Whereas African American smokers frequently preferred menthol cigarettes, evidence suggests that menthol cigarettes alone cannot explain the racial disparity in incidence of lung cancer.
      • Brooks D.R.
      • Palmer J.R.
      • Strom B.L.
      • Rosenberg L.
      Menthol cigarettes and risk of lung cancer.
      • Sidney S.
      • Tekawa I.S.
      • Friedman G.D.
      • Sadler M.C.
      • Tashkin D.P.
      Mentholated cigarette use and lung cancer.
      • Carpenter C.L.
      • Jarvik M.E.
      • Morgenstern H.
      • McCarthy W.J.
      • London S.J.
      Mentholated cigarette smoking and lung-cancer risk.
      • Kabat G.C.
      • Hebert J.R.
      Use of mentholated cigarettes and lung cancer risk.
      • Richardson T.L.
      African-American smokers and cancers of the lung and of the upper respiratory and digestive tracts. Is menthol part of the puzzle?.
      • Kabat G.C.
      • Shivappa N.
      • Hebert J.R.
      Mentholated cigarettes and smoking-related cancers revisited: an ecologic examination.
      In addition, the incidence of lung cancer in Asian Americans, who had a lower prevalence of smoking, is overall lower than in whites.
      • Raz D.J.
      • Gomez S.L.
      • Chang E.T.
      • et al.
      Epidemiology of non-small cell lung cancer in Asian Americans: incidence patterns among six subgroups by nativity.
      However, given the same amount of smoking, lung cancer may be more likely to develop in Asian Americans than in whites.
      • Epplein M.
      • Schwartz S.M.
      • Potter J.D.
      • Weiss N.S.
      Smoking-adjusted lung cancer incidence among Asian-Americans (United States).
      Risk factors other than cigarette smoke or biological factors may be responsible for these racial differences.

      Opportunities to Reduce the Burden of Lung Cancer

      Prevention

      As noted already, the major key driver of trends in lung cancer incidence is smoking.
      US Dept. of Health and Human Services
      The Health Consequences of Smoking: A Report of the Surgeon General.
      Because of the limited efficacy of high-cost screening and treatment measures, smoking is also a key driver of lung cancer mortality.
      • Ezzati M.
      • Henley S.J.
      • Lopez A.D.
      • Thun M.J.
      Role of smoking in global and regional cancer epidemiology: current patterns and data needs.
      For this reason, effective tobacco control programs are critically important in the battle to reduce the burden of lung cancer internationally, even more so within African and Central and South American countries that have very limited access to screening and treatment measures.
      • Winkler V.
      • Ott J.J.
      • Cowan M.
      • Becher H.
      Smoking prevalence and its impacts on lung cancer mortality in Sub-Saharan Africa: an epidemiological study.
      Populations that have benefited from decreasing smoking prevalence because of coordinated tobacco control programs, such as in Australia,
      • Scollo M.M.
      • Winstanley M.H.
      Tobacco in Australia: Facts and Issues.
      California in the United States,
      • Rogers T.
      The California Tobacco Control Program: introduction to the 20-year retrospective.
      and Hong Kong,
      • Au J.S.
      • Mang O.W.
      • Foo W.
      • Law S.C.
      Time trends of lung cancer incidence by histologic types and smoking prevalence in Hong Kong 1983-2000.
      are likely to experience continued reductions in lung cancer incidence, particularly among males, over the coming years. Rates of lung cancer in females are expected to rise continuously in many countries with a very high HDI,
      • Linares I.
      • Molina-Portillo E.
      • Exposito J.
      • Baeyens J.A.
      • Suarez C.
      • Sanchez M.J.
      Trends in lung cancer incidence by histologic subtype in the south of Spain, 1985-2012: a population-based study.
      • Vanthomme K.
      • Vandenheede H.
      • Hagedoorn P.
      • Deboosere P.
      • Gadeyne S.
      Trends in site- and sex-specific cancer mortality between 1979 and 2010 in Belgium compared with Europe using WHO data.
      • Olajide O.O.
      • Field J.K.
      • Davies M.M.
      • Marcus M.W.
      Lung cancer trend in England for the period of 2002 to 2011 and projections of future burden until 2020.
      although there is evidence of a decline in other places, such as the United States.
      • Lewis D.R.
      • Check D.P.
      • Caporaso N.E.
      • Travis W.D.
      • Devesa S.S.
      US lung cancer trends by histologic type.
      • Lewis D.R.
      • Chen H.S.
      • Midthune D.N.
      • Cronin K.A.
      • Krapcho M.F.
      • Feuer E.J.
      Early estimates of SEER cancer incidence for 2012: approaches, opportunities, and cautions for obtaining preliminary estimates of cancer incidence.
      Given the lag period between smoking prevalence and resultant disease, it is almost certain that countries without strong antitobacco programs, such as China, will face an increasing burden of lung cancer in upcoming decades.
      • Paskett E.D.
      • Bernardo B.M.
      • Khuri F.R.
      Tobacco and China: The worst is yet to come.
      A comprehensive lung cancer control policy would also incorporate coordinated strategies to reduce exposure to other recognized risk factors, including secondhand smoke, air pollution, radon, asbestos, and occupational carcinogens.
      • Wong C.M.
      • Vichit-Vadakan N.
      • Vajanapoom N.
      • et al.
      Part 5. Public health and air pollution in Asia (PAPA): a combined analysis of four studies of air pollution and mortality.
      • McCarthy W.J.
      • Meza R.
      • Jeon J.
      • Moolgavkar S.H.
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
      • Mc Laughlin J.
      An historical overview of radon and its progeny: applications and health effects.

      Early Detection

      Limited options exist to detect lung cancer at an early stage, and recent development of screening tools, such as sputum and plasma-based microRNA,
      • Shen J.
      • Liao J.
      • Guarnera M.A.
      • et al.
      Analysis of MicroRNAs in sputum to improve computed tomography for lung cancer diagnosis.
      • Sozzi G.
      • Boeri M.
      • Rossi M.
      • et al.
      Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study.
      still require multicenter clinical trials for further validation.
      • Spira A.
      • Halmos B.
      • Powell C.A.
      Update in lung cancer 2014.
      However, screening for lung cancer with low-dose computed tomography in high-risk populations, which has been demonstrated to reduce mortality by 20%,
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      • Wood D.E.
      • Kazerooni E.
      • Baum S.L.
      • et al.
      Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines.
      has started to receive approval by major insurers in the United States since 2015. In countries that can afford to implement screening in a large proportion of high-risk populations, it is expected that incidence of lung cancer, including a higher proportion of early-stage lung cancer, may increase whereas mortality may decrease because of the survival advantages of early-stage cancers. These changes may also vary among racial/ethnic groups, as race-related factors such as socioeconomic status and educational attainment can affect the accessibility of and willingness to receive cancer screening.
      US Centers for Disease, Control, Prevention
      Cancer screening—United States, 2010.
      • Kiviniemi M.T.
      • Bennett A.
      • Zaiter M.
      • Marshall J.R.
      Individual-level factors in colorectal cancer screening: a review of the literature on the relation of individual-level health behavior constructs and screening behavior.
      However, the widespread implementation of low-dose computed tomography screening will likely be restricted to countries with the financial means to pay for these tests.
      • Black W.C.
      • Gareen I.F.
      • Soneji S.S.
      • et al.
      Cost-effectiveness of CT screening in the National Lung Screening Trial.
      Thus, to make a global impact on reducing lung cancer mortality rates, tobacco control to prevent the uptake of smoking remains the single most important factor.
      • Cokkinides V.
      • Bandi P.
      • Ward E.
      • Jemal A.
      • Thun M.
      Progress and opportunities in tobacco control.
      For those who already smoke, smoking cessation before or after diagnosis is expected to remain an important cost-effective approach to increasing survival.
      • Tanner N.T.
      • Kanodra N.M.
      • Gebregziabher M.
      • et al.
      The association between smoking abstinence and mortality in the National Lung Screening Trial.
      • Parsons A.
      • Daley A.
      • Begh R.
      • Aveyard P.
      Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis.

      New Treatments

      Surgical resection continues to be the most effective treatment for localized tumors, although this relies on lung cancer being diagnosed at an early stage and at present, only a small proportion of lung cancers meet this criterion.
      • Ettinger D.S.
      • Wood D.E.
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      Limitations

      One limitation of this study is that the quality of cancer data in GLOBOCAN is variable, particularly in countries with a medium or low HDI where estimates are either based on cancer registries that cover only a small portion of the population or, as in Africa, estimated from neighboring countries.
      • Ferlay J.
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      • Dikshit R.
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      In addition, international comparisons of survival outcomes can be problematic owing to differences in population coverage, quality of mortality data, and analysis methodology, even though some studies, such as CONCORD-2, have standardized these factors for the included countries. Survival estimates by lung cancer stage, histologic features, and demographic characteristics remain sparse. Although we included estimates from the literature to complement direct estimates from original data, the search of literature may not have been comprehensive.

      Conclusion

      The global disease burden of lung cancer is likely to increase well through the first half of this century in view of the increasing global trends in lung cancer incidence and mortality and the small improvements in survival. Greater availability of population-based cancer data in countries with medium or low HDI is essential to assess the current burden and monitor emerging trends in these countries. Any primary prevention interventions will necessarily include stronger tobacco control initiatives at the government level in addition to coordinated efforts to improve the air and environmental quality. In addition, targeted strategies tailored to those geographical, racial, and sociodemographic subgroups of the population at highest risk of lung cancer and strategies to personalize the treatment of lung cancer are essential to reduce the burden of lung cancer worldwide.

      Acknowledgments

      We are grateful to Grace Dy, MD, for reviewing the molecular epidemiology and treatment sections of this article.

      Supplementary Data

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