Lung cancer is one of the malignancies with the highest incidence and mortality rates in the world, and seriously endangers human health [1]. According to the Global Cancer Epidemiology Statistics (GLOBOCAN), there were approximately 2.207 million new cases of lung cancer and 1.796 million new lung cancer deaths worldwide in 2020 [2]. In September 2023, Nature Reviews Clinical Oncology published a review titled "The global burden of lung cancer: current status and future trend", which provides an overview of the global epidemiology of lung cancer, discusses lung cancer risk factors and global efforts to reduce risk, and summarizes global lung cancer screening policies and their implementation [3]. This article summarizes the main points of the review for the benefit of readers.
Epidemiology of lung cancer
Lung cancer is histologically broadly divided into small cell lung cancer and non-small cell lung cancer (NSCLC), with the latter accounting for more than 85% of all cases. Globally, the most common histologic subtype of NSCLC is adenocarcinoma (40%), followed by squamous cell carcinoma (25%). There are significant differences in lung cancer incidence and mortality internationally, which largely reflect different smoking patterns, which in turn vary according to gender and economic development trends. The authors of this article divide countries into economically developed countries, emerging economies, and low- and middle-income countries based on their Human Development Index (HDI) scores.
Economically developed countries
In economically developed countries, the incidence of lung cancer is generally decreasing. Among them, the incidence of men began to decline in the 80s of the 20th century, and the peak of incidence in women was later than that of men (90s of the 20th century), and the incidence rate decreased slightly every year since then, but the extent of the decline in incidence varies from country to country.
In recent years, the lung cancer mortality rate in the United States has declined, but there is still a large gap between different ethnic groups, and the lung cancer mortality rate in European men has been declining, while the lung cancer mortality rate in women has not decreased in most European countries. In economically developed countries such as Japan and South Korea, lung cancer mortality rates in both men and women are declining.
Emerging economies
In the past 20 years, the rapid economic growth of emerging economies has led to a large correlation between the incidence and mortality of lung cancer and the degree of economic development. Brazil, the largest emerging economy in South America, has seen a decline in the mortality rate of lung cancer in men since the early 90s of the 20th century, but the mortality rate of lung cancer in women is still increasing. The burden of lung cancer in China is directly related to the high smoking rate, and the incidence and mortality of lung cancer are high in both urban and rural areas. However, with the implementation of public health measures, smoking prevalence in some urban areas of China, such as Beijing and Shanghai, began to decline. Compared to other emerging economies, India has a lower incidence and mortality rate of lung cancer, but the incidence of smoking and air pollution varies significantly in different regions.
Low- and middle-income countries
Low- and middle-income countries in Latin America, Asia, and Africa have limited lung cancer registry data. Age-standardised incidence and mortality rates for lung cancer in these low- and middle-income countries are generally lower due to lower smoking prevalence and the risk of death from other causes, such as infectious diseases.
Global lung cancer risk factors
Smoking is a recognized risk factor for lung cancer, along with lifestyle and environmental exposures such as biomass fuel exposure, occupational exposure, and pollution. In addition, genetic risk and gender are also non-negligible risk factors for lung cancer.
Smoking
Smoking significantly increases the risk of lung cancer, and the number and number of years smoked are directly proportional to the risk of developing malignancy. As early as the 50s of the 20th century, there was a global consensus that smoking is a high-risk factor for lung cancer, and the World Health Organization (WHO) established the Framework Convention on Tobacco Control (FCTC) to reduce the health burden caused by smoking. But until 2019, it was estimated that more than 1 billion people worldwide still smoked regularly.
Secondhand smoke, as a recognized risk factor, is estimated to increase the risk of lung cancer by 20%~30%. E-cigarettes have been on the rise in recent years, and while the epidemiological link between e-cigarettes and lung cancer needs to be tracked for a longer period of time, their smoke may contain a variety of carcinogens, including polycyclic aromatic hydrocarbons and aldehydes. In this regard, regulatory strategies to restrict the use of e-cigarettes vary from country to country.
Environmental exposure
Untreated biomass fuel emissions contain carcinogens such as benzene and cycloaromatic hydrocarbons, both of which are associated with an increased risk of lung cancer. Interventions to reduce indoor air pollution caused by biomass fuels include programmes such as replacing wood stoves, installing chimneys, and changing the fuel type to oil, however, these efforts have not been shown to improve the health problems associated with household use of biomass fuels.
慢性阻塞性肺疾病 (COPD)
Smoking is a common risk factor for COPD and lung cancer. Several studies have shown that COPD is an independent risk factor for developing lung cancer, regardless of the length of smoking and the total amount of cigarettes smoked, and its severity is associated with increased incidence and mortality from lung cancer. In addition, data from large-scale genetic studies suggest a genetic link between COPD, emphysema, and lung cancer.
Human immunodeficiency virus (HIV) infection
Lung cancer is the leading cause of cancer death in people living with HIV as defined by non-AIDS. Higher smoking rates in people living with HIV can lead to a 2-5-fold increased risk of lung cancer. At the same time, the risk and characteristics of lung cancer in HIV-infected people may vary because the virus itself directly promotes tumorigenesis, virus-related immunosuppression, and lung inflammation associated with infection and non-infection.
Dietary and metabolic factors
Several epidemiological studies have confirmed the effect of diet on lung cancer risk. Risk factors include red meat, processed meat, and vitamin E supplementation intake, and protective factors include fruit and vegetable intake and vitamin B6 and methionine levels. In addition, based on the results of some randomized controlled trials, the US Preventive Services Task Force does not recommend the use of β-carotene for cancer prevention, and the current evidence is insufficient to support the use of other dietary supplements for lung cancer prevention.
In terms of endocrine metabolism, there is evidence that increased waist circumference, waist-to-hip ratio, and insulin resistance are associated with an increased risk of lung cancer.
Genetic risk factors
Lung cancer has a unique subtype distribution (e.g., lung cancer with EGFR alterations) in different geographic regions (e.g., East Asia) and specific patient populations (e.g., women and never-smokers). Regional differences in the percentage of tumors expressing specific molecular markers reflect the impact of different risk factors, such as smoking prevalence and proportion of exposure to untreated biomass fuels, and have important implications for the detection and treatment management of lung cancer. Family history of lung cancer is one of the known risk factors for lung cancer, and lung cancer heritability (the proportion of lung cancer risk differences caused by genetic differences between individuals) is a research difficulty and hot spot in the field. At the same time, with the continuous reduction of genotyping costs and the increasing popularity of technology, polygenic risk scores combined with traditional lung cancer risk factors may become an important part of lung cancer risk prediction.
Screening and the global burden of lung cancer
Develop evidence-based guidelines
48% of lung cancer patients were diagnosed with distant metastases, and the 5-year relative survival rate was 8%. In contrast, the 5-year survival rate for patients diagnosed with localized lung cancer ≥ 60%. Therefore, early diagnosis is essential to improve lung cancer prognosis. The US National Lung Cancer Screening Test (NLST) and the Dutch-Belgian Lung Cancer Screening Test (NELSON) have sufficient statistical power and follow-up capacity to assess the reduction in lung cancer mortality, and both studies have shown that low-dose CT (LDCT) improves survival in high-risk populations.
Although LDCT screening has been observed in the NLST and NELSON trials to reduce lung cancer mortality, false-positive results can still occur, leading to unnecessary invasive surgery. Existing studies have sought to improve the stratification (e.g., biomarkers and/or predictive models) of patients with LDCT detection of nodules, which may reduce the risk of unnecessary harm from screening in the future.
Following the release of NLST results, clinicians in some Asian countries, including China, Japan, and South Korea, developed guidelines for screening populations at high risk of lung cancer. In some low- and middle-income countries, the NLST and NELSON tests may not be appropriate because of the high incidence of granulomatous diseases (e.g., tuberculosis) that may increase the detection rate of false-positive results.
The value of LDCT for early diagnosis
With the increasing popularity of screening, the early diagnosis rate of lung cancer has increased significantly. LDCT screening has been shown to be economically beneficial in the United States, with greater benefit for patients who have expanded the inclusion criteria to 25 years < time to quit smoking. In addition, due to the recent implementation and the lack of a harmonized national lung screening protocol, there is limited data on lung cancer screening that have global impact in other countries.
Challenges to the widespread implementation of LDCT
Although there is strong evidence to support the effectiveness of LDCT for lung cancer screening, its practical application rate is still low. In the US, the constraints to LDCT screening can be summarized in three ways: patient-related factors, provider-related factors, and health-care system-related factors as a whole.
Internationally, although LDCT screening may have economic benefits in the long run, its upfront implementation cost will still limit its wide application in lung cancer screening, and even if the cost limiting factors are eliminated, the utilization rate of the target population is only between 25%~50%.
Other constraints to the implementation of LDCT screening include lack of access to screening centres and lack of infrastructure to assess screening. To this end, it is important to rapidly diagnose and treat lung cancer patients identified by screening by strengthening patient and provider education, staffing and resourcing to identify those eligible for lung cancer screening, and improving infrastructure for timely screening and follow-up.
The future direction of lung cancer screening
In addition to LDCT screening, the development of a blood test involving the detection of circulating tumor material (liquid biopsy) is also a research hotspot. Non-invasive biomarkers currently being evaluated include assays based on microRNA, cell-free DNA, circulating autoantibodies, and nasal gene expression. The successful development and implementation of these tests may reduce barriers to screening, thereby reducing lung cancer mortality.
The impact of advances in treatment on lung cancer mortality
The mortality rate of lung cancer patients in economically developed countries decreases with the decline in incidence, and more advanced treatments can improve patient outcomes. A U.S. evaluation reported that targeted therapy reduced mortality in patients with ALK rearrangements and EGFR-mutant NSCLC. Immune checkpoint inhibitors have improved the prognosis of patients with driver-negative advanced NSCLC as a new therapeutic modality. In countries where these new treatments are widely available, lung cancer mortality is expected to have a population-level impact. However, most low- and middle-income countries have relatively limited access to emerging therapies for lung cancer, and the impact of targeted therapies and immune checkpoint inhibitors on lung cancer mortality may be limited.
epilogue
Lung cancer is a major source of malignancy morbidity and mortality worldwide. This article highlights the major international trends in lung cancer epidemiology, lung cancer risk factors, and lung cancer screening. In economically developed countries such as the United Kingdom and the United States, the incidence and mortality of lung cancer are declining, and lung cancer screening can further reduce the mortality rate while improving the early diagnosis rate, helping to reduce the global burden of lung cancer. While the number of smokers has decreased in most low- and middle-income countries, smoking is still widespread overall, and tobacco control remains key to reducing lung cancer incidence and mortality in most parts of the world. In addition, studies using genetics and other clinical risk factors to further refine lung cancer risk assessment and identify populations for screening, especially among non-smokers, may be of great significance in the future to improve patient outcomes. Further research into the biology of lung cancer is also expected to improve the individualized treatment of lung cancer patients.
bibliography
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3.Amanda L ,R R V ,P J W . The global burden of lung cancer: current status and future trends. [J]. Nature reviews. Clinical oncology,2023,20(9):624-639.
Disclaimer: This article is published with the support of AstraZeneca and is intended for healthcare professionals only
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