Lung cancer staging: a true story
Authors: Klaus F Rabe
Journal: The Lancet Respiratory Medicine (2015)

In The Lancet Respiratory Medicine, Neal Navani and colleagues report data from a multicentre trial to assess the use of endobronchial ultrasound (EBUS) transbronchial aspiration (TBNA) for the staging of lung cancer.1Navani N Nankivell M Lawrence DR et al.on behalf of the Lung-BOOST trial investigatorsLung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial.Lancet Respir Med. 2015; (published online February 4.)http://dx.doi.org/10.1016/S2213-2600(15)00029-6Google Scholar In 2008, when recruitment for this trial started, 1·6 million new cases of lung cancer occurred worldwide, accounting for 13% of all cancers. During the same period, 1·4 million people died of the disease, representing 18% of all cancer deaths.2Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (30567) Google Scholar Most lung cancers (about 80%) are non-small-cell lung cancers (NSCLC),3Devesa SS Bray F Vizcaino AP Parkin DM International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising.Int J Cancer. 2005; 117: 294-299Crossref PubMed Scopus (625) Google Scholar for which surgery is a curative option. However, more than 65% of patients present with locally advanced or metastatic disease4Morgensztern D Ng SH Gao F Govindan R Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey.J Thorac Oncol. 2010; 5: 29-33Summary Full Text Full Text PDF PubMed Scopus (396) Google Scholar at the time of diagnosis, and 40% of patients with NSCLC have distant metastases at the time of presentation.5Quint LE Tummala S Brisson LJ et al.Distribution of distant metastases from newly diagnosed non-small cell lung cancer.Ann Thorac Surg. 1996; 62: 246-250Summary Full Text PDF PubMed Scopus (277) Google Scholar An updated lung cancer staging system based on an up-to-date database6Goldstraw P Crowley J Chansky K et al.The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.J Thorac Oncol. 2007; 2: 706-714Summary Full Text Full Text PDF PubMed Scopus (2923) Google Scholar and an up-to-date histological classification system7Travis WD 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: 244-285Summary Full Text Full Text PDF PubMed Scopus (3640) Google Scholar are pivotal for the management of the disease. Although most patients are initially diagnosed via a conventional chest radiograph, various technologies are now available for further staging of patients. 18F-fluorodeoxyglucose (18F-FDG) PET has an increasing role for the staging of lung cancer and might in the future have a major role in the prediction and assessment of treatment responses.8Reck M Heigener DF Mok T Soria JC Rabe KF Management of non-small-cell lung cancer: recent developments.Lancet. 2013; 382: 709-719Summary Full Text Full Text PDF PubMed Scopus (632) Google Scholar The sensitivity of the method is variable and depends on the generation of scanners used, ranging from 68% to 100%.9Cuaron J Dunphy M Rimner A Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer.Front Oncol. 2012; 2: 208PubMed Google Scholar The importance of the method lies in its high negative predictive value and the detection of distant metastases, which reduces unnecessary thoracotomies.10Fischer B Lassen U Mortensen J et al.Preoperative staging of lung cancer with combined PET-CT.N Engl J Med. 2009; 361: 32-39Crossref PubMed Scopus (458) Google Scholar These outcomes form the basis for the clinical strategy to proceed with surgical resection immediately after a negative 18F-FDG PET scan; positive responses mandate tissue verification because of the fairly low positive predictive value. Mediastinoscopy, still widely advocated as the surgical gold standard for tissue verification, has a sensitivity of about 80%,11Annema JT van Meerbeeck JP Rintoul RC et al.Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.JAMA. 2010; 304: 2245-2252Crossref PubMed Scopus (503) Google Scholar and its use in the staging of lung cancer is decreasing in favour of new endoscopic ultrasound techniques such as EBUS and endo-oesophageal ultrasound (EUS). The endoscopic techniques have a high positive predictive value and a higher sensitivity than surgical staging, which means these techniques should now be the first step for tissue verification after a positive CT or 18F-FDG PET scan. Another substantial advantage of endoscopic techniques is the real-time biopsy sampling of suspect lesions, by contrast with conventional transbronchial fine needle aspirations, and the immediate availability of cell material for on-site cytological assessment. Additionally, any cytological specimen obtained through endoscopic ultrasound devices can undergo molecular characterisation of tumour tissue through the analysis of tumour DNA.12van Eijk R Licht J Schrumpf M et al.Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR.PLoS One. 2011; 6: e17791Crossref PubMed Scopus (158) Google Scholar In their study,1Navani N Nankivell M Lawrence DR et al.on behalf of the Lung-BOOST trial investigatorsLung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial.Lancet Respir Med. 2015; (published online February 4.)http://dx.doi.org/10.1016/S2213-2600(15)00029-6Google Scholar which included 133 patients recruited from six centres in the UK, Navani and colleagues investigated the role of EBUS-TBNA in patients with suspected stage I to IIIA lung cancer. Their findings lend support to previous data showing the usefulness of this technique from larger randomised trials,11Annema JT van Meerbeeck JP Rintoul RC et al.Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.JAMA. 2010; 304: 2245-2252Crossref PubMed Scopus (503) Google Scholar, 13Silvestri GA Gonzalez AV Jantz MA et al.Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e211S-e250SCrossref PubMed Scopus (1062) Google Scholar but adds the important result that, under the described trial circumstances, time to treatment decision was significantly shorter in the EBUS group (14 days, 95% CI 14–15) than in the group that had full conventional diagnosis and staging (29 days, 23–35; hazard ratio 1·98 [1·39–2·82], p<0·0001). The investigators conclude—correctly—that clinicians should follow present guideline recommendations to use EBUS-TBNA for the staging of non-small-cell lung cancer, and support the claim already made by others11Annema JT van Meerbeeck JP Rintoul RC et al.Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.JAMA. 2010; 304: 2245-2252Crossref PubMed Scopus (503) Google Scholar that this procedure should be the first diagnostic step. In the study, 30 patients (45%) in the EBUS-TBNA group did not need any other diagnostic step, compared with eight (12%) in the conventional diagnosis group. The study was designed as a pragmatic, randomised controlled trial. This approach, in which exclusion criteria are minimised, should allow for the inclusion of heterogeneous groups of patients with a wide range of diagnoses, with patient groups defined by presentation rather than diagnosis—a theoretical advantage of the study design that was not fully taken advantage of by Navani and colleagues.1Navani N Nankivell M Lawrence DR et al.on behalf of the Lung-BOOST trial investigatorsLung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial.Lancet Respir Med. 2015; (published online February 4.)http://dx.doi.org/10.1016/S2213-2600(15)00029-6Google Scholar Pragmatic, randomised clinical trials are necessary and findings from such studies are important when complex procedures are being assessed and when strict placebo groups are not an option. Frequently, as in the present case, large, well controlled trials have already been done and provide some evidence that still has to be translated into usual clinical care. However, pragmatic trials can have their own challenges related to patient recruitment, funding, and the stringency with which common practice is defined. The number of patients recruited and randomly assigned during more than 3 years in Navani and colleagues' study was surprisingly low (133); the participants are therefore unlikely to be consecutive cases, and this slow recruitment will have resulted in some bias in patient selection. According to a report14UK Office for National StatisticsCancer incidence and mortality in the United Kingdom, 2008–10.http://www.ons.gov.uk/ons/dcp171778_289890.pdfGoogle Scholar from the UK Office for National Statistics, about 163 100 males and 159 800 females were newly diagnosed with cancer each year between 2008 and 2010 in the UK. Lung cancer was the second most common newly diagnosed cancer in both males (mean 23 398) and females (mean 18 766) in this period. These data represent age-standardised incidence rates of 60 new cases per 100 000 men, and 40 new cases per 100 000 women each year, which translate into a staggering mean number of deaths from lung cancer of 19 668 men and 15 374 women each year in the UK alone. These figures are alarming, and because smoking remains one of the most prominent risk factors for this devastating disease, public health and political efforts for education and tobacco control are more urgently needed than ever. Undetected mediastinal metastases occur in up to 28% of patients with lung cancer,10Fischer B Lassen U Mortensen J et al.Preoperative staging of lung cancer with combined PET-CT.N Engl J Med. 2009; 361: 32-39Crossref PubMed Scopus (458) Google Scholar and probably the most substantial advance in the staging of lung cancer has been the introduction, and by now widespread use, of transoesophageal (EUS) and transbronchial (EBUS) ultrasound for diagnosis and staging.13Silvestri GA Gonzalez AV Jantz MA et al.Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e211S-e250SCrossref PubMed Scopus (1062) Google Scholar Evidence from a meta-analysis15Zhang R Ying K Shi L Zhang L Zhou L Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal lymph node staging of lung cancer: a meta-analysis.Eur J Cancer. 2013; 49: 1860-1867Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar suggests that the combination of EUS and EBUS investigations (sometimes done with an EBUS scope only) is more sensitive than either procedure alone, and this approach might qualify as the next gold standard for adequate lung cancer staging if these instruments and skills in these clinical techniques become available worldwide. For the early stages of lung cancer, the clinical landscape has permanently changed. The introduction of endoscopic ultrasound techniques such as EBUS-TBNA provides exact and minimally invasive mediastinal staging to be used for prognostication.11Annema JT van Meerbeeck JP Rintoul RC et al.Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.JAMA. 2010; 304: 2245-2252Crossref PubMed Scopus (503) Google Scholar In view of the large and unremitting burden of lung cancer worldwide, efforts are needed to ensure that the equipment, knowledge, and skills necessary for the use of these approaches are available in all countries. I have received grants from the German Federal Ministry of Education and Research, Altana Pharma, Novartis, and Boehringer Ingelheim, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceutical, Novartis, Takeda, and Intermune. These declarations are outside of the submitted work. Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trialTransbronchial needle aspiration guided by endobronchial ultrasound should be considered as the initial investigation for patients with suspected lung cancer, because it reduces the time to treatment decision compared with conventional diagnosis and staging techniques. Full-Text PDF Open Access