European Respiratory Society
Lung Cancer

Lung cancer is the most common cause of death from cancer worldwide – it is estimated to cause nearly one in five cancer deaths. Most lung cancer patients are diagnosed late and for many of them, there are currently no curative therapy options available, meaning long-term survival is still low. Nevertheless, enormous progress has been made in the field during the last decade. This Monograph provides a comprehensive overview of the current knowledge of and advances in lung cancer, covering areas such as: screening; tobacco control; COPD; diagnosis; therapy; and treatment of early stage lung cancer from both a surgeon's and radiation oncologist's perspective. Very recent achievements in innovative fields, such as targeted therapies and immunotherapies, are also discussed.

  • ERS Monograph
  1. Page vii
  2. Page ix
  3. Page xiii
  4. Page 1
    Georgia Hardavella, King's College Hospital London, Dept of Respiratory Medicine, 2nd Floor Cheyne Wing, Denmark Hill, London, SE5 9RS, UK. E-mail:

    This chapter aims to offer a brief overview of the epidemiology of lung cancer worldwide and particularly in Europe. It presents important epidemiological data in terms of incidence, mortality and 5-year survival, identifies developing epidemiological trends based on published data, and at the same time tries to highlight the needs and areas of potential interest for future epidemiological studies in lung cancer.

  5. Page 12
    John K. Field, Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Roy Castle Building, 200 London Road, Liverpool, L3 9TA, UK. E-mail:

    Lung cancer CT screening has the potential to save many lives if implemented in Europe. The National Lung Screening Trial (NLST) found a 20% reduction in lung cancer mortality following three annual CT screenings, with a cost per quality-adjusted life year of US$81 000 in the USA. The European trials have provided evidence for: 1) the use of a risk prediction model to select high-risk individuals; 2) the use of volumetric analysis and volume doubling time to determine the care pathway for CT-detected nodules; 3) the potential for undertaking biennial screening after 2 years of scans with no evidence of disease; 4) the importance of integrated smoking cessation, which uses the CT screen as a way to augment quit rates. The NELSON (Dutch–Belgian Randomised Lung Cancer Screening Trial) and the pooled European trial data will be available in 2016, so it is imperative we start planning for the implementation of lung cancer screening now.

  6. Page 24
    Thierry Urban, Département de Pneumologie, CHU ANGERS, 4, rue Larrey, 49000, Angers, France. E-mail:

    Tobacco control is the major contributor to the decline in adult tobacco use as a result of reduced initiation and increased cessation, and to subsequent declines in smoking-related mortality, particularly for lung cancer in men. The smoking prevalence has reached a plateau at 20–30% in developed countries and is on the rise in developing nations. The World Health Organization Framework Convention on Tobacco Control has been developed in response to the globalisation of the tobacco epidemic.

    In lung cancer patients, smoking cessation and relapse prevention are opportunities to improve cancer survival rates, reduce the complications of treatment and improve quality of life. Data provide sufficient evidence to deliver advice to quit at diagnosis, particularly in the case of lung surgery. In advanced disease, both chemotherapy and radiation treatment are likely to produce fewer complications and less morbidity among nonsmokers than smokers. Supportive and cognitive behavioural therapies combined with pharmacological treatments are needed to provide the best chance to quit smoking.

  7. Page 38
    Juan P. de-Torres, Pulmonary Dept, Clínica Universidad de Navarra, Pamplona, 31200, Spain. E-mail:

    Epidemiological and case–control studies have shown that COPD is an independent risk factor for lung cancer. The presence of airway obstruction and/or emphysema increases the risk of having lung cancer by two to three fold. Recent research has highlighted several potential common pathways that may explain this deadly association. These include chronic retention of airborne carcinogens, the presence of chronic inflammation, and common genetic and epigenetic risk factors.

    Smoking prevention and smoking cessation are the most important measures for primary prevention of both COPD and lung cancer. Recent data suggest that lung cancer screening in patients with COPD, especially those with mild-to-moderate disease, could potentially decrease lung cancer mortality, one of the most common causes of death.

    The association between COPD and lung cancer means that the clinical management of these patients requires a multidisciplinary team that includes a respiratory medicine physician. The pulmonologist's role ranges from determining preoperative risk to handling the consequences of oncologic treatments, such as COPD exacerbations.

  8. Page 50
    Carlos Robalo Cordeiro, Centre of Pneumology, Coimbra University Hospital, 3000 Coimbra, Portugal. E-mail:

    Idiopathic pulmonary fibrosis seems to be increasingly likely as an independent risk factor for lung cancer, although its precise frequency is uncertain. Studies focussing on the cellular and molecular pathways have shown that the main findings concern changes in cell proliferation, genetics, oncogenic pathways, cell communication and tissue invasion. Cigarette smoking is the most significant risk factor. In this subset of patients, there seems to be a predominance of SCC, although tumours tend to be peripheral. Prognosis is poor and treatment is challenging if we are to assure that patients receive the best treatment for each condition.

  9. Page 64
    Keith M. Kerr, Dept of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZD, UK. E-mail:

    Contemporary management of patients with lung cancer requires a comprehensive diagnosis embracing anatomical, morphological and molecular features of the tumours. Accurate, consistent histological diagnosis also provides invaluable epidemiological information and contributes to our understanding of the pathogenesis of the disease. The World Health Organization (WHO) histological classification is fundamental, combined with TNM staging, to proper diagnosis of surgically resected cases and has recently been revised. Most patients, however, have only small biopsy or cytology specimens for diagnosis, where the WHO classification cannot be applied in full, and where IHC has become a key factor in refining the likely diagnosis. The increasing diversity of treatments offered to patients with all types of lung cancer and the recognition of therapeutically important biological differences between tumour subtypes has placed accurate pathological diagnosis in the spotlight. Subtyping of NSCLC and appropriate pathological assessment are required to follow current guidelines for the triage of cases for molecular pathology testing.

  10. Page 79
    Kwun M. Fong, Dept of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, Brisbane 4032, Australia. E-mail:

    Lung cancer research has been positively informed by genetic and now genomic technologies and discoveries. In the last few years, we have seen the emergence of cancer genomic data in the public arena; information that is challenging long-held theories of cancer mutational biology and changing how clinicians are thinking about a future with genomics-based lung cancer care. Lung cancer mutation catalogues will continue to expand, giving rise to an appreciation of tumour biology beyond the classic clinical–pathological standpoint. This will lead to new considerations, including how best to exploit this data for diagnostics and therapeutics. Research is needed to characterise the vast and complex cancer mutations, distinguish drivers from passengers, and validate and functionally characterise cancer genomes in order to generate information that can meaningfully alter clinical management in a cost-effective manner. International research collaborations represent an encouraging model for engaging, sharing insights and learning how to best use and contribute to clinical applications of cancer genomics.

  11. Page 95
    Florian Laenger, Institute of Pathology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail:

    The discovery of druggable molecular targets in NSCLC has led to a shift from the former “one size fits all” chemotherapy approach to treatment selection based on tumour biology. Recent work has demonstrated that most known driving mutations are homogeneously distributed in NSCLCs, allowing meaningful molecular analysis and therapy based on small tissue samples. Although currently, a mix of methods is necessary to analyse NSCLCs, NGS techniques will allow the simultaneous analysis of most relevant mutations and translocations in NSCLCs in the near future. At the moment, approved drugs are available for patients with tumours revealing EGFR mutations and ALK translocations, although there are ongoing clinical trials for many more targets and patients showing secondary resistance mechanisms. Thus, comprehensive profiling of all NSCLCs before and during treatment will become the standard of care for NSCLC patients.

  12. Page 119
    Ernst Jan M. Speel, Dept of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail:

    Current state-of-the-art diagnosis of lung cancer involves an increasing number of morphological and molecular analyses on tissue, on which a multidisciplinary team of physicians base a treatment strategy. However, most lung cancer patients present with advanced disease, which may hamper sampling of sufficient tissue material for diagnosis due to fragile health and/or tumour location. Furthermore, the interval between patients seeing a specialist and the start of treatment should be limited as this may influence the prognosis.

    In this chapter, we review the current practice in lung cancer diagnosis, including sampling, transportation and processing of tissue, as well as morphological, immunohistochemical and molecular analysis on resection, biopsy and cytological material. We particularly focus on factors that may affect adequate tissue quality and diagnosis (i.e. collection of representative tumour tissue and variables in the downstream workflow), as well as factors influencing the outcome of molecular analyses. Finally, recommendations are provided to optimise adequate tissue diagnosis and, as a consequence, clinical diagnosis and treatment.

  13. Page 136
    Pascal A. Thomas, Dept of Thoracic Surgery, Aix-Marseille University, North Hospital, Chemin des Bourrely, 13915 Marseille, France. E-mail:

    Lobectomy with lymphadenectomy is the standard of care for patients with early stage NSCLC and the use of minimally invasive approaches are associated with reduced morbidity when compared with thoracotomy. Segmentectomy with lymphadenectomy seems to provide a curative effect equivalent to that of lobectomy for stage IA tumours of ≤2 cm and for pure or predominant ground glass opacities. The combination of lung sparing resections with minimally invasive approaches results in preserved pulmonary function, improved quality of life and very low morbidity. This benefit persists in so-called high-risk patients. Among patients with clinical stage IA managed with sublobar resections, more than 25% are proved to have a more advanced pathologic stage at surgery, suggesting that alternative ablative therapies would result in an incomplete resection in a similar proportion. Moreover, resection samples tumour tissue that is adequate in quantity and quality, and provides material for “research biopsies” to consolidate tissue availability for clinical trials, translational research, and in biobanks.

  14. Page 148
    Esther G.C. Troost, Helmholtz-Zentrum Dresden-Rossendorf, OncoRay – National Center for Radiation Research in Oncology, University Hospital and Medical Faculty Carl Gustav Carus of Technische Universität Dresden, Department of Radiation Oncology, Fetscherstraße 74, 01307 Dresden, Germany. E-mail:

    Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiotherapy (SABR) are increasingly being delivered to medically inoperable patients with peripheral stage I NSCLC or to patients refusing surgery. The outcome and toxicity profiles of SBRT and SABR are favourable when compared to surgery. Even though retrospective reports of SABR/SBRT for central tumours report comparably safe and effective results, prospective clinical studies should be performed in order to gain solid evidence. Imaging during follow-up of operable patients and resectable tumours should primarily consist of CT, with the addition of PET when recurrence is suspected. With the lack of direct comparison of SABR/SBRT versus surgery in randomised, prospective clinical trials, patients should be offered shared-decision making.

  15. Page 159
    Christophe Dooms, Dept of Respiratory Diseases, University Hospitals KU Leuven, Leuven, Belgium. E-mail:

    In the absence of distant metastasis, accurate mediastinal nodal staging is the most important prognostic factor for lung cancer. Contrast enhanced CT is an imperfect means of staging the mediastinum, but it provides information on lymph node size and anatomical borders of the nodal stations. An integrated PET-CT, guides clinicians in the next step, i.e. either tissue verification of mediastinal nodes or direct to surgery.

    Linear endosonography has become the preferred invasive procedure to perform mediastinal nodal staging of lung cancer. A combined EBUS and oesophageal EUS approach enables systematic mediastinal nodal sampling of at least nodal stations 4R, 4L and 7.

    A low threshold for considering a confirmatory video-assisted mediastinoscopy (VAM) should be maintained after a negative combined endosonography. The role of VAM has been redefined: it lowers the post-test probability after a negative endosonography to approximately 5%, and allows bimanual nodal dissection of stations 2L and 4L, which are rarely dissected at the time of lung resection.

  16. Page 167
    Paul E. Van Schil, Dept of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail:

    Locally advanced NSCLC represents a heterogeneous group of different disease entities, ranging from initially resectable to potentially resectable after induction therapy, and finally to nonresectable tumours.

    In restaging after induction therapy, repeat mediastinoscopy provides pathological evidence of response after induction therapy but is less accurate than a first procedure. When N2 disease is discovered during thoracotomy after negative, careful preoperative staging, a resection should be performed if it is possible for it to be complete. In discrete N2 involvement, surgical resection may be recommended in patients with proven mediastinal downstaging after induction therapy who can preferentially be treated by lobectomy. Infiltrative, bulky N2 disease is mostly treated with combined chemoradiation. In stage IIIB NSCLC, surgical resection is only indicated in carefully selected cases. Complete resection remains the most important prognostic factor.

    Every patient with locally advanced lung cancer should be discussed within a multidisciplinary tumour board. As surgical resection might be challenging in these cases, treatment in an experienced centre is recommended.

  17. Page 178
    Dirk De Ruysscher, Dept of Radiation Oncology, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail:

    The backbone of treatment for locally advanced NSCLC should be chemotherapy in all suitable patients.

    In fit patients with resectable disease, concurrent chemotherapy and radiotherapy, intensive chemotherapy followed by resection, chemotherapy followed by intensive (i.e. accelerated) radiotherapy or concurrent chemoradiotherapy followed by resection are all viable options with none proven to be superior over the other. Across all trials, tri-modality therapy was shown to be the best way to achieve local tumour control; however, no randomised trial has been large enough to show a possible overall survival benefit. Bi-modality therapy thus remains the standard, except in situations where local tumour control is a prerequisite, e.g. in exemplary cases with Pancoast tumours.

    In nonresectable locally advanced NSCLC, concurrent chemoradiotherapy is the standard of care with doses of 60–66 Gy in 2 Gy fractions. In patients who are unsuitable for concurrent schedules, induction chemotherapy followed by accelerated radiotherapy is an alternative treatment with curative intent.

  18. Page 186
    Sanjay Popat, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK. E-mail:

    Chemotherapy continues to be the cornerstone of lung cancer therapeutics in patients without known actionable mutations, despite advances in molecular therapeutics. In NSCLC, a therapeutic plateau had been reached with platinum-doublet chemotherapy. However, the development of pemetrexed and its differential activity by histology has heralded a new era in lung cancer diagnostics such that NSCLC subtypes are now critical to decision-making. Nevertheless, several questions still remain, including the optimal treatment cycle number, to use cisplatin or carboplatin, the role of maintenance therapy, and optimal management of performance status 2 patients. For SCLC, chemotherapy has been the cornerstone of therapy for the last 30 years. A therapeutic plateau has been reached for first-line therapy where despite trials of newer schedules, doses, supportive care and drugs, platinum–etoposide remains a standard. Chemotherapy plays a minor but important role for relapsed SCLC and an important challenge is the identification of patients most likely to benefit from systemic therapy.

  19. Page 202
    Elisabeth Quoix, Service de Pneumologie, Hôpitaux Universitaires, 1 place de l'hôpital, 67091 Strasbourg cedex, France. E-mail:

    Lung cancer incidence increases with age, with a median age at diagnosis between 63 and 72 years depending on the country and the diagnostic procedures performed.

    The treatment of elderly patients, and especially systemic treatment, is of utmost importance. However, treating elderly patients has some caveats: geriatric syndromes, comorbidities and polypharmacy interfering with the metabolism of the drugs are frequent; and renal function may necessitate an adaptation of the doses. Finally, haematopoietic reserves are often reduced, needing more extensive use of granulocyte colony stimulating factors. Thus, there has been quite a long period of therapeutic nihilism regarding these patients, but studies dedicated to elderly patients have increased in number in the last 15 years, allowing for the development of recommendations regarding some clinical situations. For example, whereas there are no specific recommendations for peri-operative chemotherapy or locally advanced NSCLC, they do exist for metastatic-stage NSCLC and for first-line systemic treatment of SCLC.

  20. Page 215
    Silvia Novello, Dept of Oncology, University of Turin, San Luigi Gonzaga University Hospital, Regione Gonzole, 10, 10043 Orbassano, Italy. E-mail:

    Cytotoxic chemotherapy has historically been the cornerstone of advanced lung cancer treatment, but in recent years, new insights into the molecular pathways of this tumour have led to important therapeutic advances. The definition of different molecular profiles characterise some subpopulations that potentially will benefit from each target agent in terms of efficacy and quality of life. This landscape is evolving quickly as new oncogenic drivers are becoming the target for specific drugs. In this chapter, the state of the art will be presented together with perspectives on targeted therapies in lung cancer.

  21. Page 234
    Nevin Murray, Dept of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6. E-mail:

    The success of cancer genomics research in transforming the clinical care of patients with advanced ADC of the lung has been a powerful incentive to identify molecular abnormalities in SCLC that can be treated with targeted agents. A considerable number of drugs have already been tried in SCLC clinical trials without notable success. Efforts to identify molecular targets for SCLC have been impeded by a paucity of adequate tissue for translational research in a disease in which resections are uncommon. Molecular abnormalities are extremely complex in this tobacco hyper-mutated tumour. Additionally, the circumstances for clinical research are difficult where patients with recurrent disease are frequently in rapid decline during the window of opportunity for biopsies, genomic studies, identification of a suitable target, and administration of novel agents. Despite these challenges, interesting work is moving forward with newly identified molecular targets emerging from comprehensive genomic profiling efforts. There is also the intriguing possibility that a high antigenic load from many mutations may be an asset for immunotherapy studies.

  22. Page 247
    Niels Reinmuth, Dept of Thoracic Oncology, LungenClinic Großhansdorf, Wöhrendamm 80, 22927 Großhansdorf, Germany. E-mail:

    Immune evasion is recognised as a key strategy for cancer survival and progression. Hence, various approaches to restore anti-tumour immune responses are currently being investigated. In particular, early clinical trials have shown that agents targeting immune checkpoints, such as the CTLA4 receptor and the programmed cell death protein 1 receptor, have the potential to improve tumour responses and survival in lung cancer patients. With multiple studies under way, there are high expectations that treatment outcomes in patients with lung cancer who are ineligible for surgical resection may be improved by the incorporation of immunotherapies in the various treatment cascades.

  23. Page 261
    Julien Mazières, Thoracic Oncology Unit, Respiratory Disease Dept, Hôpital Larrey, CHU Toulouse, Chemin de Pouvourville, 31059 Toulouse Cedex, France. E-mail:

    Even if the prognosis for lung cancer remains poor, we have entered a new and hopeful era for its management. Within the last decade, rapid advances in molecular biology, pathology, bronchology and radiology have provided a rational basis for improving outcomes. The role of physicians is thus changing accordingly and all pulmonologists should be involved in every step of disease management, starting from the identification of high-risk populations, to palliative care and advanced cancer. Herein, we will address the main changes expected in the field of lung cancer treatments over the next 5 years and will focus on the future role of pulmonologists within this new era.