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Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

2016; Elsevier BV; Volume: 27; Linguagem: Inglês

10.1093/annonc/mdw326

1569-8041

Silvia Novello, Fabrice Barlési, Raffaele Califano, Tanja Čufer, Simon Ekman, Matteo Giaj Levra, Keith M. Kerr, Sanjay Popat, Martin Reck, Suresh Senan, Gonzálo Varela, Johan Vansteenkiste, Solange Peters,

Lung Cancer Research Studies

Primary lung cancer remains the most common malignancy after non-melanocytic skin cancer, and deaths from lung cancer exceed those from any other malignancy worldwide [1.Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Google Scholar]. In 2012, lung cancer was the most frequently diagnosed cancer and the leading cause of cancer death in male populations. Among females, lung cancer was the leading cause of cancer death in more developed countries, and the second leading cause of cancer death in less developed countries [2.Torre L.A. Bray F. Siegel R.L. et al.Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Google Scholar]. In 2013 in the European Union, lung cancer mortality fell in men by 6% compared with 2009, while cancer death rates increased in women by 7%, thereby approaching male counterparts [3.Malvezzi M. Bertuccio P. Rosso T. et al.European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women?.Ann Oncol. 2015; 26: 779-786Google Scholar]. A significantly higher proportion of lung cancer is diagnosed in patients aged 65 and over [4.GLOBOCAN. 2012 Cancer incidence, mortality and prevalenceworldwide [database online]. http://www-dep.iarc.fr/ (11 January 2016, date last accessed).Google Scholar], and the median age at diagnosis is around 70 years [5.Howlader N.N.A. Krapcho M. et al.SEER Cancer Statistics Review, 1975–2010. National Cancer Institute, Bethesda, MD2013http://seer.cancer.gov/Google Scholar]. Data from 2012 revealed that in the USA, lung cancer did represent the leading cause of cancer death in males from the age of 40 years and in females from the age of 60 years [6.Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2016.CA Cancer J Clin. 2016; 66: 7-30Google Scholar]. A subset of patients with non-small-cell lung cancers (NSCLCs) presents at a younger age ( 60 years who do not smoke compared with men. This could justify the different incidence, which may not be due to a real difference among genders specifically. Pathological diagnosis of all sample types should be made according to the 2015 WHO classification. The classification discusses the approach to surgically resected tumours, but also has recommendations for small biopsy and cytology diagnosis, which are the only samples available for most patients. Therapeutic decisions for NSCLC patients are dependent upon specific tumour histological subtype, and this should be given whenever possible. Immunohistochemistry (IHC) should be used to increase the specificity of diagnosis in the small sample setting and reduce the NSCLC-NOS (not otherwise specified) rate to fewer than 10% of cases diagnosed [IV, A] [18.Travis W.D. Brambilla E. Burke A.P. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th edition. IARC Press, Lyon, France2015Google Scholar]. Minimal IHC should be used. Two markers only, p40 or p63 to predict squamous cell carcinoma and TTF1 to predict adenocarcinoma, are generally all that is required [18.Travis W.D. Brambilla E. Burke A.P. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th edition. IARC Press, Lyon, France2015Google Scholar]. Excessive, unnecessary IHC will consume tumour tissue and may prevent subsequent molecular analysis. Obtaining adequate tissue material for histological diagnosis and molecular testing is important, to allow for individual treatment decisions. Tumour rebiopsy at disease progression should be considered and is recommended in the subgroups where it might guide subsequent treatment [IV, A]. An example is the use of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against T790M-mutated resistant tumours, the most common finding in EGFR-mutated tumours relapsing after first-/second-generation EGFR TKI therapy [19.Sequist L.V. Waltman B.A. Dias-Santagata D. et al.Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011; 3: 75ra26Google Scholar]. Pathologists should take steps to ensure that tissue handling and processing prioritises all testing required for treatment selection. Genetic alterations, which are key oncogenic events (driver mutations), have been identified in NSCLC, with two of these—EGFR mutations and the anaplastic lymphoma kinase (ALK) rearrangements—determining approved, selective pathway-directed systemic therapy. A personalised medicine synopsis table is shown in Table 1.Table 1A personalised medicine synopsis table for metastatic NSCLC [20.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Google Scholar]BiomarkerMethodUseLOE, GOREGFR mutationAny appropriate validated method, subject to external quality assuranceUsed to select patients for EGFR TKI therapy, identifying those, with sensitising mutations, most likely to respondV, AALK gene rearrangementAny appropriate validated method, subject to external quality assurance. Standard approach has been FISH, or less often, multiplex PCR or RT-PCR. Certain IHC approaches may be used as a substitute primary test. IHC may also be used to screen patients, positive cases confirmed by an orthogonal method (FISH, PCR)Used to select patients for ALK tyrosine kinase inhibitor therapy, identifying those, with a positive test, most likely to respondV, AAdapted from [20.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Google Scholar] by permission of Oxford University Press.NSCLC, non-small-cell lung cancer; LOE, level of evidence; GOR, grade of recommendation; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridisation; PCR, polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; IHC, immunohistochemistry. Open table in a new tab Adapted from [20.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Google Scholar] by permission of Oxford University Press. NSCLC, non-small-cell lung cancer; LOE, level of evidence; GOR, grade of recommendation; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridisation; PCR, polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; IHC, immunohistochemistry. Activating (sensitising) EGFR mutations are predictive for response to the EGFR TKIs gefitinib, erlotinib and afatinib. Such treatments result in improved response rate (RR) and progression-free survival (PFS), better tolerability and superior quality of life (QoL) compared with platinum-based chemotherapy in the first-line setting, as demonstrated in several randomised trials [21.Lee J.K. Hahn S. Kim D.W. et al.Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis.JAMA. 2014; 311: 1430-1437Google Scholar]. EGFR mutations are found in ∼10%–12% of Caucasians with adenocarcinoma and are more frequent in never smokers, females and in patients of East Asian ethnicity. EGFR mutation testing is recommended in all patients with advanced non-squamous cell carcinoma (NSCC) [I, A] [20.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Google Scholar]. Molecular EGRF testing is not recommended in patients with an unequivocal diagnosis of SCC, except in never/former light smokers ( 2 cm but 3 cm or less in greatest dimension T2Tumour >3 cm but 7 cm or less or tumour with any of the following features (T2 tumours with these features are classified T2a if 5 cm or less); involves main bronchus, 2 cm or more distal to the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2aTumour >3 cm but 5 cm or less in greatest dimension T2bTumour >5 cm but 7 cm or less in greatest dimension T3Tumour >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium or tumour in the main bronchus (<2 cm distal to the carinaa but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe) T4Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, separate tumour nodule(s) in a different ipsilateral lobeRegional lymph nodes (N) NXRegional lymph nodes cannot be assessed N0No regional lymph node metastases N1Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)Distant metastasis (M) M0No distant metastasis M1Distant metastasis M1aSeparate tumour nodule(s) in a contralateral tumour with pleural nodules or malignant pleural (or pericardial) effusionb M1bDistant metastasisAJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; TNM, tumour-node-metastasis. Used with the permission of the AJCC, Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com [183.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook. 7th edition. Springer, New York, NY2010Google Scholar].aThe uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.bMost pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is non-bloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging element and the patient should be classified as M0. Open table in a new tab Table 3Anatomic stage/prognostic groups according to the AJCC/ UICC TNM staging systemAnatomic stage/prognostic groups Occult carcinomaTXN0M0 Stage 0TisN0M0 Stage IAT1a,bN0M0 Stage IBT2aN0M0 Stage IIAT2bN0M0T1a,bN1M0T2aN1M0 Stage IIBT2bN1M0T3N0M0 Stage IIIAT1a,b, T2a,bN2M0T3N1, N2M0T4N0, N1M0 Stage IIIBT4N2M0Any TN3M0 Stage IVAny TAny NM1AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; TNM, tumour-node-metastasis. Used with the permission of the AJCC, Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com [183.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook. 7th edition. Springer, New York, NY2010Google Scholar]. Open table in a new tab AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; TNM, tumour-node-metastasis. Used with the permission of the AJCC, Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com [183.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook. 7th edition. Springer, New York, NY2010Google Scholar]. aThe uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a. bMost pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is non-bloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging element and the patient should be classified as M0. AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; TNM, tumour-node-metastasis. Used with the permission of the AJCC, Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com [183.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook. 7th edition. Springer, New York, NY2010Google Scholar]. In the presence of a solitary metastatic lesion on imaging studies, including pleural and pericardial effusion, efforts should be made to obtain a cytological or histological confirmation of stage IV disease. A proposal for an eighth staging edition has been made by the International Association for the Study of Lung Cancer (IASLC) and will be submitted to the UICC and the AJCC for inclusion in the new TNM classification for lung cancer, which is due to be published in late 2016 and enacted in January 2017 [37.Goldstraw P. Chansky K. Crowley J. et al.The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.J Thorac Oncol. 2016; 11: 39-51Google Scholar]. The treatment strategy (Figure 1, Figure 2, Figure 3, Figure 4) should take into account factors like histology, molecular pathology, age, PS, co-morbidities and the patient's preferences. Treatment decisions should ideally be discussed within a multidisciplinary tumour board, who can evaluate and change management plans including recommending additional investigations and changes in treatment modality [38.Ung K.A. Campbell B.A. Duplan D. et al.Impact of the lung oncology multidisciplinary team meetings on the management of patients with cancer.Asia Pac J Clin Oncol. 2016; 12: e298-e304Google Scholar]. Systemic therapy should be offered to all stage IV patients with PS 0-2 [I, A].Figure 2Treatment algorithm for stage IV NSCC. NSCC, non-squamous cell carcinoma; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; PS, performance status; BSC, best supportive care; M