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Lung Cancer in Republic of China

  • Yung-Hung Luo
    Affiliations
    Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Republic of China

    School of Medicine, National Yang-Ming University, Taipei, Republic of China

    Institute of Clinical Medicine, National Yang-Ming University, Taipei, Republic of China
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  • Chao-Hua Chiu
    Affiliations
    Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Republic of China

    School of Medicine, National Yang-Ming University, Taipei, Republic of China
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  • Chih-Hsi Scott Kuo
    Affiliations
    Thoracic Oncology Unit, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan City, Republic of China

    College of Medicine, Chang Gung University, Taoyuan City, Republic of China
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  • Teh-Ying Chou
    Affiliations
    Institute of Clinical Medicine, National Yang-Ming University, Taipei, Republic of China

    Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Republic of China
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  • Yi-Chen Yeh
    Affiliations
    School of Medicine, National Yang-Ming University, Taipei, Republic of China

    Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Republic of China

    Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Republic of China
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  • Han-Shui Hsu
    Affiliations
    Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Republic of China

    Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Republic of China
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  • Sang-Hue Yen
    Affiliations
    Department of Radiation Oncology, Taipei Municipal Wanfang Hospital, Taipei Medical University, Taipei, Republic of China
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  • Yuan-Hung Wu
    Affiliations
    School of Medicine, National Yang-Ming University, Taipei, Republic of China

    Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Republic of China
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  • James Chih-Hsin Yang
    Affiliations
    Department of Oncology, National Taiwan University Cancer Center, Taipei, Republic of China
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  • Bin-Chi Liao
    Affiliations
    Department of Oncology, National Taiwan University Cancer Center, Taipei, Republic of China
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  • Te-Chun Hsia
    Affiliations
    College of Health Care, China Medical University, Taichung, Republic of China

    Department of Internal Medicine, China Medical University Hospital, Taichung, Republic of China
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  • Yuh-Min Chen
    Correspondence
    Corresponding author. Address for correspondence: Yuh-Min Chen, MD, PhD, Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road, Taipei 112, Republic of China.
    Affiliations
    Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Republic of China

    School of Medicine, National Yang-Ming University, Taipei, Republic of China
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      Introduction

      Located in the west Pacific between Japan and the Philippines, the Republic of China has a population of more than 23 million people. Malignant tumors are the leading cause of death in the Republic of China, and lung cancer is the main cause of death for male and female individuals with cancers.
      Ministry of Health and Welfare, Taiwan
      Cause of death statistics.
      In 2018, the five-year survival rate of lung cancer was approximately 26.5%. Between 1998 and 2018, the number of lung cancer deaths increased from 5749 to 9388. Approximately 70% of the 14,282 individuals diagnosed as having cancers of the lung, bronchus, or trachea in 2017 had stage III or IV lung cancer. These statistics reveal the severe threat of lung cancer to the health and well-being of the Taiwanese people.
      Health Promotion Administration
      Ministry of Health and Welfare, Taiwan. 2017 Cancer Registry Annual Report.
      In 1995, the Taiwanese government implemented the National Health Insurance (NHI) program to improve the efficiency, accessibility, and coverage of health care. The program is compulsory for all citizens, regardless of age, sex, or employment status.
      National Health Insurance Administration
      Ministry of Health and Welfare, Taiwan. National Health Insurance.
      In 2019, the satisfaction rate of the general public toward the NHI was 89.7%.
      National Health Insurance Administration, Ministry of Health and Welfare
      Public satisfaction with National Health Insurance System in 2019.
      The program provides comprehensive medical services for individuals with lung cancer, including those who are economically disadvantaged.

      Epidemiology

      Of all malignancies in the Republic of China, 12.8% were in the lung, bronchus, or trachea, accounting for 19.2% of all cancer deaths in 2017. From 1986 to 2017,
      Health Promotion Administration
      Ministry of Health and Welfare, Taiwan. 2017 Cancer Registry Annual Report.
      ,
      • Chen C.J.
      • Chen K.Y.
      • Li Y.J.
      Epidemiological characteristics and preventive strategies of cancers in Taiwan. S.Y.
      the overall age-standardized incidence of lung cancer in the Republic of China increased from 16.5 to 37 cases per 100,000. The incidence in men and women increased from 22.5 to 43.5 and from 9.5 to 31.6 cases per 100,000, respectively. The age-standardized mortality rate increased from 21 to 23.1 deaths per 100,000. In men and women, this rate increased from 28 to 31.6 and from 13.5 to 15.9 deaths per 100,000, respectively (Fig. 1). The incidence of lung cancer has not decreased with time, indicating that much remains to be done to prevent and treat this disease. The age-standardized incidence of lung cancer by regions in the Republic of China is found in Figure 2,
      Health Promotion Administration, Ministry of Health and Welfare, Taiwan
      Cancer Registry Online Interactive Query system.
      ranging from 16.5 to 42.4 per 100,000 in 2017. The increase in mortality rate over time underscores the severity of its threat to public health and reveals the unmet needs for its effective long-term treatment. Furthermore, trends in the survival rate of patients with lung cancer shed light on this problem. Of the 10 most common cancers in the Republic of China, lung cancer has the lowest overall 5-year survival rate; from 2012 to 2016, this rate (among patients with stages I to IV lung cancer) was 75.2%, 45.2%, 24%, and 8% respectively,
      Taiwan Caner Registry
      Five-year relative survival rate for cancer.
      ,
      Health Promotion Administration, Ministry of Health and Welfare, Taiwan
      Cancer quality information management systems.
      indicating that only a relatively small proportion of approximately 10% to 30% of patients achieve remission. In other words, approximately 70% to 90% of the patients with lung cancer will die within 5 years. Thus, early detection (e.g., through effective screening) and surgical treatment are essential to reduce the rate of mortality. Moreover, these would help improve the overall survival rate.
      Figure thumbnail gr1
      Figure 1Age-standardized incidence and mortality of lung cancer in the Republic of China (1981–2017).
      Figure thumbnail gr2
      Figure 2Age-standardized incidence rates of lung cancer by regions in the Republic of China, 2017.
      With the passage of the Tobacco Hazards Prevention Act in 1997 and the promotion of smoking cessation, the adult smoking rate in the Republic of China dropped from 21.9% in 2008 to 13.0% in 2018, a substantial reduction of 40.6%. More than half of the patients with lung cancer are nonsmokers.
      • Yang P.
      National lung screening program in Taiwan.
      Nevertheless, nearly 3 million individuals remain exposed to tobacco smoke.
      Health Promotion Administration, Ministry of Health and Welfare, Taiwan
      Survey of smoking behavior in Taiwan.
      In general, smokers have a higher risk of lung cancer than nonsmokers, and women have a higher risk than men. The risk of pulmonary squamous cell carcinoma is up to 5 to 10 times higher in smokers than in nonsmokers and that of pulmonary adenocarcinoma is up to 1.5 to 3 times higher.
      Health Promotion Administration, Ministry of Health and Welfare, Taiwan; 2016 Cancer Registry Annual Report.
      ,
      Health Promotion Administration, Ministry of Health and Welfare, Taiwan
      Survey of smoking behavior in Taiwan.
      Therefore, efforts to reduce the smoking rate and secondhand smoke exposure rate must continue.

      Screening

      Screening is one of the most effective ways to control cancer. No screening tool for lung cancer had been proven effective until 2011, when the National Lung Screening Trial (NLST) reported that annual screening through low-dose computed tomography (LDCT) of the chest resulted in significantly reduced lung cancer mortality.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      Its effectiveness was confirmed in the Nederlands-Leuvens Longkanker Screenings Onderzoek trial.
      • 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.
      To the best of our knowledge, the first large lung cancer screening program in the Republic of China was conducted between 1979 and 1986. It was a collaborative program, initially conducted by the Taipei Veterans General Hospital and the S.Y. Dao Cancer Prevention Foundation and later joined by the Lung Cancer Foundation in Memory of Kwang-Shun Lu and the Republic of China Anti-Tuberculosis Association in 1982. Eligible participants were aged 40 years or over, had a smoking history, and had no history of suspected or known lung cancer. The screening procedures comprised chest radiography and sputum cytology performed every 4 months. In the first 3 years, the program was hospital based. It was later changed to a community-based screening program performed by medical professionals operating diagnostic equipment in mobile radiograph vehicles. In the first round, 47 diagnoses of lung cancer were made among 19,694 participants.

      Hsing CT. Bull S.Y. Dao Mem Fund. 1982;18:20–22.

      In the 8-year study period, 94 diagnoses of lung cancer were made among 111,153 participants.
      SY, DAO Cancer Prevention Foundation
      Lung cancer screening from 1979 to 1986.
      On the basis of the NLST findings, several U.S. medical societies recommended LDCT lung cancer screening in high-risk populations between 2011 and 2013. In the Republic of China, a task force for this purpose was organized with collaboration among three medical societies (i.e., the Taiwan Society of Pulmonary and Critical Care Medicine, the Radiological Society of the Republic of China, and the Taiwan Lung Cancer Society) in 2013. The consensus they reached, which was based on evidence from the NLST, recommends annual LDCT screening in heavy smokers. Furthermore, the task force acknowledges that with approximately 50% of patients newly diagnosed as having lung cancer being nonsmokers in the Republic of China, lung cancer in nonsmokers is a major public health problem. An LDCT study on nonsmokers is suggested. The prospective, single-arm Taiwan Lung Cancer Screening in Never Smoker Trial (TALENT), sponsored by the Ministry of Health and Welfare (MOHW), was launched in 2014. This project aims to develop a model of lung cancer risk in nonsmokers, establish the protocol for future LDCT screening programs, and provide evidence of cost-effectiveness. It plans to enroll 12,000 nonsmokers with at least one of the following lung cancer risk factors: a family history of lung cancer (less than or equal to third-degree relatives), a history of secondhand smoke exposure, chronic lung disease (e.g., tuberculosis and chronic obstructive pulmonary disease), exposure to cooking smoke (cooking index ≥ 110), and cooking without using a ventilation hood. The final patient was enrolled in July 2019. The first-round results are expected to be available before the end of 2020. It is hoped that its results can inform not only public health policy makers in the Republic of China but also medical societies or health authorities worldwide.

      Diagnosis and Staging

      As is done in other countries, diagnosis and staging of lung cancer in the Republic of China involve various invasive and noninvasive modalities, including computed tomography (CT), 18F-fluoro-2-deoxy-D-glucose positron emission tomography, magnetic resonance imaging, and transthoracic or transbronchial tissue biopsy.
      In the Republic of China, biopsy method is typically based on the availability and accessibility of the modality. Radial-probe endobronchial ultrasound-guided biopsy with or without fluoroscopy assistance is widely practiced for peripheral lung lesions.
      • Kuo C.H.
      • Lin S.M.
      • Chen H.C.
      • Chou C.L.
      • Yu C.T.
      • Kuo H.P.
      Diagnosis of peripheral lung cancer with three echoic features via endobronchial ultrasound.
      ,
      • Huang C.T.
      • Tsai Y.J.
      • Ho C.C.
      • Yu C.J.
      Radial endobronchial ultrasound-guided transbronchial biopsy for peripheral pulmonary malignancy: biopsy- or brushing-first?.
      In addition, convex-probe endobronchial ultrasound, used for the diagnosis and staging of central thoracic or lymph node lesions, is available in most of the top 10 hospitals that specialize in lung cancer treatment. This technique is unique in that it narrows the differential diagnosis between lymph node metastasis and tuberculosis lymphadenopathy in tuberculosis-prevalent regions, such as the Republic of China.
      • Kuo C.H.
      • Chen H.C.
      • Chung F.T.
      • et al.
      Diagnostic value of EBUS-TBNA for lung cancer with non-enlarged lymph nodes: a study in a tuberculosis-endemic country.
      In a few medical centers in northern Republic of China, transbronchial cryoprobe biopsy is also performed in cases of tumors with central airway invasion.
      • Chou C.L.
      • Wang C.W.
      • Lin S.M.
      • et al.
      Role of flexible bronchoscopic cryotechnology in diagnosing endobronchial masses.
      Notably, these transbronchial biopsy procedures are mostly conducted under conscious sedation by pulmonologists rather than under general anesthesia by surgeons.
      • Hsieh C.H.
      • Lin T.Y.
      • Wang T.Y.
      • et al.
      The safety and efficacy of alfentanil-based induction in bronchoscopy sedation: a randomized, double-blind, controlled trial.
      CT- or ultrasound-guided core needle biopsy is the widely available transthoracic approach. Physicians may choose such methods in cases in which the lesions are close to the chest wall. Furthermore, they are used when transbronchial approaches are not available. In cases in which the sole lesion is pleural effusion, thoracoscope-assisted pleural biopsy (pleuroscopy) may be used.
      • Chen C.H.
      • Cheng W.C.
      • Wu B.R.
      • et al.
      Feasibility and safety of pleuroscopic cryobiopsy of the pleura: a prospective study.
      Contrast-enhanced CT for thoracic and abdominal regions are a routine, including a whole-body 18F-fluoro-2-deoxy-D-glucose positron emission tomography scans. Lung cancer diagnosis typically involves assessment of brain metastasis, for which the technique used depends on the availability of equipment at a hospital. In general, magnetic resonance imaging is standard practice. CT scan may also be used. In most of the top 10 hospitals, when clinical staging for particular cases is challenging or controversial, a multidisciplinary meeting of oncologists, pulmonologists, radiologists, pathologists, and surgeons is held to reach a consensus.

      Pathology

      The pathologic diagnosis of lung cancer in the Republic of China follows the recommendations in the 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus, and Heart.
      • Travis W.D.
      • BE B.A.P.
      • Marx A.
      • Nicholson A.G.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      In more than 96% of the cases, tumor classification is confirmed through either or both histologic and cytologic examination.
      Health Promotion Administration
      Ministry of Health and Welfare, Taiwan. 2017 Cancer Registry Annual Report.
      For small biopsy specimens, a limited initial panel of immunohistochemical markers comprising one squamous marker and one glandular differentiation marker (e.g., p40 and TTF-1, respectively) is recommended for NSCLC. For resection specimens, a report template or checklist is issued by the Taiwan Society of Pathology to guide pathologists.
      Taiwan Society of Pathology
      Lung cancer checklist.
      After pathologic diagnosis, molecular testing for targetable mutations is routinely performed in patients with advanced nonsquamous NSCLC. The most prevalent targetable mutation, EGFR mutation can be identified in approximately 55% of patients with lung adenocarcinoma in the Republic of China.
      • Hsu K.H.
      • Ho C.C.
      • Hsia T.C.
      • et al.
      Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan.
      The NHI reimburses testing for EGFR mutations in patients with advanced nonsquamous NSCLC. According to a 2019 survey by the Taiwan Society of Pathology, commercial real-time polymerase chain reaction assays are the principal testing methods for such mutations in pathology laboratories (Taiwan Society of Pathology, unpublished data, 2019). In patients with EGFR wild-type lung cancer, testing for ALK rearrangement is also routinely performed. Approximately 10% of patients with EGFR wild-type lung adenocarcinoma are positive for EML4-ALK rearrangements in the Republic of China.
      • Hsu K.H.
      • Ho C.C.
      • Hsia T.C.
      • et al.
      Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan.
      Most pathology laboratories use immunohistochemistry (IHC) with the VENTANA ALK (D5F3) CDx Assay (VENTANA Medical Systems, Oro Valley, AZ). Fluorescence in situ hybridization for ALK rearrangement is performed in only a few laboratories (Taiwan Society of Pathology, unpublished data, 2019). For ROS1 rearrangement, IHC is most often used as a screening tool, followed by confirmatory fluorescence in situ hybridization or next-generation sequencing (NGS). Testing for other less common targetable mutations, such as BRAF, NTRK, RET, and MET alterations, is usually performed using targeted gene NGS panels. Academic institutions, medical centers, and local or international biotechnology companies alike offer numerous clinically oriented in-house or commercial NGS panels. However, they are not reimbursed by the NHI or supported by pharmaceutical industry funds.
      For patients with EGFR, ALK, and ROS1 wild-type NSCLCs, programmed death-ligand 1 (PD-L1) IHC testing is reimbursed by the NHI (one test per lifetime). Most pathology laboratories use PD-L1 assays approved by the Food and Drug Administration (FDA) in the United States. A 2019 survey by the Taiwan Society of Pathology revealed that the PD-L1 IHC 22C3 pharmDx (Dako, Carpinteria, CA) is the most common assay provided by participating pathology laboratories and that 40% of pathology laboratories offer more than one type of FDA-approved PD-L1 assays (Taiwan Society of Pathology, unpublished data, 2019).
      Most molecular testing laboratories are accredited by the Taiwan Accreditation Foundation ISO 15189 or the College of American Pathologists and actively participate in external quality assurance programs. The Taiwan Society of Pathology offers annual molecular proficiency testing for EGFR mutation, ALK IHC, and PD-L1 IHC for lung cancer.

      Surgical Approaches

      With the rapid development of technology, minimally invasive surgery has become possible and beneficial in all fields of surgery.
      Health Promotion Administration
      Ministry of Health and Welfare, Taiwan. 2017 Cancer Registry Annual Report.
      ,
      • Barta J.A.
      • Powell C.A.
      • Wisnivesky J.P.
      Global epidemiology of lung cancer.
      In the Republic of China, almost 90% of patients with thoracic diseases receive video-assisted thoracoscopic surgery as a primary treatment.
      • Liu C.Y.
      • Hsu P.K.
      • Chien H.C.
      • Hsieh C.
      • Ting C.
      • Tsou M.
      Tubeless single-port thoracoscopic sublobar resection: indication and safety.
      In a study by Chen et al.,
      • Chen J.S.
      • Cheng Y.J.
      • Hung M.H.
      • Tseng Y.D.
      • Chen K.C.
      • Lee Y.C.
      Nonintubated thoracoscopic lobectomy for lung cancer.
      nonintubated thoracoscopic lobectomy was found to be technically feasible and equally safe as lobectomy performed with intubation in selected patients. In 2011, the NLST Research Group reported that LDCT screening can reduce lung cancer mortality by approximately 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.
      Recent years have found a rise in the rate of this approach and subsequently a substantial increase in cases with pulmonary ground-glass opacity (GGO). To remove these small pulmonary lesions, precise localization is mandatory. Techniques include chest CT-guided localization with dye, hook wire, micro coil, and indocyanine green; electromagnetic navigation bronchoscopy localization; or localization in a hybrid operation theater.
      • Hsu P.K.
      • Wu Y.C.
      The feasibility of electromagnetic navigation-guided percutaneous microcoil localization for thoracoscopic resection of small pulmonary nodules.
      ,
      • Lin C.W.
      • Ko H.J.
      • Yang S.M.
      • et al.
      Computed tomography-guided dual localization with microcoil and patent blue vital dye for deep-seated pulmonary nodules in thoracoscopic surgery.
      Results from a propensity score-matched analysis comparing electromagnetic navigation- and CT-guided methods of percutaneous transthoracic localization revealed similar results.
      • Hung C.T.
      • Chen C.K.
      • Chang Y.Y.
      • et al.
      Electromagnetic navigation-guided versus computed tomography-guided percutaneous localization of small lung nodules before uniportal video-assisted thoracoscopic surgery: a propensity score-matched analysis.
      The authors concluded that the two methods were comparable for the preoperative localization of small lung nodules before uniportal video-assisted thoracoscopic surgery.
      Because patients with small pulmonary GGO lesions have a favorable prognosis, sublobar resection with or without mediastinal lymph node dissection may be appropriate to preserve pulmonary function and avoid complications. In a 2020 study by Lin et al.,
      • Lin Y.H.
      • Chen C.K.
      • Hsieh C.C.
      • et al.
      Lymphadenectomy is unnecessary for pure ground-glass opacity pulmonary nodules.
      the consolidation-to-tumor ratio (CTR) was found to be a satisfactory preoperative predictor of lymphatic metastasis in patients with lung cancer with GGO lesions. For patients in whom the GGO lesions present CTR greater than or equal to 50%, radical resection is mandatory to avoid local recurrence. By contrast, for patients in whom their GGO lesions present CTR less than 50%, lymphadenectomy may not be necessary because lymph node metastasis is unlikely.
      • Lin Y.H.
      • Chen C.K.
      • Hsieh C.C.
      • et al.
      Lymphadenectomy is unnecessary for pure ground-glass opacity pulmonary nodules.

      Radiation Approaches

      Radiotherapy is highly accessible in the Republic of China, offered by 333 board-certified radiation oncologists at 81 hospitals. The health care system is equipped with more than 143 medical linear accelerators, six CyberKnifes, nine GammaKnifes, 20 TomoTherapy, and 37 remote-afterloading brachytherapy systems in the Republic of China.
      Particle therapy, which has long been available at two proton centers, has rapid, widespread embracement in recent years. A number of proton centers are under construction, all equipped with the latest image-guiding and pencil-beam systems. A carbon ion particle therapy system is also under construction, with a planned launch date in 2022. Reactor-based boron neutron capture therapy is available for compassionate use.
      • Jiang S.H.
      • Hsueh Liu Y.W.
      • Chou F.I.
      • et al.
      The overview and prospects of BNCT facility at Tsing Hua Open-pool reactor.
      Intensity modulated radiotherapy, including volumetric-modulated arc therapy, is covered by the NHI and has become standard of care for thoracic radiotherapy. Stereotactic body radiation therapy or stereotactic ablative radiotherapy is also covered for medically inoperable early stage lung cancer.
      Regulated by the Cancer Control Act,
      Ministry of Health and Welfare
      Cancer control act.
      radiotherapy administration is mostly dependent on treatment guidelines. According to the 2017 Cancer Registry Annual Report of the Health Promotion Administration of the MOHW,
      Health Promotion Administration
      Ministry of Health and Welfare, Taiwan. 2017 Cancer Registry Annual Report.
      47.7% of the patients with stage IIIB NSCLC received radiotherapy as part of their first-course treatment, with 29.1% receiving concurrent chemoradiotherapy. Although evidence of locally aggressive treatment for oligometastatic lung cancer is increasing, the NHI has also started to reimburse high-precision radiotherapy for oligometastatic tumors.

      Systemic Therapy (Targeted Therapy)

      The Republic of China has participated or played leading roles in early phase and late-phase development of most molecular-targeted agents, such as gefitinib, afatinib, osimertinib, alectinib, ceritinib, brigatinib, lorlatinib, crizotinib, capmatinib, and tepotinib.
      • Yang J.C.
      • Shih J.Y.
      • Su W.C.
      • et al.
      Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.
      • Jänne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer.
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study [published correction appears in Lancet Oncol. 2019;20:e10].
      • Paik P.K.
      • Felip E.
      • Veillon R.
      • et al.
      Tepotinib in non–small-cell lung cancer with MET Exon 14 skipping mutations.
      • Mok T.S.
      • Wu Y.L.
      • Thongprasert S.
      • et al.
      Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma.
      • Yang J.C.
      • Ou S.I.
      • De Petris L.
      • et al.
      Pooled systemic efficacy and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small cell lung cancer.
      • Soria J.C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study [published correction appears in Lancet. 2017;389:908].
      • Camidge D.R.
      • Kim H.R.
      • Ahn M.J.
      • et al.
      Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer.
      • Wu Y.L.
      • Yang J.C.
      • Kim D.W.
      • et al.
      Phase II study of crizotinib in East Asian patients with ROS1-positive advanced non–small-cell lung cancer.
      • Bang Y.J.
      • Su W.C.
      • Schuler M.
      • et al.
      Phase 1 study of capmatinib in MET-positive solid tumor patients: dose escalation and expansion of selected cohorts.
      The treatment of advanced or metastatic NSCLC is in line with many international guidelines, such as the Pan-Asian–adapted European Society for Medical Oncology Clinical Practice Guidelines, which are endorsed by oncology societies in many Asian countries, including the Taiwan Oncology Society.
      • Wu Y.L.
      • Planchard D.
      • Lu S.
      • et al.
      Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS.
      The reimbursement guidance or scope of benefits for anticancer drugs is defined by the Republic of China’s single-payer NHI system.
      National Health Insurance Administration
      Ministry of Health and Welfare, Taiwan. National Health Insurance.
      EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and afatinib) are reimbursed as first-line therapy for advanced or metastatic EGFR mutation-positive NSCLC (stages IIIB, IIIC, and IV; Table 1). Dacomitinib is reimbursed for only advanced or metastatic EGFR exon 21 L858R or exon 19 deletion-positive NSCLC without central nervous system metastasis (stages IIIB, IIIC, and IV). Osimertinib is reimbursed as first-line treatment for only metastatic EGFR exon 19 deletion-positive NSCLC (stage IV) without central nervous system metastasis or as a second-line treatment after failure of EGFR tyrosine kinase inhibitors therapy, with proven presence of EGFR T790M mutation through rebiopsy. The diagnosis of EGFR mutation must be made using NHI-reimbursed tissue-based companion in vitro diagnostics. Osimertinib reimbursement requires preapproval and renewal every 3 months through the submission of imaging evidence of nonprogression. Bevacizumab plus erlotinib and ramucirumab plus erlotinib both received regulatory approval as first-line treatments for advanced EGFR mutation-positive NSCLC. However, they are not covered under the NHI system. Afatinib is reimbursed as a second-line treatment for platinum-pretreated advanced or metastatic lung squamous cell carcinoma.
      Table 1Availability (Reimbursement) of Systemic-Targeted Therapies in the Republic of China
      Targeted therapiesAvailability
      Indication
       Gefitinib, erlotinib, or afatinib, first line, EGFR mutation-positiveAvailable
       Dacomitinib, first line, EGFR mutation-positive (EGFR exon 21 L858R mutation and exon 19 deletion)Available with restriction
       Osimertinib, second line, post-EGFR TKI, EGFR T790M-positiveAvailable
       Osimertinib, first line, EGFR mutation-positive (EGFR exon 21 L858R mutation and exon 19 deletion)Available with restriction
       Crizotinib, first line, ALK-positiveAvailable
       Crizotinib, any line, ROS1-positiveAvailable
       Alectinib or ceritinib, first line, ALK-positiveAvailable
       Alectinib or ceritinib, second line, ALK-positive, postcrizotinibN/A
       Brigatinib, second line, ALK-positive, postcrizotinibAvailable
       Lorlatinib, second line, ALK-positive, postalectinib, or ceritinibAvailable with restriction
       Dabrafenib plus trametinib, BRAF V600E–positiveN/A
       Entrectinib or larotrectinib, NTRK fusion–positiveN/A
      Molecular testing
      EGFR mutation, first lineAvailable
      EGFR T790M mutation, second lineN/A
      ALK rearrangementAvailable (IHC only)
      ROS1 rearrangementN/A
      BRAF V600E mutationN/A
      NTRK fusionN/A
       IHC, immunohistochemistry; N/A, not available; TKI, tyrosine kinase inhibitor.
      ALK fusion is usually detected early through IHC. ALK inhibitors, crizotinib, alectinib, and ceritinib, are reimbursed as first-line treatments for advanced or metastatic ALK-positive NSCLC. However, alectinib and ceritinib have been approved but are not reimbursed as second-line treatments for crizotinib-pretreated, ALK-positive NSCLC, for which the only reimbursed drug is brigatinib. Lorlatinib has been approved for the treatment of alectinib or ceritinib-pretreated, ALK-positive NSCLC but is reimbursed only in patients with brain metastasis. Notably, the reimbursement of ALK inhibitors requires preapproval and renewal every 3 months through the submission of imaging evidence of nonprogression. Both crizotinib and entrectinib have been approved for advanced or metastatic ROS1-positive NSCLC, but only crizotinib is reimbursed. Combination therapy of dabrafenib plus trametinib has been approved but is not reimbursed for the treatment of advanced or metastatic BRAF V600E-positive NSCLC. Larotrectinib and entrectinib have received approval for treating metastatic NTRK fusion-positive NSCLC but are not reimbursed. As of September 28, 2020, no drug has received approval for the treatment of MET exon 14 skipping-, HER2 mutation-positive, or RET fusion-positive NSCLC.
      As mentioned previously, the diagnostics for ROS1 rearrangement, NTRK fusion, BRAF V600E mutation, MET exon 14 skipping, HER2 mutation, and RET fusion, such as tissue NGS, are not reimbursed in the Republic of China. We encourage patients with wild-type EGFR and ALK-negative tumors to participate in clinical research programs or clinical trials that provide tissue or plasma NGS tests to detect potentially targetable genetic alterations. The Taiwan Lung Cancer Consortium is a platform conducting tissue tests and clinical trials, especially investigator-initiated trials.
      Taiwan ClinicalTrials
      Consortium Member. Lung Cancer Consortium.
      It has close connections with domestic lung cancer care experts and engages in international collaboration with consortiums in other countries such as Singapore and Australia.

      Systemic Therapy (Chemotherapy and Immunotherapy)

      In the Republic of China, molecular diagnosis is routinely performed for every patient newly diagnosed as having advanced adenocarcinoma and is conditionally implemented in those with squamous cell carcinoma. Patients with tumors lacking driver mutations typically receive chemotherapy and occasionally immunotherapy according to the guidelines for approval and reimbursement of the FDA and NHI Administration of the MOHW.
      National Health Insurance Administration
      Ministry of Health and Welfare, Taiwan. National Health Insurance.
      Platinum-based doublet chemotherapy is a standard first-line treatment for pan-negative NSCLC. In patients with nonsquamous NSCLC, four to six cycles of platinum-pemetrexed treatment followed by pemetrexed maintenance is preferred. Currently used chemotherapeutics comprise platinum, pemetrexed, gemcitabine, vinorelbine, taxane, and TS-1. The combination of chemotherapy with either or both antiangiogenetic agents and immunotherapy as first-line treatment is approved by the FDA of the MOHW but not reimbursed by the NHI. Thus, such treatments are infrequently administered. In April 2019, reimbursement for pembrolizumab was granted as a standard first-line treatment for patients with EGFR/ALK/ROS1 wild-type advanced NSCLC whose PD-L1 tumor proportion scores are greater than or equal to 50% according to the Dako 22C3 (Dako) or SP263 (VENTANA Medical Systems) IHC test results.
      National Health Insurance Administration
      Ministry of Health and Welfare, Taiwan. National Health Insurance.
      For the other patients with nonresectable advanced or metastatic NSCLC whose PD-L1 expression is greater than or equal to 50% and for whom platinum-based chemotherapy has failed, immunotherapy (e.g., with programmed cell death protein-1/PD-L1 inhibitors, nivolumab, pembrolizumab, and atezolizumab) can be used as second-line or third-line treatment according to PD-L1 test results. Durvalumab is approved for consolidation therapy in patients with advanced-stage III NSCLC and for combination therapy in patients with advanced SCLC but is not reimbursed. Tables 2 and 3 present the treatment options for patients with EGFR/ALK/ROS1 wild-type advanced lung cancer under the NHI benefit package.
      Table 2Chemotherapy Availability for Patients With Different Types of Pan-Negative Advanced Lung Cancer (Covered Under the NHI Program)
      Nonsquamous NSCLCSquamous cell carcinomaSmall cell carcinoma
      PlatinumPlatinumPlatinum
      PemetrexedGemcitabineEtoposide
      GemcitabineTaxaneTopotecan
      TaxaneVinorelbine
      VinorelbineTS-1
      TS-1
      NHI, National Health Insurance.
      Table 3Immunotherapy Availability for Patients With Pan-Negative Advanced Lung Cancer Whose PD-L1 TPS Are Greater Than or Equal to 50% (Covered Under the NHI Program)
      NSCLCSCLC
      Pembrolizumab (first line and later line)
      Nivolumab (second line or later line)N/A
      Atezolizumab (second line or later line)
      N/A, not available; NHI, National Health Insurance; PD-L1, programmed death-ligand 1; TPS, tumor proportion score.

      Conclusions

      Both the incidence and mortality rate of lung cancer in the Republic of China are high. Exposure to tobacco smoke is an important risk factor for this disease. Therefore, continual efforts for reducing both smoking rate and secondhand smoke exposure rate are imperative. An ongoing screening trial for lung cancer in nonsmokers, a major public health problem, will be used to develop protocols for future lung cancer screening programs. Under the NHI system, comprehensive medical services, including precision pathology diagnosis, modern thoracic surgery, advanced systemic treatments, and contemporary radiotherapy can be efficiently provided to the entire population, with constant consideration of new, cost-effective treatments. The Republic of China has actively participated or played key roles in numerous clinical trials of systemic therapies. Through close connections between domestic lung cancer care providers and international collaboration, more efforts and resources can be implemented to prevent lung cancer and improve the outcome of this fatal disease.

      Acknowledgments

      The authors thank the Taiwan Lung Cancer Society for the technical assistance with this manuscript.

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