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

Abstract

incidence and epidemiologyPrimary lung cancer is the most common malignancy after non-melanocytic skin cancer, and the leading cause of human cancer deaths worldwide [1.Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (30017) Google Scholar]. While it has been the most important cause of cancer mortality in men since the 1960s, it has equaled breast cancer as a cause of mortality in women since the 1990s. Lung cancer is still increasing both in prevalence and mortality worldwide. In developed countries, the latter has begun to decline in men, reflecting a decrease in smoking, and is reaching a plateau for women in most European countries and in the United States—where lung cancer death rates in women are approaching those of men. Lung cancer deaths in women are expected to increase (+7%) in the EU in 2012 [2.Malvezzi M. Bertuccio P. Levi F. et al.European cancer mortality predictions for the year 2012.Ann Oncol. 2012; 23: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar].Non-small-cell lung cancer (NSCLC) accounts for 80–85% of lung cancers, while small-cell lung cancer has been decreasing in frequency over the last two decades.Smoking is the main cause of lung cancer, responsible for 80% of cases. The observed variations in lung cancer rates across countries largely reflect differences in the stage and degree of the tobacco epidemic, with reported crude incidence rates between 2/100 000–80/100 000 and 1/100 000–39/100 000 for men and women, respectively. There are several other known risk factors including exposure to asbestos, arsenic, radon, and non-tobacco-related polycyclic aromatic hydrocarbons, and interesting hypotheses about indoor air pollution (e.g. coal-fueled stoves and cooking fumes) suspected to contribute to the relatively high burden of non-smoking-related lung cancer in women.Prevalence of lung cancer in females without a history of tobacco smoking is estimated to represent 19% compared with 9% of male lung carcinoma in the United States [3.Wakelee H.A. Chang E.T. Gomez S.L. et al.Lung cancer incidence in never smokers.J Clin Oncol. 2007; 25: 472-478Crossref PubMed Scopus (415) Google Scholar]. Women are overrepresented among younger patients, raising the question of gender-specific differences in the susceptibility to lung carcinogens [4.Edwards B.K. Brown M.L. Wingo P.A. et al.Annual report to the nation on the status of cancer 1975–2002, featuring population-based trends in cancer treatment.J Natl Cancer Inst. 2005; 97: 1407-1427Crossref PubMed Scopus (834) Google Scholar]. In recent times, an increase in the proportion of NSCLC patients who are never smokers has been observed, particularly in Asian countries [5.Toh C.K. Gao F. Lim W.T. et al.Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.J Clin Oncol. 2006; 24: 2245-2251Crossref PubMed Scopus (296) Google Scholar]. These new epidemiological data have resulted in ‘non-smoking-associated lung cancer’ being considered a distinct disease entity, where specific molecular and genetic tumor characteristics are being recognized.diagnosisPathological diagnosis should generally be made according to the World Health Organization (WHO) classification. The International Association for the Study of Lung Cancer (IASLC) classification of adenocarcinoma, however, provides new recommendations and also addresses important issues not covered by the WHO classification concerning small biopsy samples and cytology. Adoption of these recommendations is strongly advised [6.Travis W.D. Brambilla E. Noguchi M. et al.International Association for the Study of Lung Cancer/American Thoracic Society. European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3496) Google Scholar]. Specific subtyping of all NSCLC is now necessary for therapeutic decision- making and should be carried out wherever possible. Predictive immunohistochemistry should be used to reduce the NSCLC not otherwise specified (NSCLC-NOS) rate to fewer than 10% of cases diagnosed [6.Travis W.D. Brambilla E. Noguchi M. et al.International Association for the Study of Lung Cancer/American Thoracic Society. European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3496) Google Scholar]. Obtaining adequate tissue material for histological diagnosis and molecular testing is important to allow individual treatment decisions. Re-biopsy at disease progression should be considered [7.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: 75ra26Crossref PubMed Scopus (2648) Google Scholar].Genetic alterations that are key oncogenic events have been identified in NSCLC, with two of these to date offering the chance of selective pathway-directed systemic therapy.Activating (sensitizing) epidermal growth factor receptor (EGFR) mutations are predictive for response to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib and result, in this context, in an improved response rate (RR) and progression-free survival (PFS) in combination with better tolerability of treatment and a better quality of life (QoL) when compared with chemotherapy as first-line therapy, as demonstrated in several randomized trials. The incidence of EGFR mutations in the Caucasian population is ∼10% and is higher in never-smokers, the adenocarcinoma subtype, and in women and is also higher in East-Asian patients. An EGFR mutation status should be systematically analyzed—with sequencing as a standard—in advanced NSCLC with a non-squamous histology [II, A]. Testing is not recommended in patients with a confident diagnosis of squamous cell carcinoma, except in never/former light smokers (<15 packs per year) [II, A] [8.Rekhtman N. Paik P.K. Arcila M.E. et al.Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations.Clin Cancer Res. 2012; 18: 1167-1176Crossref PubMed Scopus (311) Google Scholar].The EML4-ALK fusion gene, resulting from an inversion in chromosome 2, has been identified as an oncogenic driver [9.Kwak E.L. Bang Y.J. Camidge D.R. et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3777) Google Scholar]. It is encountered more frequently in never-smokers, the adenocarcinoma subtype and in younger patients, representing probably ∼5% of adenocarcinoma [10.Shaw A.T. Yeap B.Y. Mino-Kenudson M. et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1615) Google Scholar]. ALK activity can be efficiently targeted by the TKI crizotinib, and routine testing for ALK rearrangements should be discussed where this drug is available. Testing may focus upon a non-squamous histology and never/former light smokers particularly in the absence of an activating (sensitizing) EGFR mutation or a KRAS mutation [II, A]. However, testing protocols may include smokers and be carried out in parallel with EGFR/KRAS mutation analysis.Currently, the detection of the translocation by fluorescence in situ hybridization (FISH) is standard, but immunohistochemistry may have a role in screening out negative cases [11.Yi E.S. Chung J.H. Kulig K. Kerr K.M. Detection of Anaplastic Lymphoma Kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review.Mol Diagn Ther. 2012; 16: 143-150Crossref PubMed Google Scholar].staging and risk assessmentA complete history including smoking history and comorbidities, weight loss, performance status (PS), and physical examination must be recorded.Laboratory: Standard tests including routine hematology, renal and hepatic function, and bone biochemistry tests are required. The routine use of serum markers—such as carcinoembryonic antigen (CEA)—is not recommended.radiology•Contrast-enhanced computed tomography (CT) scan of the chest and upper abdomen.•Imaging of the central nervous system (CNS) is reserved for patients with neurological symptoms or signs.•Brain imaging should be performed in patients eligible for a loco-regional treatment. Magnetic resonance imaging (MRI) is more sensitive than CT scan.•Bone scan or local bone imaging (including MRI) is required in the presence of clinical suspicion of bony lesions not evaluable on CT scan.•Positron emission tomography (PET) CT scan offers the highest sensitivity for mediastinal lymph nodes and distant metastasis assessment.NSCLC is staged according to the Union for International Cancer Control (UICC) system (7th edition) and is grouped into the stage categories shown in Tables 1 and 2. Measurement of lesions should follow RECIST criteria v1.1 [12.Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (17464) Google Scholar].Table 1Tumor–node–metastasis classificationTXPositive cytology onlyT1≤3 cmT1a≤2 cmT1b>2–3 cmT2Main bronchus ≥2 cm from carina invades visceral pleura, partial atelectasisT2a>3–5 cmT2b>5–7 cmT3>7 cm; chest wall, diaphragm, pericardium, mediastinal pleura, main bronchus <2 cm from carina, total atelectasis, separate nodule(s) in the same lobeT4Mediastinum, heart, great vessels, carina, trachea, esophagus, vertebra; separate tumor nodule(s) in a different ipsilateral lobeN1Ipsilateral peribronchial, ipsilateral hilarN2Subcarinal, ipsilateral mediastinalN3Contralateral mediastinal or hilar, scalene, or supraclavicularM1Distant metastasisM1aSeparate tumor nodule(s) in a contralateral lobe; pleural nodules or malignant pleural, or pericardial effusionM1bDistant metastasis Open table in a new tab Table 2Stage groupingOccult carcinomaTXN0M0Stage 0TisN0M0Stage IAT1a,bN0M0Stage IBT2aN0M0Stage IIAT2bN0M0T1a,bN1M0T2aN1M0Stage IIBT2bN1M0T3N0M0Stage IIIAT1a,b, T2a,bN2M0T3N1, N2M0T4N0, N1M0Stage IIIBT4N2M0Any TN3M0Stage IVAny TAny NM1 Open table in a new tab In the presence of a solitary metastatic site on imaging studies, including pleural and pericardial effusion, efforts should be made to obtain a cytological or histological confirmation of stage IV disease. An evaluation of resectability or the suitability of radiotherapy with curative intent should be made in the context of a solitary brain or adrenal lesion or oligometastatic disease confined to the lungs. This would include functional cardio-respiratory evaluation, brain imaging, PET and, if needed for decision-making, invasive mediastinal node evaluation.treatment of stage IV NSCLCThe treatment strategy should take into account the histology, molecular pathology, age, PS, comorbidities, and patient's preferences. Treatment decisions should ideally be discussed within a multidisciplinary tumor board. Systemic therapy should be offered to all stage IV NSCLC patients with a PS 0–2 [I, A].In any stage of NSCLC, smoking cessation should be highly encouraged because it improves the outcome.first-line treatmentPlatinum-based combination chemotherapy prolongs survival, improves QoL, and controls symptoms in patients with a PS 0–1.Several regimens have shown comparable efficacy [13.Schiller J.H. Harrington D. Belani C.P. et al.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002; 346: 92-98Crossref PubMed Scopus (4773) Google Scholar]. The expected toxicity profile should contribute to the selection of the chemotherapy regimen, taking into account the following conditions:•Several meta-analyses have showed higher RRs for cisplatin combinations when compared with carboplatin combinations. The overall survival (OS) was significantly superior for cisplatin in the subgroup of non-squamous tumors and in patients treated with third-generation regimens, including gemcitabine and taxanes in one meta-analysis [I, B] [14.Ardizzoni A. Boni L. Tiseo M. et al.Cisplatin-versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.J Natl Cancer Inst. 2007; 99: 847-857Crossref PubMed Scopus (550) Google Scholar]. Cisplatin-based chemotherapy is associated with more digestive, and neuro- and nephrotoxicity; while hematotoxicity is more often observed with carboplatin.•Pemetrexed is preferred to gemcitabine in patients with non-squamous tumors, based upon a survival benefit demonstrated in a pre-planned subgroup analysis of one large randomized clinical trial [II, B] [15.Scagliotti G.V. Parikh P. von Pawel J. et al.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol. 2008; 26: 3543-3551Crossref PubMed Scopus (2863) Google Scholar]. Pemetrexed use should be restricted to non-squamous NSCLC in any line of treatment [16.Ciuleanu T. Brodowicz T. Zielinski C. et al.Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.Lancet. 2009; 374: 1432-1440Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar, 17.Scagliotti G. Hanna N. Fossella F. et al.The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies.Oncologist. 2009; 14: 253-263Crossref PubMed Scopus (641) Google Scholar].•According to a randomized clinical trial, bevacizumab improves OS when combined with a paclitaxel–carboplatin regimen in patients with non-squamous histology NSCLC and PS 0–1 and may be offered after the exclusion of contraindications [I, A] [18.Sandler A. Gray R. Perry M.C. et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006; 355: 2542-2550Crossref PubMed Scopus (5199) Google Scholar]. While its addition to gemcitabine–cisplatin improved the RR and PFS, but not the OS in a subsequent phase III trial [19.Reck M. von Pawel J. Zatloukal P. et al.Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.J Clin Oncol. 2009; 27: 1227-1234Crossref PubMed Scopus (1385) Google Scholar], two meta-analyses showed a consistent substantial improvement of the RR, PFS, and OS for the combination of bevacizumab- and platinum-based chemotherapy compared with platinum-based chemotherapy in eligible patients with non-squamous NSCLC [20.Lima A.B. Macedo L.T. Sasse A.D. Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis.PLoS One. 2011; 6: e22681Crossref PubMed Scopus (84) Google Scholar, 21.Soria J.M.A. Reck M. Sandler A. et al.Meta-analysis of randomized phase II/III trials adding bevacizumab to platin-based chemotherapy as 1st-line treatment in patients with advanced non-small cell lung cancer (NSCLC).Ann Oncol. 2010; 21: viii147Google Scholar]. Therefore, the combination of bevacizumab and other platinum-based chemotherapies may be considered in eligible patients [I, A].•A randomized phase III trial demonstrated an OS benefit of cetuximab when delivered with vinorelbine–cisplatin in EGFR-expressing NSCLC patients with PS 0–2, independently of histology; however, this did not lead to regulatory approval [I, B] [22.Pirker R. Pereira J.R. Szczesna A. et al.Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet. 2009; 373: 1525-1531Abstract Full Text Full Text PDF PubMed Scopus (1250) Google Scholar]. A subset analysis reported that quantitative evaluation of EGFR expression by immunohistochemistry (H-score) identified a subgroup of patients with high EGFR expressing tumors who selectively benefited from the addition of cetuximab to chemotherapy [23.Pirker R. Pereira J.R. Von Pawel J. et al.EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study.Lancet Oncol. 2012; 13: 33-42Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. Prospective H-score data are, however, lacking.•Non-platinum-based combination chemotherapy with third-generation agents should be considered only if platinum therapy is contraindicated. Several meta-analyses show lower RRs for non-platinum combinations, with one of them showing inferior survival [24.Pujol J.L. Barlesi F. Daures J.P. Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials.Lung Cancer. 2006; 51: 335-345Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar] [I, A].Timing and duration of palliative first-line treatment: Chemotherapy should be initiated, while the patient has a good PS. For most patients, four cycles of chemotherapy are recommended, notably when maintenance treatment is considered, with a maximum of six cycles [25.Park J.O. Kim S.W. Ahn J.S. et al.Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.J Clin Oncol. 2007; 25: 5233-5239Crossref PubMed Scopus (176) Google Scholar] [II, B].PS ≥2 patientsChemotherapy prolongs survival and possibly improves QoL [26.Gridelli C. Ardizzoni A. Le Chevalier T. et al.Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel.Ann Oncol. 2004; 15: 419-426Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar] in NSCLC patients with a PS of 2, when compared with best supportive care (BSC) [I, B]. Single-agent chemotherapy with gemcitabine, vinorelbine, and taxanes represents an option [27.Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancerThe elderly lung cancer vinorelbine Italian Study Group.J Natl Cancer Inst. 1999; 91: 66-72PubMed Google Scholar]. Superiority of carboplatin and paclitaxel combination over monotherapy has been identified in a subgroup analysis within large phase III trials, with an acceptable toxicity profile [28.Lilenbaum R. Villaflor V.M. Langer C. et al.Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials.J Thorac Oncol. 2009; 4: 869-874Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 29.Quoix E. Zalcman G. Oster J.P. et al.Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.Lancet. 2011; 378: 1079-1088Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar]. A prospective phase III trial randomizing 217 patients between single-agent pemetrexed versus carboplatin and pemetrexed was presented at ASCO 2012, showing a strong benefit in OS for the platinum doublet [30.Lilenbaum R. Mauro M. Pereira J.R. et al.A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2.J Clin Oncol 30. 2012; 30 (abstr 7506)Google Scholar]. Therefore, platinum-based combinations may also be considered as an alternative [II, B].Poor PS (PS 3–4) patients should be offered BSC [II, B] in the absence of tumors with activating (sensitizing) EGFR mutations.elderly patientsTwo randomized phase III trials established single-agent chemotherapy as the standard of care for first-line therapy for clinically unselected elderly advanced NSCLC patients [27.Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancerThe elderly lung cancer vinorelbine Italian Study Group.J Natl Cancer Inst. 1999; 91: 66-72PubMed Google Scholar, 31.Gridelli C. Perrone F. Gallo C. et al.Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.J Natl Cancer Inst. 2003; 95: 362-372Crossref PubMed Scopus (772) Google Scholar]. A recent prospective randomized trial comparing monthly carboplatin plus weekly paclitaxel versus single-agent vinorelbine or gemcitabine in patients aged 70–89 years with a PS of 0–2 has reported a survival advantage for combination therapy [29.Quoix E. Zalcman G. Oster J.P. et al.Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.Lancet. 2011; 378: 1079-1088Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar].Benefit was observed across all subgroups, but increased toxicity (notably febrile neutropenia and sepsis-related deaths) was observed. Platinum-based chemotherapy is the preferred option for elderly patients with PS 0–1—as well as selected PS2—and adequate organ function, while a single-agent approach might remain the recommended treatment of elderly unfit or comorbid patients, who are more likely to present with more treatment-related adverse events [I, B].use of TKIsFirst-line treatment with a TKI (erlotinib or gefitinib) should be prescribed to patients with tumors bearing an activating (sensitizing) EGFR mutation because of significantly higher RR, longer PFS, and better QoL when compared with first-line chemotherapy [32.Mok T.S. Wu Y.L. Thongprasert S. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (6950) Google Scholar, 33.Rosell R. Carcereny E. Gervais R. et al.Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2012; 13: 239-246Abstract Full Text Full Text PDF PubMed Scopus (4354) Google Scholar] [I, A]. Patients with PS 3–4 may also be offered an EGFR TKI [II, A]. Continuation treatment beyond progression is an issue remaining to be defined. In EGFR wild-type (WT) patients, EGFR TKIs are not recommended as first-line therapy, being inferior to chemotherapy [I, A].Patients with NSCLC harboring an ALK rearrangement should be considered for crizotinib, a dual ALK and MET TKI, during the course of their disease. Upfront comparisons with chemotherapy are not available to date and the optimal strategy of treatment is still to be determined [34.Shaw A.T. Yeap B.Y. Solomon B.J. et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar].brain metastasis treatmentThere are several approaches to the treatment of limited-number metastatic brain lesions, including surgery and radiosurgery, alone or in combination with whole-brain radiation therapy (WBRT). WBRT remains standard when local approaches are not possible. Brain responses to chemotherapy have been reported at a comparable level to extracranial disease. The OS was not modified by delaying WBRT after front-line cisplatin-based chemotherapy in a randomized phase III trial [35.Robinet G. Thomas P. Breton J.L. et al.Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95-1.Ann Oncol. 2001; 12: 59-67Abstract Full Text PDF PubMed Scopus (225) Google Scholar] [II, B]. In patients with EGFR-mutated NSCLC, the place of WBRT in addition to EGFR TKI, which was shown to result in a response also at the brain level in several reports, remains to be prospectively evaluated [36.Porta R. Sanchez-Torres J.M. Paz-Ares L. et al.Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.Eur Respir J. 2011; 37: 624-631Crossref PubMed Scopus (279) Google Scholar]. Systemic therapy is therefore a reasonable option for patients with no or relatively minor symptoms from brain metastases with early radiotherapy intervention in the case of the development or progression of symptoms while on treatment [II, B].maintenance treatmentSo-called ‘continuation maintenance’ and ‘switch maintenance’ therapy are terms that have been used to refer respectively to either the use of an agent included in first-line treatment or the introduction of a new agent after completion of platinum-based chemotherapy.Two recent randomized phase III switch maintenance trials have reported improvements in the PFS and OS with pemetrexed or erlotinib [16.Ciuleanu T. Brodowicz T. Zielinski C. et al.Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.Lancet. 2009; 374: 1432-1440Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar, 37.Cappuzzo F. Ciuleanu T. Stelmakh L. et al.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.Lancet Oncol. 2010; 11: 521-529Abstract Full Text Full Text PDF PubMed Scopus (1138) Google Scholar] versus placebo following four cycles of platinum-based chemotherapy. In the case of pemetrexed, this benefit was seen only in patients with a non-squamous histology. Subgroup analyses revealed the greatest benefit in efficacy in patients with stable disease (SD) after induction treatment compared with patients with a confirmed response. These results led to a label restriction for switch maintenance with erlotinib in patients with SD after induction treatment [16.Ciuleanu T. Brodowicz T. Zielinski C. et al.Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.Lancet. 2009; 374: 1432-1440Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar, 37.Cappuzzo F. Ciuleanu T. Stelmakh L. et al.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.Lancet Oncol. 2010; 11: 521-529Abstract Full Text Full Text PDF PubMed Scopus (1138) Google Scholar]. Neither trial addressed the question of the strategy of ‘early second-line’ versus similar second-line treatment at progression. Decisions about maintenance must take into account the histology, response to platinum-doublet chemotherapy, remaining toxicity after first-line chemotherapy, PS, and patient preference [I, B]. Any patient with a tumor bearing an activating (sensitizing) EGFR mutation should receive an EGFR TKI as maintenance, if not received as a first-line therapy [II, A].Randomized trials investigating continuation maintenance have consistently shown an improvement of the PFS but not the OS [38.Zhang X. Zang J. Xu J. et al.Maintenance therapy with continuous or switch strategy in advanced non-small cell lung cancer: a systematic review and meta-analysis.Chest. 2011; 140: 117-126Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Recently, a large phase III randomized trial of continuation maintenance with pemetrexed versus placebo after four induction cycles of cisplatin plus pemetrexed chemotherapy demonstrated a PFS and OS improvement [39.Paz-Ares L. De Marinis F. Dediu M. et al.PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).J Clin Oncol. 2012; 30 (abstr LBA7507)Google Scholar]. Continuing pemetrexed following the completion of first-line cisplatin plus pemetrexed chemotherapy is therefore recommended in patients with a non-squamous histology [40.Paz-Ares L. de Marinis F. Dediu M. et al.Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial.Lancet Oncol. 2012; 13: 247-255Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar] [I, B].Of note, two studies employing cetuximab and bevacizumab, administered concomitantly to chemotherapy and further continued as monotherapy until disease progression, have demonstrated survival benefits, but the specific role of the maintenance phase cannot be appreciated in this context [18.Sandler A. Gray R. Perry M.C. et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006; 355: 2542-2550Crossref PubMed Scopus (5199) Google Scholar, 22.Pirker R. Pereira J.R. Szczesna A. et al.Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised