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Lung Cancer in Greece

      Introduction

      Greece is a South European country, located at the east part of the Mediterranean basin and the southern edge of the Balcan Peninsula, with a population of 10,720,000 in 2019. In the past decade, Greece’s mixed economy has gradually recovered from the financial deficit crisis that burst out in 2009 and led to the supervised funding of the country from the European Union (EU) and International Monetary Fund for several years. With a nominal per capita income of U.S. $31,413 in 2019 (adjusted to purchasing power parity), Greece has now reached approximately two-thirds of the EU-28 average.
      OECD. Gross
      domestic product (GDP).
      Nevertheless, the economic depression has significantly affected health care investments and funding. The Greek health care model is mixed, with the public sector mainly financed through compulsory social insurance, covering approximately 90% of the population, whereas a substantial number of beneficiaries also profit from private insurance funding, which is gradually growing. Federal health spending per capita was U.S. $2384 in 2019 and accounting for 7.8% of the country’s gross domestic product in the same year, which approaches the median annual spending for health care among the 28 countries of the EU.
      OECD. Gross
      domestic product (GDP).
      With the average life expectancy climbing up to 81.3 years in 2017, the country’s needs for investment in public and private health care have been expanded in parallel, rendering the challenge for improving outcomes even greater.
      United Nations Development Programme
      Human Development Reports. 2018 statistical update: human development indices and indicators.
      Greek men can now anticipate 78.9 years and women 83.9 years of longevity, which is slightly above the EU-28 average of 78.3 and 83.7 years, respectively. Consequently, Greece’s health development index has risen from 0.753 in 1990 to 0.870 in 2017, placing the country in the very high human development category, ranking 31st among 189 countries and 20th in the EU-28 according to the United Nations Development Program.
      United Nations Development Programme
      Human Development Reports. 2018 statistical update: human development indices and indicators.
      The unique anthropogeography of Greece, with many large and countless small islands, presents an additional challenge in terms of equal health care provision because some of the smaller islands are not easily accessible, especially in winter months.

      Epidemiology

      Over the past 25 years, Greece has witnessed, along with many other European countries, a transition in the balance in lung cancer incidence by sex, characterized by a gradual decrease in men accompanied by a slight increase in women, probably resulting from the adoption of hazardous smoking habits by many Greek women during the feminist emancipation period in the 80s and 90s. In 1995, the projected incidence of lung cancer among Greek men was reported to be 82.2 per 100,000 standardized person-years (SPYs), whereas, in Greek women, the corresponding incidence was 11.5 per SPYs.
      • Bray F.
      • Sankila R.
      • Ferlay J.
      • Parkin D.M.
      Estimates of cancer incidence and mortality in Europe in 1995.
      In 2006, the cumulative lifetime risk for diagnosis of lung cancer in Greece was 9.6% for men and 1.6% for women, reflecting the widely adopted smoking habit among Greek men.
      • Ferlay J.
      • Autier P.
      • Boniol M.
      • Heanue M.
      • Colombet M.
      • Boyle P.
      Estimates of the cancer incidence and mortality in Europe in 2006.
      Gradually, the projected annual incidence of lung cancer among Greek men declined from 82.2 per 100,000 SPYs in 1995 to 77.9 in 2008 and 78.6 in 2018, whereas it rose among Greek women from 11.5 per 100,000 SPYs in 1995 to 12.5 in 2008 and to the striking 21.0 in 2018.
      • Ferlay J.
      • Parkin D.M.
      • Steliarova-Foucher E.
      Estimates of cancer incidence and mortality in Europe in 2008.
      ,
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      In the same year (2018), the age-standardized incidence rates of lung cancer were 99 per 100,000 person-years among Greek men and 23.5 per 100,000 among Greek women, with the corresponding age-standardized mortality rates being 81.1 and 17.5 per 100,000 person-years, respectively.
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      These numbers place Greek men, in particular, in the third-place of lung cancer mortality in Europe, after Hungary and Serbia.
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      To go even further, if one takes into account the recently reported, projected standardized incidence rates for Hungary derived from the Hungarian HeLP study,
      • Kourlaba G.
      • Gkiozos I.
      • Kokkotou E.
      • Stefanou G.
      • Papaspiliou A.
      • Syrigos K.
      Lung cancer patients’ journey from first symptom to treatment: results from a Greek registry.
      Greece ranks second in lung cancer incidence among men in Europe, second only to Serbia. Consequently, it was estimated that 6690 men and 1660 women lost their lives to lung cancer in Greece in 2018,
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      thus, rendering lung cancer the leading cause of cancer-related death among Greek men and the second among Greek women, after breast cancer.
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      Despite ongoing efforts, a national lung cancer registry in Greece is still lacking. A retrospective study of a hospital-based lung cancer registry was conducted in the Oncology Unit of Sotiria Hospital in Athens
      • Kourlaba G.
      • Gkiozos I.
      • Kokkotou E.
      • Stefanou G.
      • Papaspiliou A.
      • Syrigos K.
      Lung cancer patients’ journey from first symptom to treatment: results from a Greek registry.
      ; data on 473 patients with NSCLC were analyzed. Most patients were men (78.2%), with a median age of 66.8 years. Adenocarcinoma was diagnosed in 48.9% of patients, followed by squamous cell carcinoma and SCLC (25% each type). At least 95.8% were smokers or former smokers at the time of diagnosis. Most frequent comorbidities were cardiovascular disease (58.9%), respiratory conditions (24.3%), dyslipidemia (23.3%), and diabetes mellitus (22.2%). Almost half of the patients had metastatic disease (52.7%) at the time of diagnosis, whereas the locally advanced disease was diagnosed in 28.1%. Most patients had a histologic diagnosis (93%), whereas 7% had a cytologic diagnosis only. Bronchoscopy was the main sampling method used for diagnosis, and the percentage ranged among patients with adenocarcinoma and SCLC from 39.8% to 79.2%, respectively. Patients with adenocarcinoma and squamous cell carcinoma had better performance status compared with those with SCLC.
      • Kourlaba G.
      • Gkiozos I.
      • Kokkotou E.
      • Stefanou G.
      • Papaspiliou A.
      • Syrigos K.
      Lung cancer patients’ journey from first symptom to treatment: results from a Greek registry.
      The median duration from symptom onset to diagnosis was 52 days for patients with advanced or metastatic disease, and it was shorter for those in early stages. The median duration from diagnosis to treatment was 23 days, and patients with SCLC experienced shorter elapsed time from diagnosis to referral or treatment initiation compared with other lung cancer types.
      Most patients with squamous and adenocarcinoma histologic diagnosis received systemic therapy (59.8% and 52.5%, respectively) or surgery with or without neoadjuvant treatment (34.2% and 37.2%, respectively), whereas systemic therapy was the treatment of choice for those with SCLC (92.5%). Among patients with advanced NSCLC, 13.7% had been detected with EGFR mutations. The same percentage was substantially lower (10.07%) in a large national registry of approximately 1600 patients created by the Hellenic Society for Medical Oncology.
      The percentage of patients tested for programmed death-ligand 1 (PD-L1) status has doubled during the past 2 years. Among those tested, 67% were tested before initiation of first-line treatment, and 26% of those patients had PD-L1 tumor proportion score greater than equal to 50%.
      • Kourlaba G.
      • Gkiozos I.
      • Kokkotou E.
      • Stefanou G.
      • Papaspiliou A.
      • Syrigos K.
      Lung cancer patients’ journey from first symptom to treatment: results from a Greek registry.

      Tobacco-Control Strategies

      Tobacco smoking has been particularly popular in Greece in the years that succeeded after the end of the second world war. Unfortunately, during the 1950s and 60s, there has been a wide reproduction of evidence-lacking “fake” news in various popular Greek newspapers, suggesting that smoking is not associated with lung cancer or even that it protects smokers from lung cancer (Fig. 1). Given the high prevalence of lung cancer in the Greek population in the subsequent decades and the fact that smoking and tobacco consumption in any form are major risk factors for lung cancer, efforts to restrict or ban smoking in public places have been widely implemented in the past 20 years, with various levels of success. On July 1, 2009, a nationwide campaign with the central logo “Greece stops smoking” was launched, including measures such as smoking ban in closed spaces, increased taxation, and warnings on cigarette packs, but without the close supervision of the prohibitive measures, resulting in gradual attenuation of the restrictions.
      Figure thumbnail gr1
      Figure 1Excerpts from Greek newspapers, traced from the electronic archives of the National State Library. (A) On May 17, 1954 with the quote: “An English physician advises: smoke if you want not to get cancer.” (B) On September 5, 1955 with the quote: “Let people who are worried to calm: statistics reveal that smoking does not cause lung cancer.” (C) On June 15, 1955 with the quote: “Greek cigarettes do not cause cancer. They are also less likely to cause vascular disease.”
      After 10 years, in October 2019, the Greek government implemented a stricter “ban smoking” plan, with the clear prohibition of the use of any smoking device (including e-cigarettes) in all public places and closed spaces, including restaurants, cafes, and bars, pubs, and clubs. The measures were accompanied by strict surveillance, including particular fines for the owners of the facilities who broke the regulations and a nationwide four-digit number in which the citizens could communicate and report cases of violation of the restrictions. This strict policy led to a widespread ban on smoking in all public places and nationwide adherence to the smoking ban rules. Part of this national strategy has also been the development of a number of smoking cessation medical aid facilities in many universities and public hospitals covering all major geographic regions of Greece (Fig. 2).
      Figure thumbnail gr2
      Figure 2Map of Greece with a graphic illustration of the geographic distribution of the main facilities relevant to the management of lung cancer. CT, computed tomography; EBUS, endobronchial ultrasound; PET, positron emission tomography.
      According to the data from the official statistical authority of Greece, since 1970, there has been a constant increase in cigarette smoking per person, from 2573 cigarettes in 1970 to 3772 in 1995; whereas from 2000 onwards, a gradual decrease has been recorded. In 2019, more than 30 million cigarettes were sold, accounting for approximately 3000 cigarettes or 150 packets per year per smoker.
      These values correspond to an annual cost of approximately 500 euros for a smoker of half a packet per day and 1000 euros for a smoker of one packet per day. The latter practically means that a “usual” smoker in Greece spends approximately 10,000 euros in a decade of smoking. Because of the high taxation imposed on tobacco products, the annual profit from tobacco consumption in Greece has been 3.6 billion euros in 2019, among which 2.6 billion accounts for state taxes.

      Screening

      There is currently no national lung cancer screening program in Greece. Despite positive results from the National Lung Screening Trial
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      and NELSON
      • De Koning H.
      • Van der Aalst C.
      • Ten Haaf K.
      • Oudkerk M.
      PL02.05 Effects of volume CT lung cancer screening: mortality results of the NELSON randomised controlled population based trial.
      trials, at the moment, there is no official recommendation from the Greek ministry of health regarding low dose computed tomography (CT) of the chest as an imaging screening tool for high-risk individuals. On a private level, there are efforts for lung cancer screening programs in the high-risk population in some large hospitals in Athens, Thessaloniki, and Crete on the basis of the scientific results of National Lung Screening Trial and NELSON trials. The wide implementation of this screening program is currently being discussed in terms of cost, risk prediction model, imaging interval and timing, imaging quality metrics, and potential biomarkers for lung cancer screening.

      Diagnosis

      Pathological Characteristics

      Histologic or cytologic verification is a prerequisite for establishing the diagnosis of lung cancer. Histomorphologic and immunohistochemical evaluation are mandatory for the identification of lung cancer subtypes. Biopsy is mainly obtained by bronchoscopy; other diagnostic procedures, including CT-guided transthoracic needle biopsy, mediastinoscopy, and video-assisted thoracic surgery are also available in university hospitals and several large public and private hospitals in major urban centers. Mediastinal staging is not optimal in many cases because endobronchial ultrasound (EBUS) bronchoscopy is available only in some university and large public and private hospitals (Fig. 2). The diagnostic process is often hampered by inadequate access to EBUS and mediastinal staging, repeated biopsies, and inadequate material for molecular tests.
      Molecular analysis for EGFR, ALK, BRAF, and (peculiarly) KRAS genetic alterations is reimbursed by the National Insurance Authority for all beneficiaries, whereas other targetable alterations with approved molecular agents (ROS1, HER2, RET, MET, NTRK) are not refundable and are usually performed through an available and validated NGS panel. A single exception is PD-L1, which is not yet reimbursed by national insurance but is available through diagnostic programs sponsored by pharmaceutical companies.

      Bronchoscopy

      The advent of molecular-targeted therapy and immunotherapy in lung oncology has raised the need for adequate tissue samples from the primary tumor or its metastases. Moreover, with adenocarcinoma being the most prevalent histologic type, which is often located in the lung periphery, diagnosis requires sophisticated guidance for bronchoscopic access. To cope with these needs, the field of bronchoscopy is rapidly advancing throughout the world. During the past 15 years, several institutions in Greece have implemented minimally invasive bronchoscopic techniques for the diagnosis and staging of lung cancer in central and peripheral airways and in the mediastinum and the pleura.
      Although positron emission tomography (PET) scan is helpful to indicate extrathoracic metastases, it is not able to precisely stage mediastinal involvement in lung cancer, and tissue confirmation is always warranted. EBUS–transbronchial needle aspiration is comparable with mediastinoscopy for mediastinal lymph node staging of NSCLC with a pooled sensitivity of roughly 90%.
      • Yasufuku K.
      • Pierre A.
      • Darling G.
      • et al.
      A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer.
      The addition of a transesophageal approach with the same bronchoscope (transesophageal endobronchial ultrasound) completes the mediastinal exploration giving access to paraesophageal structures and even the left adrenal gland. Thus, combined systematic EBUS and transesophageal endobronchial ultrasound–guided transbronchial needle aspiration has become the accepted standard for lung cancer initial staging.
      • Yasufuku K.
      • Pierre A.
      • Darling G.
      • et al.
      A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer.
      • Czarnecka-Kujawa K.
      • Yasufuku K.
      The role of endobronchial ultrasound versus mediastinoscopy for non-small cell lung cancer.
      • Munoz M.L.
      • Lechtzin N.
      • Li Q.K.
      • et al.
      Bronchoscopy with endobronchial ultrasound guided transbronchial needle aspiration vs. transthoracic needle aspiration in lung cancer diagnosis and staging.
      The lung cancer screening trials
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ,
      • De Koning H.
      • Van der Aalst C.
      • Ten Haaf K.
      • Oudkerk M.
      PL02.05 Effects of volume CT lung cancer screening: mortality results of the NELSON randomised controlled population based trial.
      have reported a large number of lung nodules, which are often challenging to diagnose. Several complementary bronchoscopic techniques such as CT-based virtual bronchoscopy platforms, electromagnetic navigation bronchoscopy, radial endobronchial ultrasound with or without fluoroscopic guidance with or without ultrathin bronchoscopes, robotic bronchoscopy, and hybrid modalities are all used to offer guidance for bronchoscopic access to peripheral lung nodules. A cumulative sensitivity of up to 73% for peripheral lung cancer detection has been reported in a previous meta-analysis (16 trials of 1420 patients).
      • Steinfort D.P.
      • Khor Y.H.
      • Manser R.L.
      • Irving L.B.
      Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis.
      The advent of robotic bronchoscopy may further improve this yield.
      • Yarmus L.
      • Wahidi M.
      • Lee H.
      • et al.
      The precision-1 study: a prospective single-blinded randomized comparative study of three guided bronchoscopic approaches for investigating pulmonary nodules.
      Adequate tissue sampling and staging are somehow limited in Greece, given the relative paucity of EBUS systems developed in public hospitals (Fig. 2) and by the small number of pulmonologists who have taken specific training in this method. Although the cost of EBUS/endoscopic ultrasound technologies is high, the procedure may be cost-effective as other more aggressive modalities can be avoided. The Respiratory Medicine Department of the National and Kapodistrian University of Athens recently became one of the training and accreditation centers of the European Respiratory Society EBUS training project, having implemented the highest international clinical and training standards in an effort to form a new generation of interventional pulmonologists in the country.

      Diagnostic Imaging

      Comprehensive radiological staging is mandatory for proper management of lung cancer and is completed in most cases. CT and magnetic resonance imaging are widely available in all areas of Greece, whereas bone scan facilities are available in larger islands and all urban centers in continental Greece. PET/CT scan is available in nine large academic, public, and private hospitals located only in Athens and Thessaloniki, a fact that, aside from the lack of EBUS, forces many patients to move from their residence to major urban centers to undergo the thorough diagnostic and staging procedure (Fig. 2).

      Treatment Modalities

      Surgical Approaches

      Thoracic surgeons are an indispensable member of the multidisciplinary oncology board for patients with lung cancer. Major lung resections for the treatment of lung cancer are performed in 25 accredited thoracic surgery centers in public and military hospitals (more than half of these centers offering training) and in several private hospitals (Fig. 2). Although there is no central registry, it is estimated that the annual rate of anatomical lung resections for lung cancer is approximately 2000 (roughly 20% of the new lung cancer diagnoses). Surgeons are involved in the treatment of patients with stage I and II lung cancer, whereas the multidisciplinary management of stage III and oligometastatic stage IV disease is dependent on institutional lung cancer boards. The rate of pneumonectomies has significantly dropped over the past two decades to less than 10% of all lung resections. Mediastinal lymphadenectomy or lymph node sampling is dependent on surgeon preference. There is significant progress in the adoption rate of minimally invasive approaches over the past 5 years, with several centers performing thoracoscopic (video-assisted thoracic surgery) anatomical lung resections and three accredited centers performing robotic procedures (robot-assisted thoracic surgery). Despite this progress, the estimated numbers of minimally invasive procedures remain well below the European average.
      With the increasing use of advanced bronchoscopic techniques (radial EBUS, electromagnetic radiation navigation bronchoscopy), thoracic surgeons in Greece, after an international trend, are infrequently involved in the diagnosis and staging of lung cancer. As such, cervical mediastinoscopy tends to become a forgotten art. More often, they aid in the management of the sequelae of the advanced locoregional disease, such as malignant pleural and pericardial effusions and airway stenosis.

      Radiotherapy

      Radiotherapy in Greece constitutes a completely separate and independent medical specialty from medical oncology. Radiation Oncologists participate actively in multidisciplinary oncology boards. There are currently 27 centers for radiotherapy in all large urban areas of continental Greece, but none in the islands—with the exception of Crete, the largest Greek island (Fig. 2). Of these centers, 18 are in the public sector and nine in the private one, with 52 linear particle accelerators (LINACs) plus two dedicated stereotactic radiosurgery. Recently, a large number (18) of high-energy LINACs with cutting-edge technology were installed in many university and public hospitals, 12 of them owing to a donation by the Stavros Niarchos Foundation. The increase in the number of new LINACS resulted in the improvement of care for patients both in terms of quality of irradiation techniques and in terms of waiting times for radiotherapy initiation, which has been a long-standing issue in the public health care system. A particular challenge for waiting lists in the public sector is concurrent chemo-radiotherapy for stage III inoperable NSCLC and in limited-stage SCLC, in which chemotherapy and irradiation have to be combined for optimal delivery. Three-dimensional conformal or volumetric modulated arc therapy with image guidance (image-guided radiation therapy) techniques are the standard methods for lung cancer radiotherapy treatment. Endobronchial brachytherapy is available but rarely used. Successful delivery of all requires attention to four-dimensional radiotherapy issues. Geographic distribution of radiotherapy facilities remains an important issue in Greece, as all residents of Greek islands have to move to continental Greece or Crete for several weeks to receive appropriate radiotherapy care (Fig. 2). For this reason, there is a plan to add five new centers to cover this need (Fig. 2, black triangles).

      Systemic Therapy

      The Hellenic Society for Medical Oncology (https://www.hesmo.gr/en) has developed national guidelines for the management of all solid tumors, including lung cancer (available in Greek at https://www.hesmo.gr/en/guidelines). These recommendations are largely based on international guidelines, mainly the European Society for Medical Oncology guidelines, adapted for Greek epidemiologic and pharmacoeconomic data and are updated on a yearly basis. Greece does not have a separate national authority for the approval of new anticancer agents but largely follows the approvals recommended by the European Medicines Agency (EMA). This strategy possesses the advantage that all new cancer medicines approved by EMA become simultaneously approved in Greece, but their availability largely depends on the reimbursement approval process, which requires negotiations with the National Health Technology Assessment committee and can be quite lengthy.
      All current forms of systemic anticancer treatment, namely standard cytotoxic therapy, molecular-targeted agents, and immunotherapy, are widely available in all oncology centers, some pulmonary hospitals, and medical oncology clinics across continental and island Greece (Fig. 2). All cytotoxic agents for conventional chemotherapy regimens are available and refundable. Reimbursed targeted agents include the following: (1) the vascular endothelial growth factor (receptor) inhibitors bevacizumab and vandetanib, but not ramucirumab; (2) the EGFR inhibitors gefitinib, erlotinib, afatinib, and osimertinib; and (3) the ALK inhibitors crizotinib, alectinib, ceritinib, and brigatinib. Targeted agents for other molecular drivers, such as BRAF, HER2, RET, MET, and NTRK, are available through early-access or off-label protocols (Table 1). Programmed cell death protein 1 or PD- L1 inhibitors covered by the national insurance system include first-line pembrolizumab (in patients with PD-L1 tumor proportion score >50%) and the second-line nivolumab, pembrolizumab, and atezolizumab. Chemoimmunotherapy is approved in first-line treatment for appropriate patients, including combinations of platinum-based chemotherapy with pembrolizumab or atezolizumab and bevacizumab. Durvalumab is reimbursed as maintenance treatment in stage III, PD-L1–positive NSCLC, whereas atezolizumab or durvalumab are approved in combination with platinum-based chemotherapy as first-line treatment in extensive-stage SCLC. Most of the molecular-targeted and immunotherapeutic agents require an evidence-based submission of an application to the National Drug Organization for online approval of administration and reimbursement of the drug. This process can sometimes be time-consuming and may delay approval of the drug for up to a month. The status of the main molecular-targeted and immunotherapeutic agents currently used in lung cancer in Greece is summarized in Table 1. A flowchart of the typical management of a patient with newly diagnosed advanced NSCLC is provided in Figure 3.
      Table 1Status and Availability of the Main Molecular-Targeted and Immunotherapeutic Agents Used in the Treatment of Lung Cancer in Greece, as of August 5, 2020
      SettingApproved and ReimbursedThrough Special

      Procedure for Reimbursement
      Available Through EAP or Off-Label

      Approval
      First-line NSCLC

      PD-L1 >50%
      PembrolizumabAtezolizumab
      First-line NSCLC

      Irrespective PD-L1
      Chemo + pembrolizumab

      Chemo + atezolizumab + bevacizumab
      Chemo + atezolizumab (nonsquamous only)Nivolumab + ipilimumab

      Chemo + nivolumab + ipilimumab
      Second-line NSCLCNivolumab

      Pembrolizumab (PD-L1+)

      Atezolizumab

      Docetaxel + nindetanib (nonsquamous)
      Docetaxel + ramucirumab
      EGFR + NSCLC first-lineGefitinib

      Erlotinib

      Afatinib
      Osimertinib

      Dacomitinib
      Poziotinib (exon 20)

      Mobocertinib (exon 20)
      EGFR + NSCLC second-lineOsimertinib (T790M+)

      Chemo + atezolizumab + bevacizumab
      ALK + NSCLC first-lineCrizotinibAlectinib

      Brigatinib
      ALK + NSCLC second-lineLorlatinibAlectinib

      Brigatinib
      ROS + NSCLCCrizotinibEntrectinib
      BRAF mut NSCLCDabrafenib + Trametinib
      HER2+ NSCLCAfatinib

      Dacomitinib

      Neratinib

      Trastuzumab emtansine
      RET+ NSCLCRegorafenib

      Lenvatinib

      Cabozantinib

      Sunitinib

      Sorafenib

      Vandetanib
      MET exon14 mut NSCLCCrizotinib

      Cabozantinib

      Capmatinib
      NTRK + NSCLCLarotrectinib

      Entrectinib
      Stage III inoperable

      NSCLC
      Durvalumab
      Extensive-stage

      SCLC
      Chemo + atezolizumabChemo + durvalumab
      Chemo and EAP, Chemo, chemotherapy; EAP, early access programs; Mut, mutant; PD-L1, programmed death-ligand 1.
      Figure thumbnail gr3
      Figure 3Flowchart of typical management of a patient with newly diagnosed advanced NSCLC in Greece. Atezo, atezolizumab; Beva, bevacizumab; Chemo, chemotherapy; IHC, immunohistochemistry; IO, immunooncology; Ipi, Ipilimumab; NGS, next-generation sequencing; Nivo, nivolumab; PD-L1, programmed death-ligand 1; Pembro, pembrolizumab; T-DM1, trastuzumab-emtansine.

      Clinical and Translational Research

      Academic lung cancer research in Greece is conducted mainly in university hospitals, national Research Institutes, and large public and private cancer centers. There are two main collaborative oncology groups, the Hellenic Cooperative Oncology Group (https://www.hecog.gr/en/homepage-en) and the Hellenic Oncology Research Group (http://www.horg.gr/en/index.php), each with a dedicated and active lung cancer working group. Both groups comprise most of the public and private cancer centers across Greece and have been active in the fields of clinical and translational research of thoracic malignancies for more than three decades now. In addition, several cancer centers and universities are involved in lung cancer collaborative projects with other European partners, such as the European Thoracic Oncology Platform or the Lung Cancer Group of the European Organization for Research and Treatment of Cancer. Main sources of funding include governmental grants (albeit limited after the financial crisis) and international and European grants, whereas an increasing number of Greek institutions also participate in pharmaceutical company–sponsored studies. In the past few years, some centers opened phase I units, and there is an ongoing effort to increase their number. Many thoracic oncology professionals in Greece have access to the International Association for the Study of Lung Cancer resources and are actively involved across a wide spectrum of activities.
      Clinical research in Greece is an area of growing interest not only by academic institutions but also from the central health care providers. This happens not only because patients participating in clinical trials can gain early access to innovative treatments, free laboratory and diagnostic tests, and continuous, high-quality medical care but also because research attracts international capital, enables the transfer of research expertise, and boosts entrepreneurship with no cost to the state. With a fully developed and technologically equipped health care system and highly qualified human resources, Greece aspires to become a serious partner in clinical research in Europe. Clinical trials are conducted internationally and in our country under a rigorously scientific, regulatory, and legal framework and in accordance with international guidelines (International Conference on Harmonization–Good Clinical Practice) that ensure the safety and well-being of patients in the trial, whereas procedures are monitored through ongoing audits/inspections by the national and international authorities and organizations (National Organization of Pharmaceutical Products, EMA, Food and Drug Administration).
      In the past 2 years, the number of trials that have been registered and approved by Greek authorities and the National Organization of Pharmaceutical Products has an increasing trend
      Hellenic Statistical Authority
      although the number of oncology trials and lung cancer trials, in particular, is more or less stable (Fig. 4A). The most clinical research in lung cancer concerns phase 3 international trials and some phase 2 trials each year (Fig. 4B). Authorities have now realized the importance of an extensive clinical trials program for the patients, the institutes, and the public. Therefore, a new national law has been recently introduced that accelerates the approval procedures and submerges the EU legislation: it is now estimated that approval of a clinical trial would be granted within 6 weeks from application.
      Figure thumbnail gr4
      Figure 4(A) The total number of approved interventional clinical trials in Greece by the EOF for the years 2018 and 2019. A total of 104 clinical trials were conducted in 2018. A total of 50 of them belonged to the field of oncology, and nine of them were dedicated to lung cancer. For the year 2019, the total number of approved clinical trials was 153; 48 were in the field of Oncology and 10 of them concerned with lung cancer. (B) Clinical trials in Greece for lung cancer in the past biennium, by phase. For 2018, six-phase 3 and only three phase 2 trials, whereas in 2019 we had seven phases 3 trials and three-phase 2. EOF, National Organization of Medicines.

      Future Challenges and Perspectives

      The main challenges for lung cancer care in Greece in the years to come to include, but are not limited to the following: (1) facilitating access of all citizens to specialized lung cancer facilities, especially for residents of remote continental areas and small islands; (2) improving the geographic distribution of specialized facilities, equipment, and techniques (i.e., EBUS bronchoscopy, PET/CT scan, molecular biology, and biomarkers) so that all patients can equally benefit from optimal care and research activities; (3) rationalizing governmental funding for cancer care, including tumor-oriented specialized cancer centers, hospice care facilities, and care-at-home structures; and (4) improvement in the funding for lung cancer translational and clinical research and enhancing international collaborations, thus, enabling optimal patient access to appropriate clinical trials.

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