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Stage Shift Improves Lung Cancer Survival: Real-World Evidence

Open AccessPublished:September 18, 2022DOI:https://doi.org/10.1016/j.jtho.2022.09.005

      Abstract

      Introduction

      Lung cancer is the global leading cause of cancer death. Taiwan initiated several health policies including smoking cessation, precision therapy, and low-dose computed tomography (LDCT) screening in 1997. We aimed to investigate the effect of public policies on lung cancer survival.

      Methods

      We retrieved the nationwide cancer registry from the Ministry of Health and Welfare to evaluate the smoking prevalence and lung cancer incidence and mortality from 1994 to 2020. We also conducted a retrospective analysis of clinical characteristics and survival on 17,298 patients with lung cancer from 2006 to 2019 using the National Taiwan University Hospital database.

      Results

      Taiwan initiated an anti-smoking campaign in 1997, reimbursed tyrosine kinase inhibitors since 2004, and conducted an LDCT screening trial in 2015. Lung cancer incidence keeps rising but the annual percent change in mortality rate gradually decreased from 0.41% to −2.41%. The National Taiwan University Hospital data revealed that the 5-year survival substantially improved from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020. Improvement was observed in all stages, especially late stages (stage III: from 17.2% to 35.2%; stage IV: from 7.9% to 16.5%). Furthermore, a remarkable shift in cancer stage was observed (stage 0, I, and IIincreased from 19.3% to 62.8%, and stage III and IV decreased from 70.9% to 33.8%). The prominent improvement in survival was primarily driven by the stage shift from advanced to localized, potentially curable disease.

      Conclusions

      This real-world evidence suggested an association between improved survival and LDCT screening and the diagnostic shift from late to early-stage of lung cancer, highlighting the importance of early detection for lung cancer control.

      Keywords

      Introduction

      Lung cancer is the major cause of cancer mortality worldwide.
      • Fitzmaurice C.
      • Abate D.
      • Abbasi N.
      • et al.
      Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study.
      Although the recent advances in precision therapies for lung cancer (e.g., next-generation sequencing, targeted therapy, and immunotherapy) have greatly improved the treatment response,
      • Yang C.Y.
      • Yang J.C.
      • Yang P.C.
      Precision management of advanced non-small cell lung cancer.
      the overall survival remains poor, with a 5-year survival rate of 21%.
      Cancer.Net
      Lung cancer - non-small cell: statistics.
      Cigarette smoking is the leading risk factor for lung cancer. However, lung cancer also occurs in people who never smoked.
      Cancer.Net
      Lung cancer - non-small cell: statistics.
      The prevalence of lung cancer in never-smokers have substantially increased wordwide and it is estimated that 25% of lung cancer worldwide occurs in never-smokers.
      • Subramanian J.
      • Govindan R.
      Lung cancer in never-smokers: a review.
      Lung cancer in never-smokers is more prevalent in East Asia, especially in women.
      • Fitzmaurice C.
      • Abate D.
      • Abbasi N.
      • et al.
      Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study.
      ,
      • Toh C.K.
      • Gao F.
      • Lim W.T.
      • et al.
      Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.
      In Taiwan, never-smokers even account for a higher proportion than smokers in the lung cancer population. On the basis of the report published by the Health Promotion Administration, Ministry of Health and Welfare in 2019, the smoking prevalence in patients with lung cancer was 33.7% (62.8% in male patients with lung cancer and 5.9% in women) and more than half of the patients were initially diagnosed with stage III and IV diseases,
      • Lo Y.L.
      • Hsiao C.F.
      • Chang G.C.
      • et al.
      Risk factors for primary lung cancer among never-smokers by gender in a matched case-control study.
      ,
      Health Promotion Administration
      MoHaW. Taiwan Cancer Registry (in Tranditional Chinese).
      indicating that the control of lung cancer in Taiwan needs to focus on both smokers and never-smokers.
      Taiwan has initiated several health policies for lung cancer control, including a smoking cessation program in 1997, precision lung cancer therapy in early 2000, the reimbursement of EGFR tyrosine kinase inhibitors (TKIs) by the National Health Insurance since 2004, and the low-dose computed tomography (LDCT) lung cancer screening for never-smokers with risk factors (family history of lung cancer, environmental tobacco exposure, chronic lung diseases such as tuberculosis and chronic obstructive pulmonary disease, high cooking index and cooking without using ventilation) in 2015.
      The annual screening for lung cancer with LDCT is recommended in smokers
      • Moyer V.A.
      U.S. Preventive Services Task Force
      Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement.
      because it can effectively improve the survival of lung cancer as reported in large prospective clinical trials like Natioal Lung Screening Trial (NLST) and Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON study).
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ,
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      The reduction of lung cancer mortality in these clinical trials was mainly owing to the increase of stage I disease from 24% to around 60%. However, the effectiveness of LDCT for lung cancer screening in never-smokers at risk is unclear. A nationwide lung cancer LDCT screening study in never-smokers in Taiwan (TALENT: Taiwan Lung Cancer Screening for Never Smoker Trial) was initiated with the aim of confirming the effectiveness of LDCT screening in high-risk never-smokers.
      • Yang P.C.
      PS01.02 National Lung Cancer Screening Program in Taiwan: the Talent study.
      In the TALENT study, the T0 lung cancer detection rate was 2.6%; moreover, 96.5% of diagnosed patients were at an early stage.
      • Yang P.C.
      PS01.02 National Lung Cancer Screening Program in Taiwan: the Talent study.
      On the basis of the results of the TALENT study, we hypothesized that lung cancer screening may accelerate the shift of the lung cancer stage from an advanced incurable stage (stage III–IV) toward an early curable disease (stage 0–II), which, in turn, may improve survival. In Taiwan, the LDCT program has been adopted as one of the optional items in the health examination in many medical institutes since 2011.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      To better understand the association of early detection with the mortality of lung cancer, this longitudinal retrospective cohort study was carried out to evaluate the extent of stage shift in the past decades and its effect on mortality of lung cancer using the database of the National Taiwan University Hospital (NTUH).

      Materials and Methods

      Study Design and Settings

      This longitudinal retrospective cohort study evaluated the Taiwan Cancer Registry (TCR) report, mortality annual report, and adult smoking behavior survey published by the Health Promotion Administration, Ministry of Health and Welfare from 1994 to 2020; and extracted data from 2006 to 2019 from the NTUH electronic medical record database. For the NTUH database, data of each pathologically confirmed patient with lung cancer were collected from the initial diagnosis until lost to follow-up, death, or December 31, 2019, whichever occurred first. The research ethics committee of NTUH approved this retrospective study (Research Ethics Committee number 202205068RINA), with a waiver of informed consent as all data were anonymous and deidentified before analysis. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

      Data Sources

      First, we retrieved the TCR report, mortality annual report, and adult smoking behavior survey published by Health Promotion Administration, Ministry of Health and Welfare to investigate the smoking prevalence, lung cancer incidence, and lung cancer mortality in Taiwan.
      Health Promotion Administration
      MoHaW. Taiwan Cancer Registry (in Tranditional Chinese).
      TCR is a national population-based cancer registry system established by the Ministry of Health and Welfare in 1979.
      • Chiang C.J.
      • Wang Y.W.
      • Lee W.C.
      Taiwan’s Nationwide Cancer Registry System of 40 years: past, present, and future.
      The data of patients newly diagnosed with cancer in hospitals with 50 or more beds in Taiwan are captured and reported to TCR. Data including cancer staging, detailed treatment, and recurrence information are recorded in this long-form database. Health Promotion Administration, Ministry of Health and Welfare publishes annual cancer statistics for all cancer types for policy-making and academic research.
      In addition to the nationwide report, this study also extracted real-world clinical data from the NTUH database, an electronic medical record database that contains medical records of emergency use, inpatient data, and outpatient visits at NTUH. NTUH is one of the largest medical centers in Taiwan, with more than 2600 beds and approximately 3 million outpatient visits annually. About 10% of patients with lung cancer in Taiwan were treated at NTUH annually. NTUH has implemented routine molecular testing for patients with treatment-naive lung cancer since June 2011.
      • Hsu K.H.
      • Ho C.C.
      • Hsia T.C.
      • et al.
      Identification of five driver gene mutations in patients with treatment-naïve lung adenocarcinoma in Taiwan.
      The NTUH database consists of demographics, primary and secondary diagnostic codes (International Classification of Diseases, Ninth Revision, Clinical Modification before 2016 and Tenth Revision after 2016), tumor characteristics, outpatient and inpatient medical records, treatment details, clinical assessment reports, and laboratory results. All data were deidentified, with a unique study number assigned for each patient for data linkage.

      Study Population

      The TCR report and mortality annual report consisted of all patients diagnosed with cancer in Taiwan, whereas this study only presented the outcome of the lung cancer population. For the NTUH database, all patients diagnosed with pathologically confirmed lung cancer at NTUH from 2004 to 2019 were identified. However, owing to the lack of data integrity from 2004 to 2005, the study eventually included patients diagnosed between 2006 and 2019 in the analysis.

      Outcomes

      The smoking prevalence, lung cancer incidence, and mortality retrieved from the published nationwide reports were summarized. For the analysis of the NTUH database, the primary outcome was the trends in all-cause 5-year survival from 2006 to 2011 to 2015 to 2020. The secondary outcome was the percentage of diagnosed disease stages from 2006 to 2019. Together, we aimed to investigate the association of shift in lung cancer stage with lung cancer survival.

      Statistical Analysis

      The nationwide annual percent change (APC) of lung cancer mortality rate was analyzed on the basis of the TCR data using the Joinpoint trend analysis software.
      • Kim H.J.
      • Fay M.P.
      • Feuer E.J.
      • Midthune D.N.
      Permutation tests for joinpoint regression with applications to cancer rates.
      For the NTUH database, this study used descriptive statistics to analyze the data. The 5-year survival rate was defined as the number of patients alive 5 years after the lung cancer was diagnosed divided by the number of the total identified population. The results of the 5-year survival rate were reported as the number and percentage of patients alive. The disease stage was evaluated by year to assess the changes in diagnostic characteristics over time. The distribution of disease stages was presented as the number of patients and the percentage at each stage . All analyses were conducted using the Statistical Analysis System version 9.4 (SAS Institute Inc., Cary, NC).

      Results

      Impact of Smoking Cessation and Health Policies on Lung Cancer Incidence and Survival in Taiwan

      Taiwan has implemented a smoking cessation program since 1997, reimbursed TKIs since 2004, and conducted an LDCT screening trial in 2015. According to the adult smoking behavior survey, the smoking rates have decreased (adult male: from 54.8% to 23.1%; adult female: from 3.3% to 2.9%) since 1994. Meanwhile, the incidence of lung cancer keeps rising regardless of gender (men: from 30.1 to 45.6 per 100,000; women: from 13.8 to 35 per 100,000), especially adenocarcinoma, whereas the incidence of squamous cell carcinoma gradually decreased (Fig. 1A and B ). According to the Joinpoint trend analysis of mortality rates from 1994 to 2020 in Taiwan (Fig. 2), the APC in lung cancer mortality rate has decreased gradually since 2002, with continuing decline after the start of reimbursement of targeting agents in 2004 (−1.04%). Notably, APC mortality rates declined much faster after the LDCT lung cancer screening trial in 2015 (−2.41%), indicating that the LDCT has been of great importance.
      Figure thumbnail gr1
      Figure 1The smoking rate and age-standardized incidence of lung cancer in Taiwan from 1994 to 2020. (A) Men; (B) women. Source: Taiwan Cancer Registry, Health Promotion Administration, Ministry of Health and Welfare (on the basis of WHO 2000 World Standard Population). Adult Smoking Behavior Survey. Health Promotion Administration, Ministry of Health and Welfare.
      Figure thumbnail gr2
      Figure 2Age-standardized lung cancer mortality from 1995 to 2020 in Taiwan. Rates were age-adjusted on the basis of the World Standard Population (WHO 2000–2025). APC estimates were calculated from the underlying rates using the Joinpoint Trend Analysis Software, Version 4.9, March 2021. Source: National Cancer Institute. APC, annual percent change; IO, immuno-oncology therapy; LDCT, low-dose computed tomography.
      To evaluate the incidence of lung cancer at different stages, we reviewed the annual cancer registry report of stage I and IV lung cancer and plotted the results in Figure 3A and B . The age-adjusted incidence of stage I lung cancer has been steadily rising over the past decades. For stage IV lung cancer, the age-adjusted incidence had increased since 2004 but it became more stagnant and gradually decreased after 2011, the year when LDCT was adopted in the health examination in many medical institutes, followed by a consensus report in 2015 from three medical societies (Taiwan Society of Pulmonary and Critical Care Medicine, Taiwan Lung Cancer Society, and Taiwan Radiological Society) to advocate LDCT for lung cancer screening during self-paid health examination.
      Taiwan Lung Cancer Society
      Taiwan LDCT lung cancer screening consensus.
      Figure thumbnail gr3
      Figure 3Crude rate and age-standardized incidence rate of lung cancer in Taiwan from 2004 to 2019. (A) Stage I lung cancer; (B) stage IV lung cancer. Source: Taiwan Cancer Registry, Health Promotion Administration, Ministry of Health and Welfare (on the basis of WHO 2000 World Standard Population). ASR, age-standardized rate; CR, crude rate.

      Patient Characteristics in NTUH Database

      From 2006 to 2019, a total of 17,298 patients in the NTUH database met the study inclusion criteria and were included in the analysis. Table 1 details the patient characteristics. Among these patients, 8437 (48.8%) were men; the median (interquartile range) age was 62 (57–72) years. The number of patients diagnosed with lung cancer gradually increased from 2006 (644 patients) to 2019 (2130 patients). Among the 17,298 included patients, 52.3% of them were diagnosed after 2015.
      Table 1Characteristics of Included Patients
      YearCases, n (%)Age, median (IQR), yMale, n (%)Stage, n (%)Histology, n (%)
      0–IIIIIIIVADCSCCOthers
      2006644 (3.7)67 (57–77)369 (57.3)95 (15.9)20 (3.4)123 (20.6)300 (50.3)385 (64.5)100 (16.8)112 (18.8)
      2007722 (4.2)62 (52–72)401 (55.5)146 (22.3)33 (5.0)133 (20.3)327 (49.9)452 (69.0)86 (13.1)117 (17.9)
      2008728(4.2)67 (57–72)419 (57.6)146 (21.7)22 (3.3)139 (20.7)354 (52.6)469 (69.7)90 (13.4)114 (16.9)
      2009886 (5.1)67 (57–72)509 (57.4)190 (24.5)19 (2.4)136 (17.5)359 (46.2)547 (70.4)102 (13.1)128 (16.5)
      2010895 (5.2)67 (57–77)490 (54.7)203 (26.0)38 (4.9)142 (18.2)344 (44.0)539 (68.9)124 (15.9)119 (15.2)
      2011920 (5.3)62 (57–72)526 (57.2)199 (26.0)30 (3.9)114 (14.9)359 (46.9)559 (73.0)96 (12.5)111 (14.5)
      20121068 (6.2)62 (57–72)564 (52.8)282 (31.9)58 (6.6)117 (13.3)370 (41.9)672 (76.1)109 (12.3)102 (11.6)
      20131139 (6.6)62 (57–72)599 (52.6)395 (39.7)43 (4.3)116 (11.7)383 (38.5)780 (78.5)94 (9.5)120 (12.1)
      20141209 (7.0)62 (57–72)561 (46.4)504 (45.3)56 (5.0)119 (10.7)377 (33.9)901 (81.0)96 (8.6)115 (10.3)
      20151561 (9.0)62 (57–72)743 (47.6)628 (47.1)61 (4.6)128 (9.6)441 (33.1)1096 (82.2)110 (8.2)128 (9.6)
      20161726 (10.0)62 (57–72)797 (46.2)785 (51.7)62 (4.1)142 (9.4)461 (30.4)1280 (84.3)109 (7.2)129 (8.5)
      20171765 (10.2)62 (57–72)775 (43.9)830 (52.8)53 (3.4)137 (8.7)465 (29.6)1328 (84.5)92 (5.9)152 (9.7)
      20181905 (11.0)62 (52–72)801 (42.0)987 (58.2)74 (4.4)121 (7.1)444 (26.2)1468 (86.5)92 (5.4)137 (8.1)
      20192130 (12.3)62 (52–72)883 (41.5)1128 (58.8)75 (3.9)155 (8.1)492 (25.7)1662 (86.7)119 (6.2)136 (7.1)
      Total17,298 (100.0)62 (57–72)8437 (48.8)6518 (42.7)644 (4.2)1822 (11.9)5476 (35.8)12,138 (79.5)1419 (9.3)1720 (11.3)
      ADC, adenocarcinoma; IQR, interquartile range; SCC, squamous cell carcinoma.
      All in all, 7162 patients (46.9%) were diagnosed at stage 0, I or II and 7298 (47.8%) were at stage III or IV. Most patients were adenocarcinomas (79.5%). From 2006 to 2019, we observed an increase in the percentage of early-stage along with a decline in the percentage of late-stage. The percentage of stage I lung cancer increased by 42.9% (from 15.9% to 58.8%) and that of stage IV lung cancer decreased by 24.6% (from 50.3% to 25.7%). Meanwhile, the median age changed from 67 years old to 62 years old. The subtype of lung cancer also changed dramatically. From 2006 to 2019, the percentage of adenocarcinoma increased from 64.5% to 86.7%, whereas that of squamous cell carcinoma decreased from 16.8% to 6.2%.

      Five-Year Survival Rate From 2006 to 2011 to 2015 to 2020 of NTUH

      The 5-year survival rate had substantially improved from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020 (Fig. 4A and B ). Improvement in survival was observed in all cancer stages. Moreover, the survival rate almost doubled for late-stage lung cancer, with 5-year survival rates improving from 17.2% to 35.2% for stage III and from 7.9% to 16.5% for stage IV.
      Figure thumbnail gr4
      Figure 4Improvement of 5-year survival rate of lung cancer from 2006 to 2011 to 2015 to 2020 in NTUH. (A) All stages, (B) each individual stage. Part of the information had been published in ILCN, https://www.ilcn.org/real-world-data-from-taiwan-shows-stage-shift-has-improved-lung-cancer-survival-rates/. ILCN, International Association for the Study of Lung Cancer: Lung Cancer News; NTUH, National Taiwan University Hospital.

      Stage Shift of Lung Cancer of NTUH

      Although the 5-year survival of late-stage disease was nearly doubled during the past decades, the extent of improvement was still limited compared with the overall change of 5-year survival in the total patient population. Therefore, it was inferred that the main reason for the markedly improved overall survival was the stage shift of lung cancer from an advanced incurable disease stage (stage III/IV) toward an early curable localized disease (stage 0/I/II). From 2006 to 2019, the percentage of patients with stage 0, I, or II disease at diagnosis substantially increased from 19.3% to 62.8%; in contrast, the percentage of patients with stage III or IV disease remarkably decreased from 70.9% to 33.8% (Fig. 5).
      Figure thumbnail gr5
      Figure 5Change in localized (stage 0/I/II) and advanced (stage III/IV) lung cancer from 2006 to 2019 in NTUH. NTUH, National Taiwan University Hospital.

      Discussion

      Despite the successful implementation of a smoking cessation program in Taiwan since 1997, which has led to a dramatic decline in male adult smoking rates from 54.8% in 1994 to 23.1% in 2020, the incidence of lung cancer was still going up. The smoking rate in adult females remained stationary at around 3% in the past two decades; however, the incidence of female adenocarcinoma revealed an increasing trend as also observed in men, indicating that the increases in lung cancer in Taiwan could not be explained by smoking alone. With the launch of precision lung cancer therapy, the reimbursement of gefitinib in 2004 and erlotinib in 2007 by the National Health Insurance, and the advocacy of LDCT for early detection of lung cancer and the conduct of LDCT lung cancer screening clinical trial for never-smokers with risk factors (family history of lung cancer, environmental tobacco exposure, chronic lung diseases such as tuberculosis and chronic obstructive pulmonary disease, high cooking index, and cooking without using ventilation), we observed the increase in stage I disease and decrease in stage IV disease from 2004 to 2019. Meanwhile, lung cancer mortality gradually decreased during the era of EGFR TKI reimbursement, especially after the LDCT lung cancer screening trial in 2015 (APC in lung cancer mortality: from 0.41% to −2.41%), indicating the positive effect of LDCT on lung cancer survival.
      In the retrospective analysis of the NTUH cohort, we described the disease characteristics and evaluated the trends in mortality and diagnostic staging among 17,298 patients with lung cancer from 2006 to 2019 from the NTUH database. Over the past decades, the 5-year survival rate of lung cancer has increased substantially from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020. Improvement in survival was observed in all cancer stages, especially for later stages, in which the survival rate almost doubled from 7.9% to 16.5%. With the increased survival rates, our study also revealed a significant stage shift toward an earlier stage. There was a 43.5% increase (from 19.3% to 62.8%) in the proportion of patients diagnosed with stage 0, I, or II lung cancer and a 37.1% reduction (from 70.9% to 33.8%) in the absolute number of patients diagnosed with stage IV disease. The greater improvement in overall survival (+ 32.8%) compared with the increased survival for late-stage (+8.6%) over the past decades was noticeable. This real-world evidence seemed to suggest that the improved lung cancer survival was driven by stage shift. We, therefore, proposed a hypothesis that the stage shift was primarily responsible for the uptick in lung cancer survival.
      Similar to our research, there were two longitudinal retrospective studies conducted in the United States to investigate the association between stage shifts triggered by LDCT and mortality among patients with lung cancer. The extent of stage shift and survival improvement in our study was greater than the reports in the United States. Flores et al.
      • Flores R.
      • Patel P.
      • Alpert N.
      • Pyenson B.
      • Taioli E.
      Association of stage shift and population mortality among patients with non-small cell lung cancer.
      revealed an increase from 26.5% to 31.2% in stage I/II diagnosis and a decline from 70.8% to 66.1% in stage III/IV diagnosis, whereas the mortality decreased by 3.7% from 2006 to 2016. Potter et al.
      • Potter A.L.
      • Rosenstein A.L.
      • Kiang M.V.
      • et al.
      Association of computed tomography screening with lung cancer stage shift and survival in the United States: quasi-experimental study.
      found an increased number of patients in stage I (by 3.9%) and survival rate (by 11.9%) after 2013, which was the year of the introduction of LDCT. Both studies advocated the benefits of LDCT in declining mortality by stage shift.
      In general, only 24% of patients are diagnosed at an early stage in which the survival rate is much higher (60%) and 46% of patients are not diagnosed until the late stage when the survival rate is only 6%.
      Association Lung Association
      Lung cancer key findings.
      The key to reducing mortality among patients with lung cancer is to diagnose them early when their disease is still at an early stage and patients are amenable to curative treatment. NTUH and many medical centers in Taiwan included LDCT as one of the health examination optional items since 2011; therefore, we inferred that improved survival is attributed to LDCT over the past decades in our institute. Several trials have reported that lung cancer screening by LDCT was effective in reducing the mortality of lung cancer by 20% to 24% as it triggers a “stage shift” toward early-stage lung cancer and that around 60% to 70% of cases were detected at stage I.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ,
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      ,
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      ,
      • Nawa T.
      • Fukui K.
      • Nakayama T.
      • et al.
      A population-based cohort study to evaluate the effectiveness of lung cancer screening using low-dose CT in Hitachi city, Japan.
      Our real-world evidence mirrors the positive findings that previous clinical trials reported on computed tomography–based lung cancer screening.
      Aside from the effect of lung cancer screening on survival, gene testing and precision therapy are also accountable for the decline in mortality of later stages in the past decades. In Asia, 49.1% of patients with lung cancer carry an EGFR mutation, compared with approximately 12.8% in Europe, 15.4% in North America, 33.0% in Central America, and 20.0% in Oceanian populations.
      • Melosky B.
      • Kambartel K.
      • Häntschel M.
      • et al.
      Worldwide prevalence of epidermal growth factor receptor mutations in non-small cell lung cancer: a meta-analysis.
      Effective targeted therapies for EGFR-positive tumors,
      • Hsu J.C.
      • Wei C.F.
      • Yang S.C.
      • Lin P.C.
      • Lee Y.C.
      • Lu C.Y.
      Lung cancer survival and mortality in Taiwan following the initial launch of targeted therapies: an interrupted time series study.
      such as gefitinib in 2003 and erlotinib in 2006, were facilitated in parallel with the introduction of LDCT. NTUH had implemented gene testing and precision therapy for lung cancer since 2010. Therefore, we proposed that lung cancer screening and targeted therapy together lead to the improvement in overall lung cancer survival observed in NTUH.
      However, most lung cancer screening trials were performed on smokers or ex-smokers. The proportion of never-smokers in patients with lung cancer in Asia is higher compared with the western countries.
      • Siegel D.A.
      • Fedewa S.A.
      • Henley S.J.
      • Pollack L.A.
      • Jemal A.
      Proportion of never smokers among men and women with lung cancer in 7 US states.
      Approximately 10% to 20% of patients with lung cancer in Europe and the United States are never-smokers, but the proportion of never-smokers among patients with lung cancer in Asia is 40% to 50%.
      • Cho J.
      • Choi S.M.
      • Lee J.
      • et al.
      Proportion and clinical features of never-smokers with non-small cell lung cancer.
      In Taiwan, more than half of patients with lung cancer are never-smokers, and 58.7% of them were diagnosed at a late stage,
      • Lo Y.L.
      • Hsiao C.F.
      • Chang G.C.
      • et al.
      Risk factors for primary lung cancer among never-smokers by gender in a matched case-control study.
      underscoring the importance of lung cancer screening in never-smokers to shift the lung cancer stage from an advanced incurable disease stage to an early curable one.
      Several factors were found to be associated with an increased risk of developing lung cancer in never-smokers, including secondhand smoke, air pollution, occupational exposures, and genetic susceptibility. Our recent proteogenomic study also revealed that lung cancer in smokers and never-smokers have two different disease characteristics with distinct genetic profiles and pathogenic mechanisms, which also highlighted the importance of genetic susceptibility and environmental carcinogen exposure.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in nonsmokers in Taiwan.
      The risk prediction, prevention strategy, management, and screening of lung cancer may need to be tailored to never-smokers on the basis of distinct genetic epidemiology characteristics.
      A goal to double the 5-year survival of lung cancer by 2025 was recently established by the Lung Ambition Alliance,
      The Lung Ambition Alliance
      Our initiatives.
      a global coalition. To achieve the goal, effective screening is one of the key solutions as it leads to an early diagnosis that translates to longer survival. Furthermore, an increase in public awareness of the importance of lung cancer screening is also warranted. In Taiwan, the LDCT program has been adopted as one of the optional items in the health examination in many medical institutes after the publication of the NLST study in 2011.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      Through media and press conferences, many organizations in Taiwan continuously advocate for the incorporation of LDCT cancer screening. In response to this civil appeal, several local governments support LDCT screening for people with specific occupations, such as policemen, firemen, farmers, and fishermen. In central government, the Health Promotion Administration, and the Ministry of Health and Welfare had started to commence a biannual LDCT screening program since July 1, 2022 not only for heavy smokers, but also for high-risk never-smokers who have a relative(s) with lung cancer.
      There were some limitations in this study and the results should be interpreted with caution. First, this was a retrospective study using a database containing certain demographic and clinical variables. Data for smoking status, family history, occupational exposure, and genetic characteristics were insufficient or not available. Moreover, this was a single-center study, which lacks the scientific rigor or external validity required to support the variability of practice among hospitals in Taiwan. Our data are lacking generalizability and may not reflect the whole lung cancer population in Taiwan. Finally, the study did not investigate the prevalence of lung cancer screening by LDCT over the past decades. Although the TALENT LDCT screening was introduced in 2015, it was not part of the routine practice in NTUH; although the NTUH database did include lung cancer detected from TALENT LDCT screening. Evidence to corroborate the association between LDCT and stage shift seemed to be insufficient. In the future, large-scale surveillance including multiple databases from medical institutes, with LDCT data extracted, may be needed to verify the benefits of lung cancer screening on survival that we proposed in this study.
      In conclusion, this study discovered that the annual lung cancer mortality in Taiwan significantly decreased after LDCT clinical trial in 2015. The real-world data in NTUH also revealed that the 5-year survival of lung cancer has improved substantially from 2006 to 2019, along with a significant diagnostic shift from late to early-stage of lung cancer. Although advances in precision lung cancer treatments, particularly targeted therapy, have contributed to the decline in mortality, our study suggests that improved survival is mostly associated with the shift of the lung cancer stage from an advanced incurable late-stage to an early curable one. The adoption of LDCT screening and raising public awareness are important strategies to improve lung cancer survival.

      CRediT Authorship Contribution Statement

      Ching-Yao Yang: Conceptualization, Methodology, Resources, Formal analysis, Writing – original draft.
      Yen-Ting Lin: Conceptualization, Methodology, Resources, Formal analysis, Writing – original draft.
      Ya-Hsuan Chang: Methodology and Data analysis.
      Hsuan-Yu Chen: Methodology and Data analysis.
      Li-Ju Lin: Resources, Formal analysis.
      Yi-Pin Wang: Conceptualization, Methodology, Resources, Formal analysis.
      Jin-Yuan Shih: Conceptualization, Methodology, Formal analysis, Writing - review & editing.
      Chong-Jen Yu: Conceptualization, Methodology, Formal analysis, Writing - review & editing.
      Pan-Chyr Yang: Conceptualization, Methodology, Resources, Formal analysis, Writing - original draft, Writing - review & editing.

      Acknowledgments

      This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 109-2124-M-002-012, MOST 109-0210-01-18-02, MOST 110-0210-01-22-02, 110-2314-B-002-282), Next-Generation Pathway of Taiwan Cancer Precision Medicine Program (AS-KPQ-107-TCPMP), National Taiwan University (NTU-CC-111L894101), Key and Novel Therapeutics Development Program for Major Diseases (AS-KPQ-111-KNT), and Taipei pulmonary diseases and educational foundation. The authors thank Dr. Huann-Sheng Chen and Dr. Eric J. Feuer from the National Cancer Institute for their assistance in Joinpoint analysis, and the Formosa Biomedical Technology Corp. CRO Division for editorial support.

      Data Availability

      The data and materials supporting the conclusions of this article are included in this published article (and its supplementary information files).

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