DIII-476; No. of Pages 5

Diagnostic and Interventional Imaging (2014) xxx, xxx—xxx


2014 update on non-small cell lung cancer (excluding diagnosis) V. Gounant a,b,c,∗, A. Khalil d, P. Créquit a,b, A. Lavole a,b, A.M. Ruppert a,b, M. Antoine a,e, B. Milleron b, M. Wislez a,b, M.F. Carette d, J. Assouad c, J. Cadranel a,b a

Sorbonne Universités, UPMC Université Paris 06, GRC no 04, Theranoscan, 75252 Paris, France b Service de pneumologie, Centre expert en oncologie thoracique et maladies pulmonaires rares, Hôpital Tenon, AP—HP, 4, rue de la Chine, 75020 Paris, France c Service de chirurgie thoracique, Hôpital Tenon, AP—HP, 4, rue de la Chine, 75020 Paris, France d Service de radiologie, Hôpital Tenon, AP—HP, 4, rue de la Chine, 75020 Paris, France e Service d’anatomie pathologique, Hôpital Tenon, AP—HP, 4, rue de la Chine, 75020 Paris, France

KEYWORDS Lung cancer; TNM stage; Biopsy; Chemotherapy; Targeted therapy

Abstract Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has changed with an increased incidence in non-smokers and women. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011, and they are now the most frequent histological subtype. More than half the cases of LC are diagnosed at the metastatic stage. Biopsies must provide tissue samples that are quantitatively large enough and of a good enough quality for diagnosis and to search for biomarkers. When the cancer seems to be localized, precise staging must be obtained. Treatment is based on the TNM classification. In localized stages, lobectomy associated with lymph node dissection is the standard therapy. Intraoperative chemotherapy improves survival in case of lymph node infiltration. Stereotactic radiation therapy and radiofrequency can be considered as specific cases. In cases with local progression, treatment is more controversial. In the presence of metastases, the goal is not a cure, but improving survival and quality of life. Numerous advances have been made with personalized treatment, (in particular in relation to the histological type and oncogenic addiction in tumors, access to new drugs, and improved

Corresponding author. Service de chirurgie thoracique, Hôpital Tenon, AP—HP, 4, rue de la Chine, 75020 Paris, France. E-mail address: [email protected] (V. Gounant).

http://dx.doi.org/10.1016/j.diii.2014.05.004 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Gounant V, et al. 2014 update on non-small cell lung cancer (excluding diagnosis). Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.05.004

+Model DIII-476; No. of Pages 5



V. Gounant et al. management). Clinical research in thoracic cancer is very active. The fight against tobacco should remain a priority. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc

Epidemiology of non-small cell lung carcinoma (NSCLC) With 39,495 cases diagnosed in 2012 in France and 29,949 deaths [1], lung cancer (LC) remains a major public health problem because of its frequency, but especially the severity of the disease. LC is the cause of the greatest number of cancer deaths per year in France (20%) [1]. While mortality from this disease is decreasing in men, it continues to increase in women [2]. In the last ten years, the epidemiology has changed [3]. The incidence of this disease is increasing in non-smokers (11% of LC in France) and in women. Ten years ago squamous cell carcinoma was more frequent than adenocarcinoma (39% vs 29%). Today, the distribution has changed with 46% of adenocarcinomas, 26% squamous cell carcinomas 10% large cell carcinomas and 13% small cell carcinomas. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011 [4], and now includes four new entities: adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant non-mucinous adenocarcinoma, and invasive mucinous adenocarcinoma. Because of the strong anatomoradiological correlation, this new classification also has implications for the radiologist [5]. This classification, which was developed for biopsy samples, has been adapted to small tissue specimens [6].

Cytological and biopsy tissue specimens for diagnosis More than half LC is diagnosed at the metastatic stage [3]. In this case, the physician performing the biopsy, whether s/he is an endoscopist or a radiologist, s/he must obtain specimens that are quantitatively large enough and qualitatively good enough to obtain a precise diagnosis and identify biomarkers to help determine the treatment strategy. Today, the histological type and the molecular profile are determining factors of the therapeutic strategy. The IASLC recommends searching for an EGFR mutation and an ALK translocation [7] in all metastatic adenocarcinomas, whatever the clinical features, because there are targeted therapies for these two molecular anomalies that have obtained French marketing (AMM) approval. Since 2006, INCa has organized molecular genetics platforms to determine molecular profile of tumors and identify new therapeutic targets to help develop targeted treatments and make personalized medicine a reality for patients. Biomarqueurs France is a database that includes all molecular analyses performed in INCa approved platforms since 2012. In one year, 10,000 LC have been tested [8]. It is interesting to note that a team from Grenoble [9] has shown that the reliability of transthoracic needle biopsies to determine

the histological subtype and the molecular profile of adenocarcinomas has significantly improved in just two years (72% of the biopsy specimens were adequate for molecular analyses during the first period vs 92 % during the second period). The number as well as the length of the biopsies has increased. Radiologists have improved their practices along with pathologists and biologists to adapt to new guidelines. New techniques, such as radial probe endoscopic ultrasound (EBUS) have also been developed in bronchoscopy to improve results [10] and electromagnetic navigation [11] has helped improve biopsy specimens, especially of peripheral lesions. However, very few centers have these technologies.

Initial evaluation When cancer seems to be localized, the challenges are elsewhere. The histological subtype and the molecular profile are not needed, because they do not affect the therapeutic strategy. On the other hand, disease extension should be precisely determined. Contrast-enhanced thoracic CT Scan and PET scan are recommended by the INCa [12] and the ACCP [13]. Brain imaging should be systematically performed according to the INCa (CT scan or MRI) and the ‘‘guide to good practices of imaging tests’’ (gbu.radiologie.fr) and is recommended in stage III or IV disease by the ACCP (MRI). To obtain reliable mediastinal staging, in the absence of distant metastases, imaging should be associated with mini-invasive procedures (EBUS, Endoscopic ultrasound (EUS) or mediastinoscopy) in the following cases [12,13]: mediastinal lymph nodes ≥ 10 mm, high tracer uptake on PET scan whatever the size of the lymph node, the presence of suspicious hilar lymph nodes or central location of the tumor. Results of EUS staging seem to be better than mediastinoscopy [14], which is why it is now recommended as the first imaging test [13]. The effectiveness of whole body MRI or combined with PET scan is being studied to evaluate disease extension in LC [15,16].

Advances in treatment strategies Treatment depends on the TNM stage. A lobectomy and lymph node dissection is the standard treatment for stages I and II. Video assisted surgical techniques are being developed. Infra-lobar resections, in particular segmentectomies can be discussed [13] in certain cases: tumors less than 2 cm predominantly ground glass opacity-type, or pulmonary function preventing resection of an entire lobe. Approximately 25% of patients with local stage LC have a major surgical contraindication. Stereotactic radiotherapy is an option if the tumor is less than 5 cm [13]. Radiofrequency can also be considered if the tumor is less than 3 cm but there

Please cite this article in press as: Gounant V, et al. 2014 update on non-small cell lung cancer (excluding diagnosis). Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.05.004

+Model DIII-476; No. of Pages 5


2014 update on non-small cell lung cancer (excluding diagnosis) are fewer results in the literature [13]. Results of local disease control (83—89% vs 58-68% at 5 years), overall survival (38—85% vs 47—74% at 3 years) and the rate of complications (3—38% vs 33—100%) seem to be better with stereotactic radiotherapy than with radiofrequency [17]. However, in the absence of randomized trials, these results should be taken with caution. Two phase III clinical trials (ACOSOG Z4099 and RTOG 1021 trial) comparing partial resection to stereotactic radiotherapy in high risk patients are ongoing. The best patient postoperative follow-up protocol must be determined. The IFCT phase III study comparing a protocol of a clinical examination associated with thoracic radiography to a clinical examination and thoracic and upper abdominal CT Scan and pulmonary fibroscopy in case of a squamous cell tumor, including 1775 patients operated for LC, should provide a response. Platinum-based adjuvant chemotherapy is indicated in stage II surgical patients [13]. Neoadjuvant chemotherapy is an option. Treatment of stages IIIAN2 is the subject of debate. The ACCP recommends combined radiochemotherapy [13]. Surgery as first-line treatment followed by adjuvant chemotherapy is not recommended [13]. Chemotherapy as first-line treatment followed by surgery can be considered if the N2 is small [13]. Adjuvant chemotherapy may be indicated in patients with a tumor in whom mediastinal invasion is not known before surgery (cN0 or N1 and pN2). ESMO [18] guidelines are slightly different. If the tumor is resectable, radiochemotherapy and neoadjuvant chemotherapy followed by surgery are two options. Radiochemotherapy is indicated in stage IIIB tumors, if the size of the tumor permits curative radiation. Treatment of stage IV tumors is supportive, except for rare cases of resectable pulmonary tumors with pulmonary (M1a), adrenal or cerebral metastases alone. The goal is not a cure but to improve patient survival and quality of life. The benefits of chemotherapy are real and the meta-analysis published in 1995 [19] showed better results with combination platinum and a third generation drug compared to supportive care alone. Progress has been made in the last ten years. Today the choice of chemotherapy can be adapted to tumor histology (for example, by limiting pemetrexed to non-predominantly squamous cell NSCLC). Bevacizumab, the monoclonal antibody acting on VEGF, improves progression-free survival and probably overall survival [20]. It can be combined with chemotherapy in case of non-squamous NSCLC. Indeed, during the development of bevacizumab, cases of mortality from hemoptysis were described in phase II studies in patients with squamous cell carcinomas, which is why this histological type has been excluded from this option. Nevertheless, the risk of hemoptysis persists and predictive radiological criteria have been developed [21]. The evaluation of risk by a radiologist is therefore important. First-line therapy includes 4 to 6 cycles of chemotherapy. Before the notion of maintenance therapy was introduced, there was a pause in treatment then second line treatment was begun at tumoral progression. Today this approach has been validated because maintenance therapy [22] has been shown to improve progression-free survival and overall survival. This may include real maintenance therapy or

3 continuation maintenance (the treatment used for induction is maintained when platinum therapy is stopped until progression or toxicity) or switch maintenance (induction chemotherapy is stopped and another type of treatment is begun). The predictive factors of effective maintenance therapy are still a subject of debate. Response to induction therapy may play a role. This hypothesis is being tested in France in a phase III trial (IFCT-GFPC 1101). New chemotherapies, the association with bevacizumab and maintenance therapy has improved median progressionfree survival (approximately 7 months) and overall survival can reach up to 17 months [23]. Major progress has been made in the management of metastatic NSCLC with the identification of oncogenic addictions [24]. Tyrosine kinase inhibitors EGFR (ITK-EGFR) were initially developed in a non-selected population. Clinical criteria of response to ITK-EGFR were rapidly identified (female gender, non-smokers, Asian and adenocarcinoma). EGFR gene mutations were found to be the best predictive factor of response to treatment. Today EGFR gene mutations are systematically searched for in metastatic adenocarcinomas. In the presence of an activating mutation (approximately 10% of the adenocarcinomas in France), the patient can receive ITK-EGFR as first-line therapy. Progression-free survival was better than with chemotherapy and reached 9 months in one Caucasian population [25]. The prognosis of patients with an EGFR mutation is better than others. The median overall survival reached 19 months in the Caucasian population [25]. In the absence of a mutation, ITK-EGFR (only erlotinib has an AMM for this indication) can be administered as a second line therapy or at later cycles. At tumoral progression, new tissue specimens can be obtained to determine the mechanism of resistance to ITK (appearance of a resistance mutation, histological transformation. . .) and to adapt patient management. In 2007, the ALK translocation [26] was described in NSCLC (approximately 4% of NSCLC) and in 2011, crizotinib was validated for this indication, resulting in progression-free survival of between 7 and 9 months. Other biomarkers [24] have been discovered including certain that are associated with targeted therapies. Clinical research in immunotherapy in NSCLC seems promising [27]. Last year, two phase I trials were published in the New England Journal of Medicine, one with anti-PD-1 antibodies [28], the other with an anti-ligand antibody to PD-1 [29]. Although included patients had received multiple treatments, several of them presented with objective responses. With immunotherapy, the evaluation of responseto-treatment can be difficult because the immune cascade set off by treatment can induce an initial increase in the size of targeted lesions, or the appearance of new lesions. The RECIST criteria are not adapted which is why specific immunotherapy criteria were published. [30]. Today numerous trials are underway in immunotherapy.

Conclusion In conclusion, the management of NSCLC in particular at the metastatic stage, has changed significantly in the past few years, both for diagnosis (necessity of having a large enough tissue specimen to identify oncogenic addictions) and

Please cite this article in press as: Gounant V, et al. 2014 update on non-small cell lung cancer (excluding diagnosis). Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.05.004

+Model DIII-476; No. of Pages 5



V. Gounant et al.

treatment with the availability of personalized medicine. Despite progress, the prognosis is still poor and the fight against tobacco as well as diagnostic campaigns should be a priority.


TAKE-HOME MESSAGES • Biopsy specimens should be adequate for diagnosis and the search for biomarkers. • The physician performing the biopsy and the pathologist must therefore optimize their technique. • In localized stages, precise staging must be obtained. A lobectomy associated with lymph node dissection is the standard therapy. • In metastatic stages, treatment is determined by the histological subtype and the presence of mutations, in particular EGFR. • Despite progress the prognosis is still poor. The fight against tobacco is a priority.






Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.


References [16] [1] Estimation nationale de l’incidence et de la mortalité par cancer en France entre 1980 et 2012. Partie 1 — Tumeurs solides. Traitement. INCa; 2013. [2] Bosetti C, Malvezzi M, Rosso T, Bertuccio P, Gallus S, Chatenoud L, et al. Lung cancer mortality in European women: trends and predictions. Lung Cancer 2012;78(3):171—8. [3] Locher C, Debieuvre D, Coëtmeur D, Goupil F, Molinier O, Collon T, et al. Major changes in lung cancer over the last ten years in France: the KBP-CPHG studies. Lung Cancer 2013;81(1):32—8. [4] Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, 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(2):244—85. [5] Austin JH, Garg K, Aberle D, Yankelevitz D, Kuriyama K, Lee HJ, et al. Radiologic implications of the 2011 classification of adenocarcinoma of the lung. Radiology 2013;266(1):62—71. [6] Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013;137(5):668—84. [7] Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists. International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013;8(7):823—59. [8] Barlesi F, Blons H, Beau-Faller M, Rouquette I, L’houcine Ouafik, Mosser J, et al. Biomarkers (BM) France: results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small








cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2013;31 [suppl; [25] abstr 8000]. Ferretti GR, Busser B, de Fraipont F, Reymond E, McLeerFlorin A, Mescam-Mancini L, et al. Adequacy of CT-guided biopsies with histomolecular subtyping of pulmonary adenocarcinomas: influence of ATS/ERS/IASLC guidelines. Lung Cancer 2013;82(1):69—75, http://dx.doi.org/10.1016/j.lungcan. 2013.07.010. Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. Eur Respir J 2011;37(4):902—10. Ha D, Choi H, Almeida FA, Arrossi A, Brainard J, Cicenia J, et al. Histologic and molecular characterization of lung cancer with tissue obtained by electromagnetic navigation bronchoscopy. J Bronchology Interv Pulmonol 2013;20(1):10—5. Cancer du poumon. In: Bilan initial. Collection Recommandations et Référentiels, ouvrage collectif édité par l’INCa. Boulogne Billancourt: INCa; 2011. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl.):7S—37S. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304(20):2245—52. Yi CA, Lee KS, Lee HY, Kim S, Kwon OJ, Kim H, et al. Coregistered whole body magnetic resonance imaging-positron emission tomography (MRI-PET) versus PET-computed tomography plus brain MRI in staging resectable lung cancer: comparisons of clinical effectiveness in a randomized trial. Cancer 2013;119(10):1784—91. Torigian DA, Zaidi H, Kwee TC, Saboury B, Udupa JK, Cho ZH, et al. PET/MR imaging: technical aspects and potential clinical applications. Radiology 2013;267(1):26—44. Renaud S, Falcoz PE, Olland A, Massard G. Is radiofrequency ablation or stereotactic ablative radiotherapy the best treatment for radically treatable primary lung cancer unfit for surgery? Interact Cardiovasc Thorac Surg 2013;16(1):68—73. Vansteenkiste J, De Ruysscher D, Eberhardt WE, Lim E, Senan S, Felip E, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(suppl 6):vi89—98, http://dx.doi.org/10.1093/annonc/mdt241. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311(7010):899—909. Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, et al. Meta-analysis of bevacizumab in advanced NSCLC collaborative group. Systematic review and metaanalysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013;24(1):20—30. Reck M, Barlesi F, Crinò L, Henschke CI, Isla D, Stiebeler S, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol 2012;23(5):1111—20. Gerber DE, Schiller JH. Maintenance chemotherapy for advanced non-small-cell lung cancer: new life for an old idea. J Clin Oncol 2013;31(8):1009—20. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced

Please cite this article in press as: Gounant V, et al. 2014 update on non-small cell lung cancer (excluding diagnosis). Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.05.004

+Model DIII-476; No. of Pages 5


2014 update on non-small cell lung cancer (excluding diagnosis) non-squamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31(24):3004—11. [24] Cadranel J, Crequit P, Ruppert AM, Lavole A, Gounant V, Lacave R, et al. Mutation de l’EGFR, de l’étude du gène à la pratique clinique : exemplarité ou exception ? Rev Mal Resp Actual 2013;5:108—26. [25] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as firstline 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(3):239—46.

5 [26] Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31(8):1105—11. [27] Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol 2013;31(8):1021—8. [28] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443—54. [29] Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455—65. [30] Hoos A. Evolution of end points for cancer immunotherapy trials. Ann Oncol 2012;23(Suppl. 8):47—52.

Please cite this article in press as: Gounant V, et al. 2014 update on non-small cell lung cancer (excluding diagnosis). Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.05.004

2014 update on non-small cell lung cancer (excluding diagnosis).

Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has...
488KB Sizes 3 Downloads 4 Views