Virtual Library

Abstract:
Outcomes for the majority of cancer prevention trials overall have been disappointing at best. Lung cancer remains the leading cause of cancer-related mortality worldwide, causing an estimated 156,000 deaths in the United States for 2013. Most lung cancers (>60%) are diagnosed at an advanced stage, with associated 5-year survival of less than 15%. Efforts in early diagnosis and cancer prevention remain crucial to reverse the impact of this deadly disease. For this session, I will be joined by Dr. Eva Szabo and Dr. Avi Spira to review perspectives on the past, present, and future of lung cancer chemoprevention trials. We will review a number of current concepts and important themes in lung cancer chemoprevention, including: 1. Genomic alterations in pre-malignant lesions for both lung adenocarcinoma and squamous cell carcinoma. 2. Patient stratification for applying chemoprevention. 3. Novel agents. 4. Strategies for individualized or precision chemoprevention. 5. Trial designs for rapid and efficient testing of chemoprevention hypotheses. 6. Priorities for further study. To reduce the mortality rate of lung cancer, and to prevent cancer initiation, progression and development, new techniques and approaches to cancer prevention must be developed. We will present both data and opinion regarding promising leads, routes to evaluation, and a vision for research priorities to advance the science of lung cancer chemoprevention.

Abstract:
Dr. Cummings is currently a Professor in the Department of Psychiatry & Behavioral Sciences at the Medical University of South Carolina (USA) and co-leader of the Hollings Cancer Center Tobacco Research Program. He is widely recognized for his international research on smoking behavior, product marketing and consumer perceptions, and the influence of cigarette design on smoking behavior. He is the co-chair of the International Association for the Study of Lung Cancer’s (IASLC) sub-committee on tobacco control and smoking cessation and helped IASLC develop its policy statement on electronic cigarettes (1). This session will describe the evolution of the nicotine delivery market, especially with the explosive growth of vaporized nicotine products (referred to throughout this application as VNPs which includes e-cigarettes, also referred to here as ENDS – Electronic Nicotine Delivery Systems, pressurized aerosol nicotine products, and heat no-burn tobacco products), which may represent a new paradigm for tobacco control by ostensibly offering smokers an opportunity to obtain nicotine in ways that do not cause the extreme risks for such a broad spectrum of smoking-caused diseases that make tobacco smoke the leading cause of premature death in high-income nations (2-4). The rapidly growing demand for VNPs seen in many countries suggests that these products are already having an impact on cigarette consumption today (5-6). Despite this unpromising history of harm reduction products, VNPs, of which e-cigarettes are the best know, represent a new generation of alternatives that show some promise for eventually displacing cigarettes and possibly offering real harm reduction (7). This presentation will provide an overview of e-cigarettes and other VNP products, will present data on who is using these products, whether the products can help smokers quit, and discuss safety concerns (8-9). Finally, the presentation will also provide some practical advice on how to talk to your patients about e-cigarettes (10). References 1) Cummings KM, Dresler CM, Field JK, Fox J, Gritz ER, Hanna NH, et al. E-cigarettes and cancer patients. Journal of Thoracic Oncology. 2014;9(4):438-41. 2) Abrams DB. Promise and peril of e-cigarettes: can disruptive technology make cigarettes obsolete? JAMA 2014;311(2):135-6. 3) Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes? Journal of Public Health Policy.2011;32(1):16-31. 4) Fiore MC, Schroeder SA, Baker TB. Smoke, the chief killer--strategies for targeting combustible tobacco use. NEJM. 2014;370(4):297-9. 5) Gravely S, Fong, GT., Cummings, KM., Yan, M., et al. Awareness, trial, and current use of electronic cigarettes among 10 countries: Findings from the ITC Project IJERPH. 2014;11:11691-704. 6) Yong HH, Borland R, Balmford J, McNeill A, et al. Trends in E-Cigarette Awareness, Trial, and Use Under the Different Regulatory Environments of Australia and the United Kingdom. Nicotine Tob Res (2014) doi: 10.1093/ntr/ntu231 7) Sweanor D, Yach D. Looking for the next breakthrough in tobacco control and health. South African Medical Journal. 2013;103(11):810-1. 8) McRobbie H, Bullen C, Hartmann-Boyce J, Hajek P. Electronic cigarettes for smoking cessation and reduction. The Cochrane database of systematic reviews. 2014; 12:CD010216. 9) Hajek P, Etter JF, Benowitz N, Eissenberg T, McRobbie H. Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction. 2014;109(11):1801-10. 10) Borderud SP, Li L, Y, Burkhalter JE, Sheffer CE, Ostroff JS. Electronic Cigarette Use Among Patients With Cancer. Cancer, 2014; 120(22):3527-35.

Abstract:
Introduction The neuroendocrine tumours of the lung are all malignant lesions, unified by a common characteristic of neuroendocrine differentiation, but diverse in terms of histological features, clinical presentation, aetiology and biology. In the new World Health Organisation classification of lung tumours, published in 2015, the four major types of neuroendocrine tumour (small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumour and atypical carcinoid tumour) are now included under a single heading of neuroendocrine tumours. Small cell carcinoma (SCLC) SCLC is a high-grade malignant epithelial tumour comprising relatively small cells with scanty cytoplasm, fusiform to round nuclei, finely disperse granular chromatin, inconspicuous nucleoli and prominent nuclear moulding. Mitoses, apoptosis and extensive necrosis are typical. Tumours characteristically have neuroendocrine granules visible on electron microscopy and most cases express neuroendocrine markers by immunohistochemistry. An organoid architecture with rosettes and trabeculae is uncommon, but SCLC samples are often small, precluding identification. SCLC may be seen combined with other non-small cell carcinoma (NSCLC) subtypes (Combined small cell carcinoma). Here, SCLC has priority, regardless of the relative proportion of the tumour that is SCLC. SCLC accounts for between 10-15% of cases diagnosed and is strongly associated with tobacco smoking. The typical presentation of SCLC is stage IV metastatic disease with rapid progression. Radiologically a large central mass with contiguous, bulky hilar nodes is typical and mediastinal invasion is usually evident. The vast majority of SCLC present. Production of hormonal peptides accounts for several paraneoplastic complications. Ectopic hormones (or hormone-like peptides) such as ADH or ACTH, and peptides native to the pulmonary neuroendocrine cells (calcitonin and gastrin-releasing peptide) may be produced. Large cell neuroendocrine carcinoma (LCNEC) Another high grade neuroendocrine carcinoma, characterized by morphological neuroendocrine features (rosettes, trabeculae, peripheral nuclear palisading). Cells are relatively large, cytoplasm abundant/eosinophilic, and nuclei show coarse chromatin and nucleoli. Nodular tumour, a fine vascular stroma, cribriform architecture and central comedo necrosis are common. Mitoses are abundant (always >10 per 2mm[2]: rarely <30 and averages 75). Combined tumours, with SCLC or, more often NSCLC, when adenocarcinoma is the most frequent accompaniment, are not unusual. LCNEC should demonstrate neuroendocrine differentiation by immunohistochemistry [NCAM/CD56 (~100%), Chromogranin (80-85%), synaptophysin (50-60%). At least 50% express TTF1. Usually at least two stains are positive. There is a similar, strong association between LCNEC and tobacco smoking. These are relatively rare tumours, accounting for about 4% of resected cases but true prevalence across all stages, is not clear. Presentation and radiological appearances are no different from other NSCLC cases of similar stage; the vast majority of LCNEC are diagnosed in surgical resections. They are more often peripheral than centrally located tumours. The bulky nodal/mediastinal disease common in SCLC, is uncommon in LCNEC but there may be selection and diagnostic bias driving this observation. Hormonal production and paraneoplastic syndromes are rare in LCNEC, another difference with SCLC. Carcinoid tumour Carcinoid tumours are malignant tumours, divided into typical carcinoid (TC) where there is no evidence of necrosis and mitoses number less than 2 per 2mm[2] of tumour. Atypical carcinoid tumours (AC) may show punctate necrosis and/or exhibit 2 or more, but <10 mitoses per 2mm[2]. Otherwise, the lesions are very similar histologically - small regular cells, variable cytoplasm, bland round to oval nuclei. Architecture is usually insular, trabecular but rosettes or glands occur. Spindle cell carcinoids occur mostly in thee lung periphery; insular/trabecular lesions are characteristically central. Strong neuroendocrine markers expression is expected. Proliferation markers such as Ki67 mirror, to some extent, the mitotic rate, may aid distinction from high grade neuroendocrine tumours in crushed samples but are not reliable or recommended for distinguishing TC from AC. These are rare tumours, accounting for 4-6% of primary lung ‘cancers’; atypical carcinoid account for around 10% of all lung carcinoids. Typical carcinoids may show lymph node spread in 10% cases, distant metastases are rare. In AC, distant metastases are not unusual. Syndromes related to peptides (Cushing’s, Acromegaly) or secretion of 5-HT (carcinoid syndrome) are very rare. Neuroendocrine tumour development and Genetics Precursor lesions are not described for the high grade lesions and the strong link with smoking and the common combination with NSCLC elements makes it likely that origins at least, are from the same cell populations that give rise to other NSCLC. Both central and peripheral lung epithelial compartments are capable of neuroendocrine differentiation, possibly in part driven by transcription factor ASCL1. It is also notable that a proportion of EGFR-mutated adenocarcinomas recur as SCLC after initial response to EGFR tyrosine kinase inhibitors. Carcinoid tumours probably also derive from the same epithelia, but via different mechanisms. Carcinoid and SCLC or NSCLC effectively never co-exist in the same lesion and carcinoids are not associated with tobacco smoking. Rarely carcinoids are associated with MEN type 1 syndrome, and sporadic cases may show MEN1 mutations. A rare disease called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is associated with spindle-cell carcinoid tumours, often multiple, and is considered a rare carcinoid precursor lesion. There are evolving data which show that SCLC in particular, has patterns of very frequent mutations and epigenetic changes (gene hypermethylation) reflecting tobacco carcinogenesis. SCLC and LCNEC share many features in their genetic profile and inactivating mutations of both RB and TP53 are characteristic. SCLC shares many of the characteristic deletions or losses of tumour suppressor genes seen in squamous cell carcinoma, especially in 3p loci. SCLC and LCNEC show many alterations in genes involved in cell cycle regulation. In LCNEC, some genes such as TTF1, CDKN2, STK11 and KEAP1 may be altered, akin to that seen in some squamous cell or adenocarcinomas, again, and reminiscent of the post-EGFR TKI recurrence scenario, raising the possibility of origin through divergent differentiation within ‘NSCLC precursors’. Carcinoid tumour genomics are entirely different, less well studied, and as expected, do not show a ‘tobacco signature’. As well as MEN1 mutations, alteration of genes of the methylation complex and chromatin remodelling genes are not infrequent. Carcinoid tumours are NOT precursor lesions for, and do not evolve into, SCLC or LCNEC.

Abstract:
Introduction: Small cell lung cancer (SCLC) is the most common and most virulent neuroendocrine (NE) carcinoma. For pathological and therapeutic reasons human lung cancers are traditionally divided into non-SCLCs (NSCLCs) and SCLCs which currently account for 10 – 15% of all lung cancers. While prognosis for all lung cancers is poor, it is dismal for SCLC with less than 5% for patients surviving for five years. As molecular characterization of NSCLCs is quickly taking hold in guiding personalized care of cancer patients, the approach to SCLC is still based on principles developed decades ago. There has been practically no improvement in survival for past thirty years. Following the 2013 congressional mandate demanding concentrated research focus on such recalcitrant cancers as SCLC and pancreatic cancer it will hopefully be changing. Epidemiology and Histology: SCLC is strongly associated with smoking history and commonly found both in women and men at their sixties. It is mostly a centrally located submucosal mass in major airways although peripheral tumors have been reported. At the time of diagnosis, most SCLCs have already metastasized. There are no known premalignant lesions. Histologically the tumors are characterized by sheets of poorly differentiated cells with finely granular chromatin pattern and inconspicuous nuclei, and scanty cytoplasm among other features. Mitoses (>10 per high power field), areas of necrosis and ‘Azzopardi effect’ are consistent with aggressive nature and high DNA content of the tumor. When SCLC is associated with any of the histologic types of NSCLC, it is called combined SCLC (1). Neuroendocrine (NE) Features and the Cell of Origin: Ultrastructurally SCLC is characterized by the presence of scattered dense core vesicles, a hall mark of endocrine differentiation. Functionally the cells reveal a variety of NE properties such as uptake and synthesis of bioactive amines, hormones and neuropeptides, the presence of neural receptors such as nicotinic acetylcholine receptors, antigens and ion channels with the neuron-like ability to conduct electric currents. Consequently, SCLCs may be associated with ectopic hormone secretion or paraneoplastic syndromes. In addition, airway epithelium harbors a rare cell type with similar properties that is only visible using special techniques such as electron microscopy or immunohistochemistry and called pulmonary NE cells (2). In normal lung they occur as solitary cells or innervated clusters called neuroepithelial bodies or NEBs. It has been commonly believed that the pulmonary NE cell is the precursor of SCLC although there has been no direct evidence. Recent studies applying sophisticated tracing techniques in transgenic mice support the hypothesis while still leaving open the question what happens in human lung (3). Spectrum of Neuroendocrine (NE) Differentiation in Lung Cancers: SCLC is the prototype of pulmonary NE cancers but up a third of all lung cancers may reveal a degree of NE differentiation. They range from well differentiated carcinoids and atypical carcinoids to less well differentiated SCLCs and large cell NE carcinomas (LCNECs) and finally to 10% of NSCLCs that show focal NE differentiation (NSCLC-NEs). Notably the cancers are molecularly, histogenetically, morphologically distinct entities and should be distinguished from SCLCs. Clinically SCLCs and LCNECs are high-grade NE tumors while NSCLC-NEs appear to be a more controversial entity. Molecular Pathology: SCLC presents a complex genomic landscape with a high number of mutations due to the toxic impact of tobacco smoke. The field is rapidly evolving. However, both Rb and p53 are almost invariably inactivated in SCLCs. Rb is altered in many human NE cancers regardless of the tissue of origin, while p53 mutations are common in NSCLCs. In contrast, SCLCs lack Ras mutations which are typical of many NSCLCs. Moreover, SCLCs may show overexpression or amplification of MYC genes. In addition, achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary NE cells (2), is pivotal for the survival of a majority of SCLCs and as well as NSCLC with NE features (4). Accordingly, ASCL1 is a lineage-specific oncogene for SCLCs. Efforts to identify relevant pathways regulated by this gene as well as others that might provide molecular targets for treatments are ongoing on several fronts. Tools for Investigation: Because SCLC is routinely diagnosed mainly using small bronchial biopsies or needle aspiration cytology specimens prior to cytotoxic chemo- and radiotherapies there has been a chronic shortage of suitable material for molecular and biological research. Fortunately, there are many well characterized human SCLC cell lines available that quite accurately recapitulate both molecular and histopathological features of the primary tumors. More recently, a range of genetically engineered mouse models have been generated based on the conditional ablation of both Rb and p53 tumor suppressor genes with select other genetic alterations (5). In vivo models provide important material to investigate sequential evolution of SCLC including metastases, molecular profiling and preclinical studies (6). Summary and Conclusions: SCLC is a neuroendocrine (NE) carcinoma with dismal prognosis and no substantial improvements in therapies for several decades. While the identification of effective therapies remains a major challenge, advances in understanding the biology, improved molecular techniques and sophisticated animal models have opened up novel avenues for the development of targeted therapies. References: 1. Travis WD et al. (2004). Pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: IARC Press. 2. Linnoila, R.I. (2006). Lab Invest 86, 425-44 3. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J.-Y., and Berns, A. (2011).Cancer Cell 19, 754–764. 4. Augustyn, A., Borromeo, M., Wang, T., Fujimoto, J., Shao, C., Dospoy, P.D., Lee, V., Tan, C., Sullivan, J.P., Larsen, J.E., Girard, L., Behrens, C., Wistuba, I.I., Xie, Y., Cobb, M.H., Gazdar, A.F., Johnson, J.E., Minna, J.D. (2014). Proc Natl Acad Sci U S A. 111 ,14788-93. 5. Gazdar, A.F., Savage, T.K., Johnson, J.E., Berns, A., Sage, J., Linnoila, R.I., MacPherson, D., McFadden, D.G., Farago, A., Jacks, T., Travis, W.D., Brambilla, E. (2015). J Thorac Oncol. 10, 553-64. 6. McFadden, D.G., Papagiannakopoulos, T., Taylor-Weiner, A., Stewart, C., Carter, S.L., Cibulskis, K., Bhutkar, A., McKenna, A., Dooley, A., Vernon, A.,et al. (2014). Cell 156, 1298–1311.

Abstract:
Introduction: Lung cancer is highly curable if detected at an early stage. Screening with low dose CT (LDCT) has been shown to reduce lung cancer mortality, but largely detects peripheral tumours. Due to limitation of resolution, LDCT currently cannot detect early pre-invasive central lung cancers. Evaluation of the central bronchial tree remains important in populations where central squamous carcinoma remains a significant contributor to lung cancer incidence or in patients at high risk of developing synchronous or metachronous squamous cell cancers. Imaging Technology: The imaging modality most commonly used for evaluation of the central airways is white light flexible bronchoscopy (WLB). The ability of routine white light examination to detect small pre-invasive central lung cancer remains limited. A number of technological advances and development of alternative in vivo optical imaging modalities improve the detection and evaluation of central pre-invasive lesions. These techniques include high magnification WLB, autofluorescence imaging (AFB), narrow band imaging (NBI), optical coherence tomography (OCT), confocal microendoscopy/endocystoscopy and raman spectroscopy (RS). Management: There are multiple tools available to be used with a flexible bronchoscopic approach to treat pre-invasive central lung cancers once detected. These include endobronchial electrocautery, argon plasma coagulation, cryotherapy, photodynamic therapy, brachytherapy and laser therapy. Therapeutic outcomes are dependent on multiple factors but curative rates of >85-90% are achievable. Patients are at risk of recurrence or the development of metachronous lesions and require close surveillance. Summary: The detection of early central lung cancers often requires more sophisticated tools than conventional white light bronchoscopy. The multimodality utilisation of different technologies will enable the rapid detection and diagnosis of early curable central lung cancers in selected high-risk populations. There are multiple tools available for curative treatment of early central lung cancers. References 1. Sun J, Garfield DH, Lam B, et al. The value of autofluorescence bronchoscopy combined with white light bronchoscopy compared with white light alone in the diagnosis of intraepithelial neoplasia and invasive lung cancer: a meta-analysis. J Thorac Oncol 2011;6(8):1336-1344. 2. Lee P, van den Berg RM, Lam S, Gazdar A, Grunberg K, McWilliams A, LeRiche J, Postmus P, Sutedja T. Color fluorescence ratio for detection of bronchial dysplasia and carcinoma in situ. Clin Cancer Res 2009; 15:4700-4705. 3. Herth F, Eberhardt R, Anantham D, Gompelmann D, Zakaria M, Ernst A. Narrow-band imaging bronchoscopy increases the specificity of bronchoscopic early lung cancer detection. J Thorac Oncol, 2009;4:1060-1065. 4. Lam S, Standish B, Baldwin C, et al. In vivo optical coherence tomography imaging of preinvasive bronchial lesions. Clin Cancer Res. 2008; 14: 2006–2011. 5. Thiberville L, Salaun M, Lachkar S, Dominique S, Moreno-Swirc S, Vever-Bizet C, Bourg-Heckly G. Confocal fluorescence endomicroscopy of the human airways. Proc Am Thorac Soc, 2009;6:444-449. 6. Shibuya K, Fujiwara T, Yasufuku K, Mohamed Alaa RM, Chiyo M, Nakajima T, Hoshino H, Hiroshima K, Nakatani Y, Yoshino I. In vivo microscopic imaging of the bronchial mucosa using an endo-cystoscopy system. Lung Cancer, 2011;72:184-190. 7. Short M, Lam S, McWilliams A, Ionescu D, Zeng H. Using laser Raman spectroscopy to reduce false positives of autofluorescence bronchoscopy: A pilot study. JTO, 2011;6:1206-1214. 8. McWilliams A, Shaipanich T, Lam S. Fluorescence and Navigational Bronchoscopy. Thoracic Surgery Clinics, May 2013. 9. Wisnivesky J, Yung R, Mathur P, Zulueta J. Diagnosis and Treatment of Bronchial Intraepithelial Neoplasia and Early Lung Cancer of the Central Airways. Diagnosis and Management of Lung Cancer, 3[rd] Edition, ACCP Guidelines. Chest, 2013;143 (5)(Suppl):e263S-e277S. 10. McWilliams. Clinical Applications in the Lung. In: Diagnostic Endsocopy: Series in Medical Physics and Biomedical Engineering. Eds. Zeng, H. Taylor & Francis Group 2014:pp209-220.

Abstract:
Improvements in clinical management of lung cancer have been modest over the last 20 years, with an overall 5-year survival rate just above 10% in Europe and 16% in the United States. Treatment failure is mainly due to the presence of metastatic disease at diagnosis, occurring in 70% of all patients whereas in patients resected in stage IA the 5-year survival rate is higher than 70% [1]. Detection of lung cancer at an early stage offers the real potential to reduce mortality with new chances of cure. The outcomes of the National Lung Cancer Screening Trial (NLST) have highlighted favorable prospects for lung cancer low-dose CT screening (LDCT) but the cost benefit profile of screening is still matter of debate in the scientific community [2]. In particular, the high false positive rates of LDCT lead to multiple screening rounds, repeated radiation exposure, the use of invasive diagnostic follow–up procedures with associated morbidity as well as increased time and costs. In addition, LDCT screening showed a limited impact on the more aggressive lung cancers, achieving an overall mortality reduction of only 20%. Several studies have reported blood-based biomarkers for early detection of lung cancer but so far only few of them have proven useful in lung cancer clinical practice. Beside technical issues related to difficulties in protocol standardization and lack of large scale validation in clinical trials, genetic and biological tumor heterogeneity has likely limited the successful identification of tumor-specific markers. A ground-breaking way to identify novel and more reliable biomarkers is searching for candidates by looking not only at the tumor itself but also at the interplay between the tumor and the host with the aim to identify very early changes related to the biological reactivity of the host to a developing cancer. In this respect, epigenetic markers, above all circulating microRNAs (miRNAs), could represent ideal candidates since they act as extracellular messengers of biological signals derived from the cross-talk between the tumor and its surrounding microenvironment. MiRNA are short non-coding RNA emerged as critical regulators of gene expression playing a key role in physiological and pathological mechanism. Blood circulating miRNAs were also reported to be promising biomarkers for cancer detection and prognosis [3]. MiRNAs are released into the bloodstream by different mechanisms such as passive leakage of cellular miRNAs from broken cells or active secretion through microvesicles or protein complexes by several cell subtypes [4]. Although LDCT is currently the standard of care for early lung cancer detection, it results in a general over diagnosis of indolent nodules, thus increasing unnecessary confirmatory diagnostic procedures. Non-invasive circulating miRNA assays could overcome most of these problems by exploiting the synergy between the molecular and imaging tests to reduce the number of the false positives. Two groups, in 2011, identified specific plasma and serum miRNA signatures comparing samples from patients and disease free individuals collected in three independent LDCT screening trials [5;6]. Our group reported four signatures composed by reciprocal ratios among 24 miRNAs by comparing samples collected before (n=20) and at the time (n=19) of LDCT disease detection to those of 27 control samples belonging to the INT-IEO trial [7]. These signatures were initially validated in a subset of 88 samples collected from 22 patients and 54 controls enrolled in the MILD trial [8]. Three years later, the same group developed a miRNA signature classifier (MSC), containing the 24 miRNAs previously identified, and tested its performance in enlarged validation set composed of 85 patients and 1000 controls belonging to the MILD trial [9]. The results of this study showed that the combination of MSC and LDCT reduced LDCT false-positive rate from 19.4% to 3.7% and that the MSC risk groups were significantly associated with survival. In addition, MSC was high sensitive (87%) and specific (81%) and its predictive value was confirmed by time-dependency analysis. Bianchi et al. identified a 34 miRNA signature in serum samples from 59 patients enrolled in the COSMOS trial compared to 69 disease free individuals divided in training and testing sets. Globally, the test showed an AUC of 89% in the testing set, and it was also able to rule out cancer in 79% of benign lung nodules. In addition, the 34 miRNA signature did not discriminate benign or malignant breast nodules, emphasizing the specificity of the test for lung cancer. Finally, the test did not classify pre-disease plasma samples, thus limiting the capability of the test to predict the development of the disease. Very recently, the same group refined their signature to 13 miRNAs which was validated in an independent set of 1008 subjects enrolled in the COSMOS trial [10]. Interestingly, this signature displays overlap of five miRNAs with the MSC signature (38.5%), an encouraging finding given the well known difficulty in validating expression signatures in different studies and given the differences in samples collection between these two studies (i.e. plasma vs serum). More recently, taking advantage of two screening programs with a total follow up of 23,967 person-years and a median time follow-up of 5.9 years, we analyzed the prognostic value of MSC in 84 in lung cancer patients identified in LDCT screening programs. In addition, to test the ability of the plasma MSC to monitor the disease status and recurrence during follow up, the MSC test was employed to analyze 86 longitudinally-collected plasma samples obtained from patients before and after surgical resection of primary lung tumors with a follow up time up to 4.1 years. We demonstrated that the three MSC risk groups were associated with significant differences in overall survival for the 84 subjects examined, also when adjusting for tumor stage. Moreover, the MSC risk level significantly decreased in subjects who remained disease free whereas in all relapsing patients increase of the MSC risk level was observed at the time of detection of a second primary tumor or of metastatic progression. The results presented highlight the clinical usefulness of circulating miRNAs as diagnostic, prognostic and monitoring tool in lung cancer. References 1. Goldstraw 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;2:706-14. 2. Aberle DR, Adams AM, Berg CD et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. 3. Boeri M, Pastorino U, Sozzi G. Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J 2012;18:268-74. 4. Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 2014;11:145-56. 5. Boeri M, Verri C, Conte D et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 2011;108:3713-8. 6. Bianchi F, Nicassio F, Marzi M et al. A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol Med 2011;3:495-503. 7. Pastorino U, Bellomi M, Landoni C, De Fiori E, Arnaldi P, Picchio M, et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 2003; 362(9384):593-597 8. Pastorino U, Rossi M, Rosato V et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012;21:308-15. 9. Sozzi G, Boeri M, Rossi M et al. Clinical Utility of a Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. J Clin Oncol 2014;32:768-73 10. Montani F, Marzi MJ, Dezi F et al. miR-Test: A Blood Test for Lung Cancer Early Detection. J Natl Cancer Inst 2015; 107(6): djv063.

Abstract:
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor issued from the mesothelial surface of the pleural space. A previous exposure to asbestos is the main risk factor of mesothelioma. Clinical signs are most of time late and unspecific. Chest CT-scan, a key imaging procedure, usually shows pleural effusion ±pleural thickening. PET-CT may help to differentiate MPM from pleural benign tumors, as well for distal tumor staging. But PET-CT is not recommended for the diagnosis of MPM, as well as soluble biomarkers, including mesothelin. A diagnosis of MPM based on pleural biopsies best obtained by thoracoscopy is recommended with compulsory immunohistochemistry (1, 2). The treatment of MPM is so far quite deceptive with median overall survival (OS) around 12 months, and relies mostly on chemotherapy and best supportive care (BSC). To date, only first line chemotherapy by cisplatin/carboplatin+pemetrexed is recommended by all guidelines for patients fitted for chemotherapy (3). The optimal duration of first line chemotherapy is unknown but a maximum of 6 cycles is recommended. There is no evidence supporting a maintenance treatment including by pemetrexed. Therapeutic options beyond first line treatment are presently highly limited despite nearly half of patients are clinically fitted for. According to guidelines, pemetrexed alone may be proposed again if patients did have tumor progression at least 3 to 6 months after stopping chemotherapy (1, 2). Other options exhibited deceptive response rates (4). Therefore, it is recommended in the other cases to propose patients to join clinical trials. Pathogenesis of MPM includes overexpression of growth factors (VEGF…), many genetic and epigenetic alterations and/or mutations of malignant cells (p16 INK4A/CDKN2A, BAP-1, NF-2…) responsible for cell proliferation and resistance to apoptosis, pleural inflammation and local immunosuppression induced by the tumor and favoring its growth. These elements provide the rationale for many targeted therapies and immunotherapy. But so far, very few drugs exhibited sufficient value to deserve further trials. Thus, first trials assessing anti-angiogenic drugs in MPM did not support their use in this cancer despite the key role of VEGF. A phase II trial of bevacizumab (anti-VEGF antibodies) combined with cisplatin+gemcitabine was negative (5). But other phase II trials evaluating bevacizumab with cisplatin+pemetrexed were promising with PFS of 6.9, 7.9 and 9.2 months, and DCR of 40, 57 and 88%, respectively. Therefore a phase III randomized (1:1) trial (« MAPS ») recruited 448 unresectable MPM patients to test cisplatin+pemetrexed with (arm B) or without (arm A) bevacizumab (6). Arm B non-progressive patients received bevacizumab maintenance until progression or toxicity. Median OS was significantly longer in the B arm: 18.8 [95%CI: 15.9-22.6] vs. 16.1 months [14.0-17.9] in the A arm, (adj.HR= 0.76, p=0.012). Thus bevacizumab addition to pemetrexed+cisplatin provided a significantly longer survival in MPM patients with acceptable toxicity, making this triplet a new treatment paradigm for this cancer. Pro-apoptotic agents such as proteasome inhibitors (bortezomib) or histones deacetylases inhibitors (HDACi) were also assessed with discordant results. In 2[nd]/3[rd] line treatment, vorinostat (HDACi) failed to show any significant OS gain versus placebo in a large phase III trial (7). Focal adhesion kinase (FAK) is a tyrosine kinase with multiple roles in tumor growth and resistance to chemotherapy. FAK is overexpressed with increasing activity in many human cancers, associated to a low tumor expression of the Merlin molecule, a potential predictive biomarker of FAK inhibitors. An inhibition of FAK may induce tumor cells apoptosis, reduce cancer stem cells, and modulate the activity of NF-2, frequently mutated in MPM. Thus, a trial is currently assessing FAK inhibitors (VS-6063/Defactinib) as maintenance treatment after 1[rst] line chemotherapy by platinum+pemetrexed. Phase I-II trials assessed antibodies targeting mesothelin, a mesothelial cell surface molecule overexpressed in (epithelioïd) MPM, alone or combined with Listeria toxin, showing promising results (8). Other innovative techniques including gene therapy, cellular therapy or oncovirotherapy, are also currently evaluated with first promising results. But, as in melanoma or in lung cancers, checkpoint inhibitors represent presently the most exciting tool. First results with anti-CTLA4 Ab (tremelimumab) were recently published: the main goal (RR) was not achieved but several prolonged response or stable disease were observed, justifying a larger phase II trial (n=564), assessing tremelimumab versus placebo in 2[nd]/3[rd] line treatment of MPM. Early data of a phase Ib basket trial with anti-PD-1 (Pembrolizumab) in the same setting found promising RR of 28% and DCR of 76% in PD-L1 positive MPM (2015 AACR meeting). Other trials with checkpoint inhibitors are underway. To date, the place of radiotherapy is limited in MPM, mostly with palliative intent (1). Prophylactic irradiation of chest scars and drains is highly discussed. A definitive answer on this controversial indication is hoped with a current randomized UK trial. Adjuvant radiotherapy is not validated yet as well. Limitations due to technical reasons and toxicities may be answered in the future by new modalities of radiotherapy such as IMRT. Multimodal treatment of MPM patients, whatever the surgery is (i.e. extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)) is not recommended outside clinical trials (1). Recent trials, even the highly controversial “MARS” trial, and meta-analysis undeniably plead for stopping EPP and to continue P/D only in clinical trials to find the best multimodal treatment for potentially resecable MPM patients, fitted for surgery (9). Additional intrapleural treatments (chemotherapy, photodynamic therapy (PDT) or immunotherapy) seem needed to improve significantly the post-surgery outcome, mostly as now targeted therapies such as bevacizumab may increase median OS close to 19 months in patients less selected than surgical patients! Thus, Friedberg and al found exciting OS over 31 months in patients treated by multimodal treatment including extensive P/D and intrapleural PDT (10). In conclusion, many research studies presently assess the value of targeted therapies and biomarkers, opening new perspectives in the management of MPM. Remaining questions are how to target the best patients for each drug or technique, and how to combine the different current and future therapeutic tools in MPM. But real hopes seem close now for our patients after a long dark age. References Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J 2010 ;35:479-95. van Zandwijk N, Clarke C, Henderson D, Musk AW, Fong K, Nowak A, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis. 2013; 5(6): E254-E307. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44. Zucali PA, Simonelli M, Michetti G, Tiseo M, Ceresoli GL, Collovà E, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer 2012;75:360-7. Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, et al. Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma. J Clin Oncol 2012;30:2509-15. Zalcman G, Mazières J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, and Scherpereel A. Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial. ASCO 2015 annual meeting (Chicago, USA) Abstract #150191. Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Öhman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015; 16(4): 447-56. Hassan R, Kindler HL, Jahan T, Bazhenova L, Reck M, Thomas A, Pastan I, Parno J, O'Shannessy DJ, Fatato P, Maltzman JD, Wallin BA. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res. 2014; 20(23): 5927-36. Cao C, Tian DH, Park J, Allan J, Pataky KA, Yan TD. A A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer. 2014; 83(2): 240-5. Friedberg JS. Radical pleurectomy and photodynamic therapy for malignant pleural mesothelioma. Ann Cardiothorac Surg. 2012; 1(4): 472-80.

Abstract:
The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification, due in part to remarkable advances in lung cancer genetics and therapy.[1] Multiple major changes for the common lung cancers mostly follow the 2011 lung adenocarcinoma classification sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS).[2 ] This 2015 edition follows previous WHO Classifications of Lung Tumors in 1967 and 1981, of Lung and Pleural Tumors in 1999 and Tumors of the Lung, Pleura, Thymus and Heart in 2004.[3, 4] Through support of its Pathology Committee, the IASLC has played a key role in the last three WHO Classifications.[5] With each subsequent classification, new techniques were introduced resulting in increased complexity, but greater ability to personalize therapeutic strategies that are now frequently dependent on histology and genetics. The most significant changes in the 2015 Classification involve: 1) Use of immunohistochemistry throughout the classification, when possible, not only for small biopsies/cytology, but also for resected specimens in certain settings such as solid adenocarcinoma, nonkeratinizing squamous cell carcinoma, large cell carcinoma, neuroendocrine tumors and sarcomatoid carcinomas. 2) A new emphasis on genetic studies, in particular integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients. Due to the therapeutic implications, molecular testing for EGFR mutation and ALK rearrangement is today recommended in tumors classified as adenocarcinoma and in cases where an adenocarcinoma component cannot be excluded.[2, 6] 3) A new classification for small biopsies and cytology similar to that proposed in the 2011 IASLC/ATS/ERS Classification[2] proposes that tumors that have clear morphologic patterns of adenocarcinoma or squamous cell can be diagnosed as adenocarcinoma or squamous cell carcinoma, respectively, without immuhistochemistry, unless a pneumocyte marker such as TTF-1 is desired to address primary versus metastatic adenocarcinoma. However, in the setting of poorly differentiated tumors that do not show clear differentiation by routine microscopy, a limited immunohistochemical workup is recommended to allow for an accurate diagnosis and also to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (e.g. TTF-1) and a single squamous marker (e.g. p40 or p63). Nonsmall cell carcinomas (NSCC) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical markers are regarded as NSCC not otherwise specified (NOS). If a tumor with this morphology stains with pneumocyte markers (i.e. TTF-1), it is classified as NSCC, favor adenocarcinoma and if it stains only with squamous markers (i.e. p40) it is classified as NSCC, favor squamous cell carcinoma. Using this approach, a diagnosis of NSCC-NOS can be avoided in up to 90% of cases.[7, 8 ] 4) According to the 2011 IASLC/ATS/ERS Classification of lung adenocarcinoma, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were defined as entities to have 100% or near 100% disease free survival if completely resected, respectively. Also, invasive adenocarcinomas are classified according to the predominant pattern using comprehensive histologic subtyping (CHS). Multiple studies have shown prognostic significance to this approach with favorable outcome for lepidic adenocarcinomas and poor outcome for solid and micropapillary adenocarcinomas. CHS can be helpful in staging as well: 1) along with other morphologic features, it can be useful in comparing multiple lung adenocarcinomas in a single patient in order to distinguish multiple primary tumors from intrapulmonary metastases and 2) it can also help in measuring invasive size in lepidic adenocarcinomas. Micropapillary or solid predominant subtyping also appears to predict improved responsiveness to adjuvant chemotherapy compared to acinar or papillary predominant tumors in surgically resected lug adenocarcinoma patients when analyzed by disease free survival and specific disease free survival.[9] 5) The diagnosis of large cell carcinoma is restricted only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories. 6) Squamous cell carcinomas are reclassified into keratinizing, nonkeratinizing and basaloid subtypes with the non-keratinizing tumors requiring immunohistochemistry proof of squamous differentiation. 7) Neuroendocrine tumors are grouped together in one category, although new genetic data supports previous clinical, epidemiologic and pathologic data showing that low and intermediate grade typical (TC) and atypical carcinoids (AC) are distinct from the high grade small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Ki-67 is useful to distinguish carcinoids from SCLC and LCNEC especially in small crushed biopsies. However, published data do not support incorporation into the classification, particularly in separating TC from AC. Spread through air spaces (STAS) is a newly recognized pattern of invasion which consists of micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections.[10] Future clinical trials and large scale genetic studies such as The Cancer Genome Atlas (TCGA) need to incorporate the new pathologic criteria for both small biopsies and resection specimens which now require immunohistochemistry to precisely classify poorly differentiated tumors such as solid adenocarcinoma or nonkeratinizing squamous cell carcinoma. Despite promising preliminary data, additional work is needed to develop a histological grading system for lung cancer. Acknowledgement: This abstract is presented with gratitude on behalf of the WHO Panel and the IASLC Pathology Committee. References: 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 2. Travis WD, Brambilla E, Noguchi M, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 3. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with LHS, Countries pf. Histological Typing of Lung and Pleural Tumors. Berlin: Springer; 1999. 4. Travis WD, Brambilla E, Mller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; 2004. 5. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR. Forty years of the international association for study of lung cancer pathology committee. J Thorac Oncol 2014;9:1740-9. 6. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. 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 ThoracOncol 2013. 7. Nicholson AG, Gonzalez D, Shah P, Pynegar MJ, Deshmukh M, Rice A, Popat S. Refining the Diagnosis and EGFR Status of Non-small Cell Lung Carcinoma in Biopsy and Cytologic Material, Using a Panel of Mucin Staining, TTF-1, Cytokeratin 5/6, and P63, and EGFR Mutation Analysis. JThoracOncol 2010;5:436-41. 8. Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens. JThoracOncol 2010;5:442-7. 9. Tsao MS, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, Kratzke R, Graziano SL, Popper HH, Rosell R, Douillard JY, Le-Chevalier T, Pignon JP, Soria JC, Brambilla EM. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015. 10. Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, Adusumilli PS, Travis WD. Tumor Spread Through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences Following Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

WHO CLASSIFICATION

Adenocarcinoma

Lepidic adenocarcinoma

Acinar adenocarcinoma

Papillary adenocarcinoma

Micropapillary adenocarcinoma

Solid adenocarcinoma

Invasive mucinous adenocarcinoma Mixed invasive mucinous and non-mucinous adenocarcinoma

Colloid adenocarcinoma

Fetal adenocarcinoma

Enteric adenocarcinoma

Minimally invasive adenocarcinoma Non-mucinous Mucinous

Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous

Squamous cell carcinoma

Keratinizing squamous cell carcinoma

Non-keratinizing squamous cell carcinoma

Basaloid squamous cell carcinoma

Preinvasive lesion Squamous cell carcinoma in situ

Neuroendocrine tumors

Small cell carcinoma Combined small cell carcinoma

Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma

Carcinoid tumors Typical carcinoid Atypical carcinoid

Preinvasive lesion Diffuse idiopathic pulmpnary neuroendocrine cell hyperplasia

Large cell carcinoma

Abstract:
The changes introduced in the 7[th] edition of the tumour, node and metastasis (TNM) classification for lung cancer derived from the analyses of the International Association for the Study of Lung Cancer (IASLC) database. These analyses were conducted by the members of the IASLC Staging and Prognostic Factors Committee (SPFC) and the biostatisticians of Cancer Research And Biostatistics (CRAB). For the first time in the history of the TNM classification for lung cancer, the 7[th] edition was based on a truly international database of more than 80,000 evaluable patients collected in 45 different sources in 20 countries and treated with all treatment modalities from 1990 to 2000. (1) The changes recommended by the IASLC were accepted by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC) and were eventually published in their staging manuals. With this involvement of the IASLC in the revision of the TNM classification for lung cancer, the IASLC became the most important provider of data to the UICC and the AJCC for future editions of the classification. A similar process was used for the revision of the 7[th] edition into the 8[th] edition. The IASLC made an international call for submission of more data to the IASLC database. (2) The resulting international contribution amounted to more than 77,000 evaluable patients diagnosed with either non-small cell lung cancer (70,967 patients) or small cell lung cancer (6,189 patients) from 1990 to 2010. They were submitted from 35 different databases located in 16 countries in Europe, Asia, North and South America, and Australia. (3) The different subcommittees of the Lung Cancer Domain of the IASLC SPFC were in charge of analysing the data pertaining to the T, the N and the M component of the classification, as well as the stages and the small cell lung cancer. For the T component, the prognostic impact of the T descriptors was analysed in five different populations: pT1-4N0M0R0, pT1-4anyNM0R0, pT1-4anyNM0anyR, i.e., including incomplete resections, either microscopically incomplete, R1, or macroscopically incomplete, R2; and cT1-4N0M0 and cT1-4anyNM0. Survival analyses were completed with univariate and multivariate analyses adjusted by histological type, gender, region and age. The main results showed that the capacity of tumour size to separate tumours of different prognosis was greater than that shown in previous analyses, and that its influence could be spread to all T categories; the role of visceral pleura invasion as a T2 descriptor was confirmed; the prognostic impact of endobronchial location less than 2 cm from the carina (T3 in 7[th] edition) and of total atelectasis/pneumonitis (T3 in 7[th] edition) was found to be similar to that of their T2 counterparts; diaphragm invasion was found to have worse prognosis than that of other T3 descriptors; and mediastinal pleura invasion was found to be scarcely used as a T descriptor. (4) For the N component, the present N descriptors (N0, N1, N2 and N3) were found to separate tumours of different prognosis in clinically and pathologically (both in the R0 and any R populations) staged tumours. The impact of tumour burden in the lymph nodes could also be assessed when survival was analysed according to the number of nodal stations, but this could only be analysed in the population of patients who had undergone tumour resection and systematic nodal dissection, and could not be validated at clinical staging. (5) For the M component, the 7[th] edition M1a descriptors were validated, as all showed similar survival. However, when the M1b descriptors were analysed in detail, single metastasis (one metastasis in one organ) had better prognosis than multiple metastases in one or several organs. (6) Table 1 shows the changes recommended by the IASLC SPFC based on the analyses of the new IASLC database. The described changes implied some modifications in the stage grouping, creating more stages for early and advanced disease, (7) and were also applicable to small-cell lung cancer. (8) The IASLC recommendations emphasize the prognostic impact of tumour size; simplify the T descriptors by combining some of them; maintain the current N descriptors; separate tumours with single metastasis in a distinct group; and establish more stage groupings to refine prognosis based on anatomic extent of disease. They improve our capacity to indicate prognosis, which is one of the objectives of the TNM classification, and, therefore, they should be implemented in the 8[th] edition of the TNM classification. Table 1

Descriptor	7th edition	8th edition (recommended classification)
T component
	T1a	T1a
>1-2cm	T1a	T1b
>2-3cm	T1b	T1c
>3-4cm	T2a	T2a
>4-5cm	T2a	T2b
>5-7cm	T2b	T3
>7cm	T3	T4
Bronchus <2cm from carina	T3	T2
Total atelectasis/pneumonitis	T3	T2
Invasion of diaphragm	T3	T4
Invasion of mediastinal pleura	T3	-
N component
No involvement or involvement of regional lymph nodes	N0, N1, N2, N3	N0, N1, N2, N3
M component
Metastases within the thoracic cavity	M1a	M1a
Single extrathoracic metastasis	M1b	M1b
Multiple extrathoracic metastases	M1b	M1c

References 1. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006; 1: 281-286. 2. Giroux DJ, Rami-Porta R, Chansky K et al. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol 2009; 4: 679-683. 3. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC Lung Cancer Staging Project: the new database to inform the 8[th] edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 4. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 5. Asamura H et al. J Thorac Oncol 2015; in preparation. 6. Eberhardt WEE et al. J Thorac Oncol 2015; in preparation. 7. Golstraw P et al. J Thorac Oncol 2015; in preparation. 8. Nicholson AG et al. J Thorac Oncol 2015; in preparation.

Background:
Cancer has been associated with immuno-surveillance dysfunction resulting to failure in identification and removal of malignant cells, followed by subsequent proliferation. Immune cell therapy aims to restore this immuno-surveillance function and manages micro-metastasis. DC/CIK (dendritic cell/cytokine-induced killer cells) an immune-based-maintenance therapy for advanced non-small cell lung cancer has been reported to improve progression free survival in several studies. Our early study suggested limited advantage of autologous DC vaccination in advanced NSCLC, hence, we proceeded to evaluate the response of a patient with Stage IV NSCLC to DC/CIK.

Methods:
The patient, 43-year-old nonsmoker male with family history of maternal breast cancer signed an informed consent to undergo the cell therapy protocol institutionally approved by Ethics Review Board of Lung Center of the Philippines. The patient earlier diagnosed with Stage IV NSCLC in November 2013, underwent chemotherapy of two cycles of Paclitaxel and Carboplatin and subsequently Erlotinib following partial remission. Patient had no severe existing medical condition that affected protocol compliance. The patient enrolled in November 17, 2014, and underwent hematology clearance, hematopoietic stem cell (HSC) mobilization with GCSF injection and leukapheresis. HSC’s recovered from the buffy coat were propagated in-vitro using standard procedures to produce dendritic cells and cytokine induced killer cells. Three DC/CIK treatments were given at three-week intervals consisting of 25-28x10[6] DC primed with mixed peptide antigens based on personalized circulating tumor cell (CTC) RT-PCR profile and 10-20x10[6] CIK. The blood IFN-Y level, CTC count, RT-PCR profile and PET-CT data were obtained.

Results:
DC/CIK treatment resulted to initial decline in IFN-Y levels relative to baseline which recovered in levels on the second and third treatment. The CTC count showed reduction in number (i.e., from 229 to 699 and down to one cell/ml) while the RT-PCR profile indicated downregulated expression of three tumor markers (MUC1, Recoverin and p53), obliteration of one marker (KRT19) and emergence of four markers (Brachury, NFYC, S100A14 and MAGE-A3). Meanwhile, the PET-CT results indicated significant regression of bilateral pulmonary nodules and masses; interval resolution of some hypermetabolic lymph nodes and interval increase in others consistent with metastatic lymphadenopathy; osseous metastasis with interval decrease in metabolic activity of bone lesions; and occurrence of patchy reticular and ground glass opacities in right upper and lower lobe with possible infectious or inflammatory nature; and right atrium and pulmonary artery thrombosis. Few days post-PET-CT, patient manifested difficulty of breathing, cough and back pain; initially managed for pneumonia and pulmonary embolism, but showed progressive deterioration. Repeat CT-scan imaging of chest with angiography revealed drastic size increase of right lung mass relative to previous PET-CT scan; while sample biopsy revealed poorly differentiated carcinoma of lung primary. In 28 days post-PET-CT, patient yielded to Acute Respiratory Distress secondary to aggressive tumor in right lung of primary origin.

Conclusion:
DC/CIK treatment can be a promising immunobiological maintenance therapy for advanced NSCLC with recognizable molecular and clinical benefit to patients. Optimization of protocol towards anticipative strategies addressing aggressive primary tumor relapse may have to be considered in order to realize its complimentary therapeutic potential.

Background:
Lung cancer is the leading cause of cancer death globally. Important survival benefit has been recently obtained with targeted therapies against driver mutations. Immunotherapy approach under development will probably represent a new standard option of care in pretreated patients: clinical and/or pathological prognostic factors will further be needed to select the maximum benefit treated population.

Methods:
We reviewed retrospectively clinical, pathological and efficacy data from 28 patients with metastatic NSCLC treated with anti-PD1 (programmed cell death 1) and anti-PDL1 (programmed cell death-ligand 1) check-point inhibitors in our Institution between 2013 and 2015.

Results:
28 metastatic NSCLC patients were treated: 2 (7,14%) in first line, 14 (50%) in second line and 12 (40%) patients beyond third line. 82% were males, median age was 61 years old, and 71,4% adenocarcinomas. Mutation profile was defined as 1 patient (3,5%) EGFR positive and 1 patient ROS-1 positive (3,5%). PDL-1 resulted positive by immunohistochemistry on 43% of total population. 75% of patients received anti-PDL-1 therapy versus 25% anti-PD1 check point inhibitors. With a median follow up time of 22 months, overall response rate (ORR) was 10,7% and disease control rate (DCR) was 64,3%: no differences were seen by immunotherapy strategy. ORR, DCR, and median time for treatment (MTT) were analysed according to the line of therapy and type of immunotherapy. ORR 0%, DCR 100% and MTT 104 days at first line setting; ORR 7,14%, DCR 64,28% and MTT 98 days at second line; and finally, ORR 18,18%, DCR 63,63% and MTT 67 days at third line or beyond. Most of patients remain on treatment so survival data were not reached. The most common grade III-IV adverse events related with treatment were pneumonitis (14,3%), fatigue (3,6%), hyperamylasemia (3,6%), hypertransaminasemia (3,6%) and neurologic disorders (7%).

Conclusion:
Our retrospective and local analysis confirmed immunotherapy as a safe and effective therapy option with high rate of DCR and longer MTT than standard chemotherapy, independently PD-1 or PDL-1 inhibition or line of therapy used.

Background:
Brain metastases (BM) come with poor prognosis (median survival 3 to 6 months) and data are lacking as patients are often excluded from clinical trials.

Methods:
We present the results of a subgroup of NSCLC patients with BM treated with OSE-2101 (T-cytotoxic specific immunotherapy combining 9 epitopes targeting 5 tumor associated antigens and 1 pan-DR epitope) during a phase IIb study of OSE-2101 (1 injection per 3 week for 6 injections followed by 1 injection every 2 to 3 months) in advanced stage IIIB and IV NSCLC (Barve et al. 2008. J Clin Oncol 26:4418-4425). Patients were eligible whatever the number of prior chemotherapy (chemo) lines (65.5% entering 3rd line) and patients with stable BM for 2 months could be included. Six out of 64 treated patients had BM prior to inclusion and are reviewed.

Results:

Table 1: NSCLC patients included with BM

Patient	108	150	169	132	133	135
Gender	F	M	M	M	M	M
Ethnic origin	CAU	CAU	CAU	CAU	AA	CAU
Age (years)	46	61	58	79	46	57
ECOG performance status	1	1	1	1	1	1
Previous treatment	RT 30 Gy Chemo 2 lines	WBRT 30 Gy Chemo 2 lines	RT 30 Gy Chemo 2 lines	WBRT 30 Gy Chemo 3 lines	RT 30 Gy Chemo 1 line	WBRT 30 Gy Chemo 3 lines

AA: African-American, CAU: Caucasian, Chemo: chemotherapy, F: female, Gy: Gray, M: male, RT: radiotherapy, WBRT: whole brain radiotherapy Table 2: Response to therapy

Patient	108	150	169	132	133	135
OS	30.16 mo	41 mo*	16.5 mo	9.6 mo	11 mo	7 mo**
Time without progression	11.57 mo	24.39 mo	11.9 mo	4.53 mo	6.2 mo	2 mo*[2]
CTL response (positive epitopes out of 5 tested)	3	2	5	2	1	Not tested
HTL response	+	+	+	-	-	Not tested

* Patient still alive at the time of the last follow up, ** treatment stopped after 2 injections for progressive disease. CTL: cytotoxic T lymphocytes, HTL: helper T lymphocytes, mo: months, OS: Overall survival, The 6 BM patients present long survival (median 13 mo, range 7-41) considering the advanced stage and the poor prognosis of these heavily pretreated patients. All patients had received from 1 to 3 previous chemo lines. Evaluation of CTL responses to 5 epitopes of OSE-2101 in 5 patients shows that each patient had a CTL response to at least one and up to 5 epitopes. Surprisingly patients with positive HTL response (patient 108, 150, 169) achieve the longest OS when compared with negative HTL patients (132 and 133).

Conclusion:
Long OS has been documented in NSCLC patients with BM treated with T-specific immunotherapy following RT and 1 to 3 previous chemo lines.

Background:
Advanced NSCLC is now recognized as an immune-modifiable disease, and with the approval of the first PD-1 inhibitor, immune checkpoint inhibitors represent a new standard of care for patients with previously treated squamous cell lung cancer. The objective of this study was to evaluate oncologists’ familiarity with cancer immunotherapy in the context of advanced NSCLC and the impact of an educational curriculum on narrowing gaps in clinical practices.

Methods:
An expert panel of oncologists identified educational gaps in the area of cancer immunotherapy. A series of 9 CME online activities were developed, 2 of which centered on advanced NSCLC and are the focus of this study. Interactivity questions allowed learners to self-report their familiarity with immunotherapy concepts in the management of advanced NSCLC, while case vignette and knowledge-based questions were constructed around evidence-based medicine. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to all analyses.

Results:
1368 oncologists participated in the 2 activities on advanced NSCLC. As seen in the table below participation in the education activities resulted in numerous improvements in knowledge and competence as seen in the table below. Despite improvements, several important gaps remained. Only70% of oncologists comprehend that a tumor may increase in size or new lesions appear during initial therapy with an immune checkpoint inhibitor. In addition, about half of oncologists still had difficulty grasping how immune checkpoints downregulate T cell responses. Finally, oncologists still had difficulty identifying the unique side effect profile associated with immune checkpoint inhibitors. In addition, 55% of oncologists reported they were not comfortable with managing side effects associated with these agents.

Table

	% answered correctly	% answered correctly
	Pre-Activity	Post-Activity
Comprehension of Basic Immunology
Interaction of TCR with MHC-peptide complex and co-stimulatory receptors CD28/CD80 and CD86	52%	69%
Which does not represent a role of an immune checkpoint in the adaptive immune response: CTLA-4 binds to CD28, augmenting T-cell activation	50%	57%
Knowledge of Immune System’s Role in Response to Cancer
T cell infiltration and decreased risk of recurrence	69%	76%
Disease progression on an immune checkpoint inhibitor	65%	71%
Efficacy, Safety, Limitations of Immune Checkpoint Inhibitors
Limitations PD-L1 as a biomarker	26%	70%
Durability of response	5%	30%
Unique side effect profile	41%	59%

Conclusion:
The study evaluated oncologists’ familiarity with cancer immunotherapy in advanced NSCLC and demonstrated the necessity of developing targeted educational interventions for improving the knowledge and practice patterns of oncologists. Additional education is needed to continue to improve clinicians’ competence in the use of cancer immunotherapies in the management of NSCLC.

Background:
The icotinib hydrochloride tablets (Conmana) is a novel orally administered EGFR-TKI agent, which is the first homegrown anticancer drug designed, synthesizedand screened by Betapharma (Zhejiang, China) . The preclinical animal experiments showed that the agent had an anticancer activity in vitro and in vivo whose mechanism is that icotinib can inhibit EGFR activity specifically and competitively through binding to the tyrosine of the EGFR. A head-to-head Phase III clinical trial (ICOGEN) comparing the roles of icotinib and gefitinib in treating NSCLC in China has suggested that icotinib has similar (and even better) efficacy with gefitinib in treating Chinese NSCLC patients, with much better safety profiles; furthermore, it is superior to gefitinib in terms of treatment cost. Recently, a retrospective study demostrated that icotinib is active in the treatment of patients with NSCLC both in first or second/third line. Up to date, Icotinib has completed phase I、 II and III trials, Pharmacokinetic study in Phase I clinical trial data displayde that non-linear character with saturated absorption and first-order elimination. But whether the exposure of icotinib would influence the therapeutic effects is cofused us.So Beta Pharma (China) and Peking Union Medical College Hospital (PUMCH) jointly conducted this single-center open-label Phase I clinical trial, from August 2007 to April 2009, to explore the relationship between icotinib exposure and clinical outcomes of a single dose or administration for 31 consecutive days among Chinese NSCLC patients. In this article, by analysing the clinical efficacies and pharmacokinetic characteristics of iconitib in 30 subjects, we tried to elucidate the relationship between the iconitib exposure and therapeutic effects.

Methods:
In this single-center open-label phase I clinical trial, a dose-escalation method was applied until disease progression or unacceptable toxicities. Different doses of icotinib were orally administered for 31 consecutive days in different groups until disease progression or unacceptable toxicities. Blood samples were collected in the first treatment cycle (day 1 - day 28) for the pharmacokinetic analysis. Tumor responses were assessed by using the Response Evaluation Criteria in Solid Tumors(RECIST). The plasma concentrations of icotinib were assessed by liquid chromatography–mass spectrometry (LC-MS).

Results:
Univariate analysis showed that the time to maximum (Tmax) after a single dose of icotinib was significantly correlated with the overall survival (OS) (Spearman correlation coefficient=0.441, P=0.021). Patients with higher Clast were independently associated with PFS (p=0.012). Multivariate analysis showed that the AUC0-last and AUC0-∞ after a single dose of icotinib were significantly correlated with OS (P=0.037, P=0.042, respectively).. Stratification of these subjects according to smoking status indicated significant correlation between OS and AUC0-last (Spearman correlation coefficient = -0.709, P=0.015).

Conclusion:
Iconitib is a novel EGFR TKI developed by Chinese scientists. For advanced NSCLC patients who have failed prior treatment(s), the exposure of a single dose of iconitib was significantly correlated with the treatment efficacy. This finding may provide a simple and feasible clinical indicator for predicting the survivals.

Background:
Local therapy showed promising results for the patient who had an oligo-metastasis after acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).Our study is to evaluate the efficacy and safety of continuing EGFR-TKI treatment in combination with regional chemotherapy beyond RECIST progression disease (PD) of EGFR-TKI in advanced patients with EGFR mutation-positive NSCLC.

Methods:
Advanced NSCLC patients with EGFR mutation who got a locally progressed in central lung lesion after the treatment of EGFR-TKI were included.Patients received EGFR-TKI continually in combination with super-selectedsystemicarterial infusionwith docetaxel (75 mg/m2) every 21 days until disease progression again or unacceptable side effect.Response to treatment, progression-free survival (PFS) 1 (time to RECIST PD), PFS 2(time to PD if EGFR-TKI was extended beyond RECIST PD) andtreatment-related adverse effects (AEs)were analyzed. Patient-reported outcomes were evaluated inall patients who had completed a baselineassessment and at least one post-baseline assessment based on the QLQ-LC13 scales.

Results:
A total of 6 patientswere recruited. Patients had the median age of 54.17 years (range, 40-68 years).Two patients achieved partial responses and four had stable disease. Median PFS1was 11.70±8.97 months. Median PFS2 was 5.36±1.47 months.There was one death (none treatment related). OS data are immature. No unexpected side effects were found in our study.Patients reported significantly greater reductions from baseline in the symptoms of cough, hemoptysis, chest pain and dyspnea (P<0.05 for all comparisons).

Conclusion:
Continuing EGFR-TKI in combination with super-selected systemic arterial infusion chemotherapybeyond progression for advanced NSCLC patients with EGFR mutation is feasible and warrent further investigation.

Background:
Disease stage and performance status (PS) are the most widely accepted prognostic factors of non-small cell lung carcinoma. Several other features such as sex, age, histology, and health related quality of life (HRQOL) have also been reported as prognostic factors. Adenocarcinoma, especially EGFR mutation status, influences therapeutic strategy and prognosis. However, there have been few studies evaluating prognostic factors including activating EGFR mutation status focused on lung adenocarcinoma. This study aimed to clarify prognostic factors including EGFR status in advanced lung adenocarcinoma.

Methods:
From April 2010 to December 2014, patients diagnosed with lung adenocarcinoma were identified retrospectively. Stage ⅢB, StageⅣ and recurrent post-operative patients were included. A total of 95 patients with adenocarcinoma who was measured EGFR mutation status and completed the overall health related quality of life (HRQOL) item before receiving initial cytotoxic chemotherapy were included in the analysis. We evaluated HRQOL using EORTC QOL-C30 and LC-13 (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire). The activating EGFR mutations consist of a deletion in exon 19 and a point mutation involving the replacement of leucine with arginine at codon 858 (L858R) in exon 21. EGFR mutation status, HRQOL scales, PS, age, sex, stage, data on Charlson comorbidity index, pulmonary function testing, and serum levels of white blood cells, haemoglobin, fibrinogen, calcium, alkaline phosphatases, lactate dehydrogenase were included in univariate and multivariate Cox proportional hazard analyses.

Results:
The median age was 67 years. Sixty one patients were men. Five patients had stage ⅢB , 76 had stage Ⅳand 14 were recurrent post-operative cases. Thirty two patients had activating EGFR mutation. Median survival time was 556 days. Global health status, Physical functioning, Role functioning, Social functioning, Fatigue scales of EORTC QOL-C30, Coughing scales of LC-13, EGFR mutation status, PS, Stage and serum levels of white blood cells, fibrinogen and albumin were associated with poor prognosis in univariate analyses. On multivariate analysis, Role functioning (HR: 0.988, 95% CI: 0.979-0.997), activating EGFR mutation (HR: 2.621, 95% CI: 1.401-4.906), female sex (HR: 2.158, 95% CI: 1.118-4.163) and stage (HR: 0.213, 95% CI: 0.090-0.501) were significantly predictors of survival.

Conclusion:
EGFR mutation status, Role functioning, sex and stage are significant and independent prognostic factors for survival in patients with advanced lung adenocarcinoma.

Background:
The phase III clinical study (ICOGEN) showed that Icotinib has a similar efficacy and tolerability in Asian patients with advanced non-small cell lung cancer (NSCLC) compared with Gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of the EGFR-TKI Icotinib in first-month effective (unknown EGFR mutation type) and EGFR mutation positive (exon 19 deletion or exon 21 L858R point mutation) advanced non-small-cell lung cancer patients group from Eastern Coastal China .

Methods:
In this retrospective, observational, and multicentric study, 342 Eastern Coastal Chinese patients from 5 centers in China with histologically confirmed stage IIIB/IV non-small-cell lung cancer were treated in Qingdao, China. The patients with performance status from 0 to 3 wrote informed consent, and then received the standard dose of Icotinib (125 mg three times daily) until disease progression or unacceptable toxicity between Aug, 2012 and Dec, 2013. The patients were divided into EGFR mutation positive group and First-month effective group. First-month effective group refers to those patients whose tissue sample was difficult to obtain for EGFR measure and were responsive to Icotinib for one month trial. The primary outcome was progression-free survival among patients who received at least first dose of study treatment and the patients are still in follow-up.

Results:
The disease control rate (DCR) at 4[th] month was 81.6% in first-month effective group (n=170) and 89.41% in EGFR mutation positive group (n=174). The median progression-free survival (PFS) is 13.0 months (95% CI 1.0-22.8m) in first-month effective group (n=170) and 13.9 months (95% CI 1.8-24.6m) in EGFR mutation positive group (n=174), respectively (P>0.05). The 1-year survival rate of overall patients is 65.5%, 54.70% in these groups. It is impressive that PFS from first-month effective group is similar with from EGFR mutation positive group. The characteristics of non-smoker, female gender, performance status 0 or 1 are associated with a significantly better prognosis in terms of disease control rate.The median overall survival (OS) was not reached in EGFR mutation positive patients and the first-month effective group patients. The most common treatment-related adverse events are rash (n=154[45.0%]), diarrhea (n=78[22.8%]) and increase in AST and ALT (n=61[18.12%]). Most of the drug-related adverse events are mild (grade I or II) and reversible with no grade IV toxicity.

Conclusion:
Icotinib is effective and well tolerated in advanced NSCLC patients. For those patients with unknown EGFR mutation status, Icotinib first-month effective regimen may be an optical treatment rather than standard first-line chemotherapy in the future.

Background:
It has been demonstrated that lung cancer is the most common cause of brain metastases(BM). This study was designed to analyse the association of timing and survival of BM according to histology and epidermal growth factor receptor (EGFR) mutation status in patients with metastatic nonsmall cell lung cancer (NSLCL).

Methods:
We retrospectively analysed the medical records of 268 patients with NSCLC in single center in Incheon, Korea who were tested for EGFR mutation analysis from January 2010 to August 2013. We analysed the cumulative incidence of BM regard to EGFR mutation status, the time from the diagnosis to the development of BM, the time from BM to death and median survival. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test.

Results:
Out of 268 patients, 74 (28%) had BM, 54(73%) patients already at the time of diagnosis. Synchronous BM was more frequent in patient with EGFR mutation than WT EGFR patient (79% vs. 69%). But patients with metachronous BM, time to BM diagnosis was not significantly different according to EGFR status. (p=0.298) Among the 67 patients with BM, 25(37%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations and 40 had WT (60%). The time from diagnosis of first brain metastases to death(BM-OS) was significantly longer in patient with EGFR mutation than WT (22.28 vs. 7.55 month, p<0.005). The BM-OS in EGFR mutated patients with synchronous BM was longer than in EGFR WT patients (25.42 vs. 8.86 month, p<0.005). But the BM-OS in EGFR mutated patients with metachronous BM was not significant different from WT EGFR patients. (p=0.16).

Conclusion:
NSCLC patients with EGFR mutations were more prevalent with synchronous BM than those with EGFR WT patients. EGFR mutation was associated with significantly longer survival from BM diagnosis, especially in those with synchronous BM.

Background:
EGFR mutations have become an important target to choose a treatment for non-small cell lung cancer (NSCLC) patients. The response to chemotherapy is evaluated after the patient completes the second-third course of treatment. The response to tyrosine Kinase Inhibitor (TKI) could be observed in few days, the time for response evaluation is not well-defined.

Methods:
From January 2009 to November 2014, EGFR mutation status was analysed in 360 NSCLC patients’ samples. 55 patients (15,3%) were EGFR mutation positive. Among the 55 patients, 40 patients who were stage IIIB-IV and had received treatment with either gefitinib 250 mg, erlotinib 150 mg or afatinib 40 mg once daily were included in this analysis. The principal aim was to correlate the early radiological response (ERR) to TKI by computed tomography (TC) with progression‑free survival (PFS) and overall surviv­al (OS) in NSCLC patients with EGFR mutations and stage IIIB-IV disease. Secondary objectives were to correlate the TKI response with different EGFR mutations and to evaluate the safety and efficacy of TKI treatment. The PFS and OS were estimated by the Kaplan–Meier method with (SPSSv.19). The log‑rank test was used to assess significant differences between‑groups (p<0.05).

Results:
The clinic-pathologic characteristics of the 40 eligible patients are listed in table 1. The EGFR mutations identified were mainly exon 19 deletions (12 patients) and L858R point mutations (16 patients). Twenty‑six patients (65%) had ERR. Four patients with a partial response (PR) on early CT achieved a complete response (CR). The median follow‑up time was 17 months (range 2-66 months). Among the 26 patients with ERR the median PFS was 11.8 months. The median PFS for patients with stable disease (SD) and progressive disease (PD) was 7.5 months. The overall log‑rank test for PFS, when comparing the groups of patients (ERR vs SD and PD) showed a sig­nificant difference (p<0.034). For patients with ERR the median OS was 20.1 months. The median OS for patients with SD and PD was 11.9 months. The overall log‑rank test for OS, when comparing the groups showed a sig­nificant difference (p<0.017).

Table 1: The clinic-pathologic characteristics

VARIABLES	NUMBER	%
Patients	40	100
Gender Male Female	19 21	47.5 52.5
Age (years) Median (range)	62 (40-85)
Race European Others	38 2	95 5
Smoking Yes No Former smokers	9 22 9	22.5 55 22.5
Packs-year Median (range)	35.5 (5-185)
PS 0 1 >2	14 22 4	35 55 10
Pathology diagnosis Adenocarcinoma Squamous Others	37 2 1	82.5 5 2.5
Stage IIIB IV	2 38	5 95
Number of prior chemotherapies 0 1-2 >2	17 20 3	42.5 50 7.5
TKI Erlotinib Gefitinib Afatinib	30 8 2	75 20 5

Conclusion:
The ERR to TKI could be a predictive factor of PFS and OS in NSCLC with activating EGFR mutation. Patients with SD at the first evaluation should be followed closely because of the risk of early progression.

Background:
The purpose of this study was to investigate whether outcomes with various chemotherapy regimens were affected by the specific epidermal growth factor receptor (EGFR) mutations in patients with stage IV non-small cell lung cancer (NSCLC).

Methods:
We retrospectively analyzed the association between the different EGFR mutations (exon 19 deletion, exon 21, and 18 mutations) and their response to chemotherapy. A total of 17 patients with stage IV NSCLC treated at Winship Cancer Institute of Emory University between January 2007 and February 2015 who received chemotherapy were investigated retrospectively, and their clinical date were assessed according to EFGR mutation.

Results:
14 (82.4%) females and 3 (17.6%) males were identified harboring EGFR mutations. Median age at the time of diagnosis was 66 years (SD 14.08). 12 patients (70.6%) were never smokers, and 5 (29.4%) were former or current smokers. EGFR exon 19 deletion was present in 7 patients (41.2%), exon 21 mutation in 8 (47.1%), and exon 18 in 2 (11.8%). 15 (88.2%) received chemotherapy, and 11 (64.7%) received pemetrexed-based treatment. Four patients had partial response (PR) as the best response to pemetrexed-based chemotherapy, and all of them harbored exon 21 mutation. Among patients that received other types of chemotherapies (paclitaxel, gemcitabine, navelbine and platinum), 6 with exon 21 mutation, and 2 with exon 19 deletion experienced PR. Progression-free survival (PFS) was not significantly different among the groups of mutation (p=0.3645) that received paclitaxel, gemcitabine, navelbine and platinum as chemotherapies, and PFS was also not different for pemetrexed-based regimen (p=0.4569).

Conclusion:
We did not find differential sensitivity to various chemotherapy agents based on mutation type in advanced NSCLC patients harboring an EGFR mutation.

Background:
Bone metastasis and skeletal-related events (SREs) such as pathologic fracture and spinal cord compression are common in advanced lung cancer. This study was aimed to investigate the characteristics of disease progression focused on SREs during EGFR-TKI treatment.

Methods:
We retrospectively reviewed the medical records of 3,085 Korean patients with advanced non-small cell lung cancer who were treated with gefitinib or erlotinib between 2004 and 2014. SRE associated with aggravation of bone metastasis was termed ‘bone failure (BF)’. BFs were classified into 2 categories according to the presence of accompanying disease progression of preexisting cancer lesions in extra-skeletal organs; isolated bone failure (IBF) versus non-IBF.

Results:
The incidence of SREs during EGFR-TKI treatment was 4.7% (146/3085). Among them, 60 patients experienced IBF without aggravation of disease in extra-skeletal organs. IBF was more frequent in clinical benefit group (responders and stable ≥ 6 months) than in non-clinical benefit group (53.5% vs 13.3%; P < 0.001). Adenocarcinoma histology and clinical benefit from EGFR-TKI were independent risk factors for IBF (adenocarcinoma: adjusted hazard ratio [HR] 10.283; 95% confidence interval [CI] 1.148 – 92.121; P= 0.037, clinical benefit from TKI: adjusted HR 9.463; 95% CI 3.027 – 29.584; P < 0.001). The time from the start of EGFR-TKI to the occurrence of SRE was significantly longer in IBF than that in non-IBF (9.8 vs 5.2 months; P= 0.054). Moreover, patients with IBF exhibited longer survival time from the initiation of TKI (20.1 vs 7.7 months; P = 0.008) and from the occurrence of SRE (9.2 vs 1.9 months; P = 0.006). Multivariate analysis showed that IBF was one of independent prognostic factors for better survival although the statistical significance was marginal (adjusted HR 0.492; 95% CI 0.237 – 1.021; P = 0.057).

Conclusion:
IBF without systemic disease progression frequently occurs in patients with clinical benefits from EGFR-TKI treatment and shows the better survival requiring more active treatment.

Background:
Gefitinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and is a key drug for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation. The orally administered gefitinib showed large interindividual variability in its pharmacokinetics. Some phase I studies have suggested there is a relationship between gefitinib plasma concentration and skin toxicity, diarrhea, and liver toxicity. The aim of this study was to evaluate the association of pharmacokinetics or pharmacogenomics with toxicity or effectiveness of gefitinib in patients with advanced NSCLC.

Methods:
The evaluation of pharmacokinetics was performed using sample obtained on day 1 at 0, 1, 3, 5, 8, 24 hour and day 8 and day 15 after start of gefitinib 250mg administration. Plasma concentration of gefitinib was analyzed by high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, ABCC2, CYP3A4, CYP3A5, CYP2D6 were analyzed by direct sequencing.

Results:
Thirty-five patients with advanced NSCLC (14 men and 21 women; median age, 72 years; range, 53 to 90 years) were enrolled. All patients were stage IV adenocarcinoma harboring EGFR mutation: 18 had exon 19 deletions, 16 had exon 21 L858R, and 1 had exon 18 G719A. The overall response rate was 82.9% (95% confidence interval 66.4-93.4%). The median survival time was 21.2 months, and the median progression-free survival time was 10 months. The common adverse events were rash or acne (68%), diarrhea (46%), and liver injury (63%). One patient died of drug induced interstitial lung disease (ILD). The median area under the plasma concentration-time curve of gefitinib estimated from 0 to 24 hour (AUC0-24) was 10.9 (1.5-31.3) µM·h. The peak plasma concentrations (Cmax) was achieved 5 hour after dosing, and the median was 0.84 (0.38-1.74) µM. There were no statistically significant association of pharmacokinetics or pharmacogenomics with response rate, survival, and toxicity, such as skin toxicity, diarrhea, liver injury, and ILD of gefitinib. However, one patient died of drug induced ILD showed the highest AUC and Cmax.

Conclusion:
The elevated gefitinib exposure could be associated with drug-induced ILD. Further studies of the association of pharmacokinetics or pharmacogenomics with toxicity of EGFR-TKI are needed.

Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended in the first-line setting for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs are better strategy than first-line chemotherapy in EGFR-mutant patients. Generally, EGFR-TKIs had no significant benefits in overall survival (OS) compared with chemotherapy in both first-line and second-line setting. This retrospective study compared survival benefits in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Methods:
This retrospective study included 442 EGFR-mutant patients in our institute. We examined EGFR gene status from 2007 to 2015. The patients treated from 1999 to 2015. The study group contained 173 patients treated with first-line EGFR-TKI and the control group contained 109 patients who received EGFR-TKI after first-line chemotherapy. The overall survival (OS) was assessed.

Results:
There was no significant difference between first-line chemotherapy and EGFR-TKI in OS for patients with mutation-positive NSCLC (median OS; 43 vs. 38 months, P = 1.645). There was substantial difference in OS between patients with postoperative recurrence and those with III/IV stage disease. Among patients with III/IV stage NSCLC, median OS was 40.8 months in first-line chemotherapy group, 30.5 months in chemotherapy after frontline EGFR-TKI group and 21.1 months in only EGFR-TKI group.

Conclusion:
In EGFR-mutant patients, both EGFR-TKI and chemotherapy improve the survival. Among patients with advanced NSCLC, EGFR-TKI after first-line chemotherapy may improve survival than frontline EGFR-TKI. These findings need to be validated in further randomized trials.

Background:
Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). They are often associated with significant impairment of quality of life and a poor prognosis. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have proven superior to chemotherapy in patients with advanced NSCLC that harbour an EGFR mutation.​They are now standard of care as first line treatment. Many studies, however, have excluded patients with BM. Therefore the best treatment modality for these patients remains unknown. Different treatment options include: surgery, whole brain radiotherapy (WBRT), radiosurgery, chemotherapy and TKIs. This report looks at the outcomes of patients with EGFR mutated lung cancer and BM who have undergone different treatment modalities.

Methods:
The West of Scotland Network for Lung Cancer supports over 2,000 lung cancer patients per year. We collected data on patients diagnosed with EGFR mutated lung cancer between 2012 and 2014. Patients had to have radiological evidence of BM either at time of diagnosis or subsequently. Patient demographics were recorded alongside response to different treatment modalities. Outcomes included progression free survival and overall survival.

Results:
Between 2012 and 2014, 117 patients were diagnosed with EGFR mutated lung cancer. Eleven patients had confirmed BM: 10 women, 1 man, ages 48-83 years (median 62). Nine patients had BM at presentation, one developed BM while on erlotinib and another had BM on relapse post lobectomy. The median overall survival was 28 weeks (range 10-96). Three patients remain alive at 55, 64 and 139 weeks post diagnosis. Three patients were treated with erlotinib alone. Two remain alive 64 and 55 weeks from diagnosis. The first has controlled intra and extra cranial disease, whilst the other had extracranial progression at 49 weeks. The third patient only survived 22 weeks. Three patients had WBRT, two with erlotinib. Overall survival was 19 weeks without erlotinib and 34 and 42 weeks with erlotinib. A separate patient developed BM while on erlotinib and underwent WBRT. She survived a further 13 weeks from diagnosis of BM and had an overall survival of 96 weeks. One patient achieved stable extracranial disease for 81 weeks with erlotinib. At 16 weeks, however, there was progression of an isolated BM. She underwent radiosurgery with a single 20Gy fraction and on subsequent scans has stable intracranial disease 67 weeks post radiosurgery. She remains alive 139 weeks post diagnosis. Finally, two patients received no active treatment and died at 10 and 18 weeks post diagnosis.

Conclusion:
There is currently little trial data to guide our treatment decisions in patients with EGFR mutated lung cancer and BM. In our group only 9% of patients with EGFR mutated NSCLC had BM. They underwent a variety of treatment modalities, however, numbers are too small to draw firm conclusions. Without treatment, or with WBRT alone, survival is similar to patients with advanced non EGFR mutated NSCLC. The use of a TKI either with or without radiotherapy appears to have a prolonged survival and is probably the treatment of choice. Of note, no patient in this group had a change in TKI.

Background:
First generation EGFR TKIs, erlotinib, gefitinib and icotinib, have shown excellent clinical efficacy in non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, patients eventually progress due to acquired resistance in the form of a T790M point mutation. This mutation occurs in about 50-60% of EGFR TKI treated patients. Second generation, irreversible EGFR TKIs, afatinib and dacomitinib, express even higher kinase potency in the activating mutation as well as potency against the acquired resistance mutation. Clinical efficacy of these TKIs is reduced due to the dose limiting toxicities of the drugs, attributed to wild type EGFR potency of the compounds. In order to improve clinical efficacy against the activating and double mutant EGFR tumor cells, it is important to build in selectivity against wild type EGFR to avoid dose-limiting toxicities. Here, we present BPI-7701, a novel EGFR inhibitor with high potency against the activating mutant EGFR and the T790M resistance mutation with good selectivity over wild type EGFR.

Methods:
BPI-7701 was evaluated in biochemical and in vitro assays against mutant EGFR (L858R, del ex19, del ex19/T790M) and WT EGFR. In vivo anti-tumor activity was evaluated in xenografts of HCC827 (del ex19) and H1975 (del ex19/T790M) NSCLC cells.

Results:
Biochemical assays showed that BPI-7701 inhibited del ex19 and L858R mutant EGFR, as well as the T790M resistance mutation of EGFR at IC~50 ~values lower than that of WT EGFR, showing an ~100-fold difference in activity. BPI-7701 showed growth inhibition of PC-9 (del ex19), HCC827 (L858R) and H1975 (del ex19/T790M) cells in vitro, with IC~50~ values of 11-160 nM. BPI-7701 showed an IC~50~ value of 1.25 μM against A431, wild type EGFR epithelial cells. In vivo, BPI-7701 showed greater than 90% inhibition of pEGFR at tested doses as low as 6.25 mpk in nude mice. pEGFR inhibition was dose-dependent and was maintained over the course of 24 hours. In mouse xenograft studies, BPI-7701 induced complete tumor regression in H1975 (del ex19/T790M) and HCC827 (L858R) NSCLC cell lines after 14-day repeat dose treatment. In an H1975 xenograft model, complete tumor regression occurred after 6 days of BPI-7701 treatment (14-day regimen), with 80% of mice remaining tumor-free 35 days after the completion of BPI-7701 dosing.

Conclusion:
BPI-7701 inhibits the growth of NSCLC cells with EGFR mutations and T790M resistance mutation, both in vitro and in vivo. BPI-7701 may be an excellent option for NSCLC patients with activating EGFR mutations. Clinical trials are planned to begin Q2 2016 in Asia.

Background:
Genetic variations in the epidermal growth factor receptor (EGFR) gene may alter protein expression or function and influence response to tyrosine kinase inhibitors. This study evaluates the role of genetic polymorphisms in the EGFR gene in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib. EGFR mutation status was known for all patients.

Methods:
Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and polymerase chain reaction in 354 Caucasian patients with advanced NSCLC. Hundred and seven of the patients had a somatic EGFR mutation, and all patients had been treated with erlotinib. Genotypes were correlated with clinical characteristics and outcome. A multivariate analysis was conducted adjusting for clinical relevant factors, including EGFR mutation status, using Cox proportional hazards model. A subgroup analysis was performed based on the EGFR mutation status.

Results:
Patients harboring at least one variant T allele (CT or TT) at position 181946 had a significantly longer median progression-free survival (PFS) (5.6 versus (vs.) 2.9 months; p =0.032) and overall survival (OS) (8.3 vs. 6.7 months; p=0.032) compared to patients with the CC genotype. The result remained significant in a multivariate analysis; PFS, adjusted hazard ratio (AHR)=0.73 (95% confidence interval (CI): 0.55-0.98); OS, AHR=0.72 (95%CI: 0.54-0.97). Patients carrying -216GT or TT genotypes showed a trend to a better clinical outcome compared to those with the GG genotype. The -216GT or TT and 181946CT or TT combined genotypes showed an even more pronounced association with clinical outcome compared to patients with the -216GG and 181946CC genotype (PFS, AHR=0.66 (95%CI: 0.44-0.98); OS, AHR=0.58 (95%CI: 0.38-0.87)). A subgroup analysis demonstrated that the association might be most relevant in EGFR mutation-positive patients; PFS, AHR=0.27 (95% CI: 0.11-0.68); OS, AHR=0.33 (95% CI: 0.13-0.83).

Conclusion:
A combination of 181946C>T and -216G>T polymorphisms in the EGFR gene seems to be a potential predictor of longer PFS and OS in advanced NSCLC patients treated with erlotinib; especially in EGFR mutation-positive patients. A prospective randomized study is wanted to confirm our data.

Background:
Patients with higher lymphocyte to monocyte ratio (LMR) has shown to have favorable prognostic in early stage lung cancer, non-metastatic renal cell carcinoma, gastric cancer, colon cancer, pancreatic cancer and breast cancer. However, prognostic significance of LMR in patients with advanced stage, epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer receiving first line EGFR tyrosine kinase inhibitors is not well known. We conducted a retrospective analysis to investigate the influence of baseline LMR on clinical outcomes including progression free survival (PFS) and overall survival (OS) in EGFR mutant NSCLC patients.

Methods:
This retrospective study evaluated 253 patients harboring EGFR mutation received TKIs as first line therapy for advanced NSCLC between January 2011 and October 2013. The cut- off value determined by Receiver operating characteristic (ROC) curves for LMR was 3.29. Patients were divided into high and low LMR ratio based on above cut-off level. Kaplan–Meier analysis was used for PFS and OS estimation; and the log-rank test was utilized to examine the significance of the differences of survival distributions between groups.

Results:
Among 253 patients mean age was 65.2 years, 41% were male, medium PFS was 10.3 months, medium OS was 22 months. Low baseline LMR patients had shorter PFS (low vs. high: 8.2 vs 11.6m, HR: 1.508, p=0.003), and OS (low vs. high: 14.3m vs. 32.1m HR: 2.23, p<0.001) Figure 1



Conclusion:
Our results suggest baseline LMR is a prognostic marker for EGFR mutant NSCLC patients receiving first line EGFR-TKIs.

Background:
The aim of this study is to refine the existing lung cancer graded prognostic assessment (GPA) index by analysing a cohort of patients with non-small cell lung cancer (NSCLC) tested for epidermal growth factor receptor (EGFR) mutation status and newly diagnosed brain metastases.

Methods:
We used the pathology registries of two institutions to identify 259 eligible patients diagnosed with brain metastases secondary to NSCLC between 2006 and 2014. We linked the electronic medical records of these patients to the National Death Registry. Survival is defined as from date of first treatment for brain metastases or date of brain metastases diagnosis for patients on best supportive care till death. We analysed the prognostic factors significant for survival by multivariate Cox regression and recursive partitioning analysis (RPA).

Results:
Significant prognostic factors identified by multivariate Cox regression and RPA were age, Karnofsky performance status (KPS), presence of extra-cranial metastases (ECM), number of brain metastases (BM) and presence of sensitizing EGFR mutations. Patients who were age 70 years old and above (Hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.07-2.01, reference (ref) age < 70 years old); with KPS score 70-80 (HR 2.37, 95%CI 1.69-3.34, ref KPS 90-100); with KPS score < 70 (HR 4.34, 95%CI 2.90-6.51, ref KPS 90-100); ECM present (HR 1.82, 95%CI 1.27-2.62, ref no ECM); having two or more BM (HR 1.40, 95%CI 1.01-1.95, ref less than two BM) and absence of sensitizing EGFR mutations (HR 1.97, 95%CI 1.49-2.61, ref sensitizing EGFR mutations present) were poor prognostic factors. There was a robust separation of survival curves between GPA score 0-1.0 (median survival (MS) 2.1 months), GPA score 1.5-2.0 (MS 6.3 months) and GPA score 2.5-3.0 (MS 14.1 months). The proposed modified GPA index is shown in below table.

Proposed modified GPA index

Prognostic factors / score	0	0.5	1.0
Age Group	≥70 years old	<70 years old	-
KPS	<70	70-80	90-100
ECM	Present	-	Absent
No. of BM	≥2	0-1
Sensitising EGFR mutations	Absent	-	Present

Conclusion:
EGFR mutation status is a significant prognostic factor and should be considered in the design of lung-cancer GPA index. The proposed modified GPA index need to be validated with an independent dataset.

Background:
In patients with non -small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) have been associated with sensitivity to EGRF-tyrosin kinase inhibitors (TKIs). However, clinical course of EGFR mutation subtypes are still controvertial. The aim of this study was to analyze clinical features between EGFR mutation exon 19 and 21, including treatment with EGFR-TKIs

Methods:
In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by DNA sequencing method or pyrosequencing method from paraffin blocks of tissue obtained before treatment. We reviewed clinical characteristics of the patients, retrospectively.

Results:
One hundred and sixty seven patients displayed EGFR mutations in exon 19 and exon 21 from October 2002 to December 2013. 63.6% (n=100) had EGFR 19 deletion, whereas 36.3 % (n=67) had an EGFR L858R mutation. There were no differences in sex, smoking, ECOG status, stages, blood chemistry, tumor marker, and overall survivals (OS) between two groups. Overall survival was similar in both groups. However, OS was longer in non-smoker (p=0.000), female (p=0.007), and age ≥ 65 (p=0.031) only in 19 deletion group. After treatment with gefitinib (n=74), erlotinib (n=31), and afatinib (n=2), patients with EGFR mutations had a median overall survival of 47 month. Among the patients treated with gefitinib or erlotinib, gefitinib treated patients had significantly longer progression free survival (PFS) than erlotinib treated patients in EGFR exon 19 deletions (10.3 versus 5.1 months; p=0.002), but not in exon 21 mutation. The median PFS of the patients with higher body surface area (BSA, ≥1.5 m[2]) was worse than that of those with lower BSA (3.9 vs. 8.9 month; p=0.063) in exon 21 mutation group.

Conclusion:
There are different clinical course between types of EGFR exon 19 and 21 mutations. We need confirmation in a prospective study and have to more elucidation of the biological mechanisms of the differences between the two major EGFR mutations.

Background:
Preclinical data demonstrate that the T790M clone is associated with a growth disadvantage in the absence of TKI selection. With selection stress of standard dose of TKI, T790M cells may become a dominant population. In a mathematical model, high pulse dose combined with continuous low-dose of TKI could delay the emergence of resistant clone of T790M. Clinically, some patients use lower dose of EGFR TKI due to various reasons such as toxicity. The treatment outcome in terms of PFS in this group of patients has not been reported. Whether the PFS would be impaired due to dose adjustment or unaffected and even better to support above theory may need further clarification.

Methods:
A retrospective cohort study was conducted to recruit patients with advanced NSCLC from 1997/1 to 2014/12 in a regional teaching hospital. Inclusion criteria were patients whose tumors were either tested to have sensitizing mutations of EGFR using highly sensitive methods or clinically responsive to EGFR TKI using Jackman’s criteria. Patients having titrated dose of TKI to two-thirds or less for more than 6 months were assigned to low-dose (LD) group. The standard-dose (control) group includes patients receiving daily 250 mg of Gefitinib or 150 mg of Erlotinib during whole course of treatment, matched with sex and age to LD group. The primary outcome was PFS. Secondary outcome was overall survival (OS).

Results:
LD group includes 20 patients and control group 80 patients. Patients using LD treatment were mostly due to intolerable side effects with standard dose (n=18, 90%). The median PFS was 15.4 months in the LD group and 9.3 months in control (hazard ratio 0.45, 95% CI of 0.29-0.71; p=0.018). The median OS was 31.5 months in LD and 31.4 months in control (hazard ratio 0.99, 95% CI 0.49-1.98; p=0.98). In the subgroup of Gefitinib treatment, the median PFS was 17.9 months in LD and 8.1 months in control (hazard ratio 0.35, 95% CI 0.19-0.62; p=0.0037). In patients receiving Erlotinib, median PFS was 15.3 months in LD and 12.1 months in control (hazard ratio 0.67, 95% CI 0.33-1.37; p=0.2652). Median OS was similar in LD and control in either subgroup of Gefitinib or Erlotinib.

Conclusion:
This study showed that lower dose of EGFR-TKI treatment is a non-inferior strategy for patients sensitive to EGFR TKI. Better PFS in the LD group of Gefitinib-treated patients support the theory of delayed emergence of resistant clone. Since 150 mg of Erlotinib is at its maximum tolerated dose, a dose choice of no more than optimum biologic dose may be needed to gain such benefit as Gefitinib. Larger-scale studies would be needed to confirm this finding.

Background:
Many randomized clinical trials have demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are advantageous over standard chemotherapy either as front-line treatment or as further management of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). But which subgroup of patients with EGFR mutation-positive advanced NSCLC could benefit more from EGFR-TKIs needs to be further explored. In the present study, we attempted to explore predictive factors in such cohorts of patients who received gefitinib by classification and regression tree (CART) analysis.

Methods:
Included in this study were 95 patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment at the Cancer Institute (Hospital) of the Chinese Academy of Medical Sciences between February 2010 and October 2013. Multivariate analysis of progression-free survival (PFS) was performed using recursive partitioning referred to as CART analysis to assess the effect of specific variables on PFS in subgroups of patients with similar clinical features.

Results:
The median PFS in patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment was 13.3 months (95% CI 9.4-17.2). CART analysis showed an initial split on body mass index (BMI), based on which three terminal subgroups were formed. The median PFS in the three subsets ranged from 8.2 months to 15.2 months, in which the subgroup with a BMI less than or equal to 20.768Kg/m2 had the longest PFS (15.2 months). In addition, PFS in EGFR exon 19 mutation group was better than that in other mutation site group (10.3 vs. 8.2 months).

Conclusion:
BMI and exon 19 mutation are predictors of PFS in patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment. Both active EGFR mutation and patient’s own factors could be used to predict the therapeutic efficacy of EGFR-TKIs. Figure 1Figure 2

Background:
The biological rationale for intercalated therapy in EGFR mutated NSCLC is to derive benefit both from cytotoxic and from targeted therapy, avoid their mutual antagonism, and prevent tumor repopulation during intervals of cytotoxic treatment. After a promising report from a single-arm trial of intercalated treatment (Zwitter et al, Radiol Oncol 2014;48:361), we here present a comparison to treatment with TKI alone on a similar population of patients.

Methods:
All patients were treatment-naive with metastatic EGFR mutated NSCLC, were in fair general condition and fulfilled the standard criteria for platin-based chemotherapy. Patients in the intercalated group joined a prospective clinical trial and signed informed consent. Treatment consisted of gemcitabine at 1250 mg/m2 on days 1 and 4, cisplatin at 75 mg/m2 on day 2 and erlotinib 150 mg on days 5 – 15 of a 3-weekly cycle for 4 to 6 cycles, followed by continuous erlotinib as maintenance. Due to reluctance of their physicians to join the intercalated trial, patients in the TKI alone group were treated with erlotinib or gefitinib as the standard treatment.

Results:
Regarding demographics and main prognostic factors, there was a slight disbalance in favor of the TKI alone group (Table). The intercalated trial recruited 38 patients. Treatment was well tolerated, with 6 cases of grade 4 toxicity. Complete or partial response was seen in 16 and 17 patients, respectively, for response rate of 87%. For 21 patients on TKI alone as standard treatment, precise evaluation of response was not feasible. Median time to progression was 24.3 months and 9.6 months (p < 0.05), and median survival was 34.9 and 25.8 months for the intercalated and TKI alone group, respectively.

	TKI alone 21 patients	Intercalated schedule 38 patients
Gender, Female/Male	13/8	21/17
Age, median	63	61
Age, range	42 – 70	37 – 74
Performance status, 0 - 1	18	30
Performance status, 2 – 3	3	8
Brain metastases at diagnosis	5	13

Figure 1



Conclusion:
In advanced EGFR mutated NSCLC, intercalated schedule appears superior to TKI alone. These observations should be confirmed in a randomized trial.

Background:
ENSURE study shows that 1[st] line treatment with erlotinib provides longer PFS over gemcitabine/cisplatin (GP) for stage IIIB/IV NSCLC patients with EGFR mutations. Cross-over treatments after progression of disease (PD) was allowed in ENSURE study. However, post-study treatments might have significant impact on patient survival or other clinical benefits, which is insufficiently investigated. This trial in an extension of the ENSURE study, intended to evaluate PFS in 2[nd] line progression after cross-over treatments in ENSURE.

Methods:
Chinese patients who had PD after 1[st] line treatment in ENSURE were enrolled. Enrolled patients received cross-over treatment as 2[nd] line treatment after 1[st] line PD. The primary endpoint was PFS, defined as the time of randomization in ENSURE to disease progression or death while on 2[nd] line treatment. For patients who had already progressed after 2[nd] line therapy prior to entering this extension study, relevant information would be collected retrospectively. PFS from 1[st] line PD to 2[nd] line PD was also calculated. The study was approved by IRB and all patients signed informed consent. This study was registered in clinicalgrials.gov (NCT02000531). We also retrospectively analyzed the time to 2[nd] line treatment failure (TTF) defined as the time from randomization to discontinuation of 2[nd] line treatment for any reason.

Results:
Forty-five patients (21 from erlotinib arm and 24 from GP arm) were enrolled in the final analysis in this ENSURE extension study. Limited recruitment was mainly due to later initiation of this study (from January to December of 2014), many deaths at the beginning of this study, or unwillingness to sign informed consent by some patients. Age, sex, and ECOG at baseline in erlotinib group and GP group were balanced. Among 45 enrolled subjects, 33 (73.3%) subjects completed the study. There was no significant difference in median PFS from the date of randomization in ENSURE study to 2[nd] line PD for both arms 26.3 (95%CI: 19.8 , 34.0 ) months vs 23.4 (95%CI: 17.8, 39.0 ) months, HR=1.26 (95%CI: 0.61, 2.62), p=0.529). For 2[nd] line cross-over treatment, ORR in erlotinib and GP arms was 33.3% (7PR/21) and 66.7% (16PR/24) respectively (p=0.0377). In a retrospective analysis of 175 patients from the whole ENSURE study, 63.2% patients in erlotinib arm (n=87) received 2[nd] line chemotherapy and 86.4% patients in GP arm (n=88) received 2[nd] line targeted therapy. The median TTF in erlotinib and GP arm were 29.4 (95%CI: 24.7, 34.2) and 24.7 (95%CI: 21.9, 28.4) months respectively (HR=0.74(95%CI: 0.47, 1.17), p=0.192).The subgroup analysis (mutation type, ECOG performance status, gender) for TTF between erlotinib and GP arm showed similar trend to the primary analysis.

Conclusion:
Despite limitations, both median PFS (in prospective analysis) and TTF (in retrospective analysis) for erlotinib patients were numerically larger than that in GP arm. This first cross-over treatment ENSURE extension study further confirms benefits of erlotinib as standard 1[st] line treatment for EGFR mutant NSCLC. It also supports the importance of 1[st] and 2[nd] line treatment sequence of erlotinib and platinum-based chemotherapy for the treatment of EGFR mutant NSCLC.

Background:
Crizotinib has been available in Slovakia since October 2012 for the treatment of adults with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC), based on the therapeutic indication approved by the European Medicines Agency. Purpose of this study was to assess the results achieved with crizotinib in the treatment of advanced NSCLC in clinical practice in Slovakia.

Methods:
In this multicenter retrospective study, approved by the Ethical Committee of the Specialized Hospital of St Zoerardus Zobor, the data of 30 ALK-positive patients were reviewed. FISH with break-apart probes was used for the confirmation of ALK rearrangement in all cases. MedCalc[®] was used for the statistical analyses.

Results:
Between October 2012 and August 2014, 20 out of 30 ALK-positive patients were treated with crizotinib. Ten patients did not receive crizotinib: five due to on-going first-line chemotherapy, five due to other reasons. Characteristics of the treated patients: M/W: 6/14, age (years) median 56, range 23-77, PS (ECOG/WHO): 0/1/2/3: 1/10/4/5, Histology: 19 patients adenocarcinoma, 1 NSCLC, NOS. Treatment results: RR was evaluated in 20 patients: PR + CR: 13 (12+1), 65% (95% CI: 41-85), SD: 3, 15% (95% CI: 3-38), PD: 3, 15% (95% CI: 3-38), NS: 1, 5%, DCR: 16, 80% (95% CI: 56-94), PFS: Kaplan-Meier estimate: 13 months (95% CI: 7 -18), 0S (with 60% of patients censored): 19 months (95%CI: 12 - NR), PS: significant improvement within 2 months (mean dif. –0.95, P=0.0021), toxicities grade 3/4 occurred in 11 of 20 patients (55%), hematologic: 0, non-hematologic: hepatotoxicity 3/1, pneumonitis: 1/0, diarrhea 1/0, nausea: 3/0, vomiting: 1/1, vision disorder: 1/0, peripheral edema: 1/0, QT-interval prolongation: 1/0. Crizotinib was permanently discontinued due to toxicity in only two patients.

Conclusion:
Treatment results seen in this retrospective study are encouraging and consistent with the published data from the prospective trials.

Background:
Anaplastic lymphoma kinase (ALK) gene fusions are implicated in the pathogenesis of non-small cell lung cancer (NSCLC), occurring in 3–7% of cases. Crizotinib, a first-in-class ALK inhibitor, was granted US FDA approval in 2011 to treat metastatic ALK-positive (ALK+) NSCLC. However, intrinsic and acquired resistance limits its duration of use. Ceritinib, an ALK inhibitor with activity against crizotinib-resistant NSCLC and brain metastases, was granted accelerated approval by the US FDA in 2014 for treating crizotinib-resistant ALK+ NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/day (Shaw A et al. NEJM 2014;370:1189–1197) and around 60% of patients require dose interruption or reduction. This report details our experience with the use of proactive GI AE management regimens with ceritinib.

Methods:
Proactive regimens A and B were implemented in patients with metastatic ALK+ NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to dosage. Regimen B included dicyclomine, taken with the first ceritinib dose, ondansetron, taken 30 minutes prior to dosage for the first 7 doses, and loperamide, taken as needed with the onset of diarrhea. The proactive medications were tapered off depending on patient tolerability to ceritinib. We report a case series comprising 9 patients treated at two sites with ceritinib (750 mg/day) for whom these proactive GI AE management programs were successfully implemented.

Results:
The 9 patients presented had discontinued crizotinib due to disease progression or intolerance, and received ceritinib as their 2[nd]–5[th] line of treatment (Table). Rapidly starting regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in 8/9 patients. One patient discontinued therapy due to GI toxicities despite prophylaxis. One patient required dose reduction to 600 mg/day due to Grade 3 transaminitis. Using these regimens, 78% of patients were able to remain on 750 mg/day fasting. Two patients have completed 16 and 12 months of therapy, and remain on ceritinib 750 and 600 mg/day, respectively. Figure 1



Conclusion:
Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750-mg/day ceritinib dose.

Background:
The anaplastic large cell kinase gene (ALK)-positive is a special type of non-small cell lung carcinomas (NSCLC). Although Ventana IHC (D5F3) and FISH showed high coincidence for detecting ALK rearrangement, discordant results exist in some cases. Treatment strategy as well as efficacy of crizotinib in these cases is such an issue. We studied and reported the efficacy of crizotinib in six lung adenocarcinomas patients with ALK IHC positive and FISH negative.

Methods:
All histologic and cytologic specimens were stained by IHC with an anti-ALK monoclonal antibody (D5F3, Roche) with the OptiView DAB IHC Detection Kit (Roche) and OptiView Amplification kit (Ventana Medical Systems, Inc., Tucson, AZ). All histologic and cytologic samples were also tested by FISH, which was carried out using the Vysis ALK Break Apart FISH probe kit. Three samples [one histologic (patient 1) and two cytologic samples (patients 2 and 6), patients’ numbers were listed in Table 1] were still enough to further perform for EML4-ALK fusion by qRT-PCR. Two samples [one histologic(patient 1) and one cytologic sample(patient 6)] were still enough to further perform for next generation sequencing (NGS) analysis (using modified circulating single molecule amplification and resequencing technology, cSMART). The follow up data from 6 lung adenocarcinoma patients with ALK IHC-positive and FISH-negative who received crizotinib treatment were collected.

Results:
Table 1 showed the clinicopathological characteristics and the therapeutic efficacy of crozitinib for 6 patients in the study. The patients have achieved a response rate of 66.7% (4/6). Pathologically, for patient 1, the 3 unique DNA templates with EML4->EXOC6B->ALK fusion were identified in 710 DNA copies in tumor tissue. The fusion ratio is only 0.42%. For patient 6, we detected 75 unique DNA templates in total 495 DNA copies with 15.15% fusion ration in cytologic specimen. The fusion types of patient 1 and 6 were confirmed by sanger sequencing. Some unknown mechanisms caused the 3 gene fragments fusion of patient 1, the complex fusion type and low fusion ratio cause FISH negative.

Table 1：Patient Characteristics, pathologic characteristics and molecular tests in 6 cases

Patient NO.	Gender	Age	Smoking history	ALK IHC	ALK FISH	NGS-ALK	PFS (month)	Assessment
P1	Female	31	Never smoked	+	6%	E13:EXOC6B :A20	7.46+	Partial response
P2	Male	48	Ever smoker	+	10%	-	11.96+	Stable disease
P3	Female	49	Never smoked	+	6%	-	19.94+	Partial response
P4	Male	59	Ever smoker	+	6%	-	6.60+	Partial response
P5	Male	69	Ever smoker	+	10%	-	15.08+	Partial response
P6	Female	65	Never smoked	+	12%	E13:A2	3.58	Stable disease

ALK FISH: % of split signals by FISH; NGS: Next generation sequencing; +: No progressive disease was observed at the time of analyse.

Conclusion:
Lung adenocarcinoma patients with ALK IHC-positive and FISH-negative may also response to crizotinib. Ventana IHC is another candidate method for detecting ALK. One new fusion type EML4->EXOC6B->ALK fusion was verified and the patient with this fusion type showed partial response to crozitinib.

Background:
Neoadjuvant therapy is also known as induction therapy or preoperative therapy. For lung cancer, the neoadjuvant medication includes chemotherapy and targeted medication. Neoadjuvant chemotherapy is widely used in clinical practices, but targeted therapy is still rare in the preoperative applications. To our knowledge, this is the first report of neoadjuvant crizotinib and following surgery of pulmonary adenocarcinoma.

Methods:
Crizotinib had already been recommend as the standard treatment for advanced lung adenocarcinoma with anaplastic lymphoma kinase gene rearrangement. First-line therapy with crizotinib prolonged progression-free survival and improved qulity of life among selected patients. The possibility of using crizotinib as neoadjuvant therapy is interesting because of low toxicity of tyrosine kinase inhibitors. Here we report two cases affected by locally advanced lung adenocarcinoma, in whom one-month crizotinib treatment rendered the tumors reduction to surgical removal.

Results:
These two patients with ALK-positive stage IIIA received oral crizotinib 250mg twice daily in thirty days, and crizotinib was well tolerated with rapid, prominent responses following by surgery in a week. The sequential therapy of case 1 showed the less adverse events in crizotinib than chemotherapy, while case 2 revealed more obvious responses.

Conclusion:
For pulmonary adenocarcinoma patients with ALK rearrangement, crizotinib could achieve a higher remission rate and less adverse events as compared with the chemotherapy, suggesting that crizotinib may be better option for neoadjuvant therapy. A propositional clinical trial exploring the ability of preoperative crizotinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of ALK gene rearrangement is urgently needed.

Background:
Crizotinib has been commercially available since August 2011 for the treatment of locally-advanced or metastatic ALK+ non-small cell lung cancer (NSCLC). In April 2014, a second-generation ALK inhibitor, ceritinib, was approved in the US for use after intolerance to or progression on crizotinib. Tumor progression, which varies by anatomical site and extent, is complex and evolves over time, often with insidious onset. Considering this heterogeneity, it is currently unclear at which point physicians may decide to change therapy. The objective of this study was to evaluate physicians’ decision-making with regard to determining progression during crizotinib treatment of locally-advanced or metastatic ALK+ NSCLC. This research question is particularly relevant with the introduction of new, effective treatment options available to patients who progress on first-line ALK inhibitor therapy.

Methods:
In July-November 2014, US oncologists were invited to respond to a survey regarding their decision-making with regard to treatment changes following progression on crizotinib for patients with locally-advanced or metastatic ALK+ NSCLC. Information was also collected on the characteristics of their practice.

Results:
Of the 34 oncologists who responded to the survey, 59% were from private practice, 26% were from an academic practice, and 15% were from an institutional practice. In terms of practice size, 53% were from small/intermediate practices of 2-9 oncologists, and the rest were from larger practices. Half (50%) of physicians had their practice in an urban setting; 35% were in a suburban and 15% were in a rural setting. Responding physicians had been in practice for an average of 12 years. When asked to indicate all of the clinical scenarios for which they would modify or discontinue crizotinib therapy, 62% of the physicians indicated that they would do so following disease progression detected on scan; 53% following either new or worsening symptoms; 29% following the development of new metastases in the brain; 35% following the development of new metastases elsewhere; 29% following onset of a paraneoplastic neurological disorder; and 26% following lack of improvement of patient's symptoms.

Conclusion:
The study suggests there is substantial heterogeneity in the clinical scenarios physicians would consider for modifying or discontinuing therapy after progression on crizotinib. These findings highlight the need for further clinical guidance with regard to the early identification of progression on crizotinib, and in particular, for a better understanding of the optimal point to switch from crizotinib when patients present with different manifestations of disease progression.

Background:
Lung cancer is the leading cause of cancer related deaths worldwide, with approximately 1.8 million new cases diagnosed in 2012 resulting in an estimated 1.6 million deaths (Torre 2015). The basic tools of diagnosis include the assessment of clinical status (Rivera 2013), imaging to determine the size and location of tumors as well as the presence of metastases (Liam 2015), and tissue biopsies for establishing tumor histology and molecular subtype (Ofiara 2012). Correct characterization of the primary tumor can be particularly challenging when presentation includes confounding elements such as multiple lesions and/or no definite mass at the primary site. The accuracy and timing of molecular testing can play a vital role in compressing the diagnostic window for adenocarcinoma of the lung, allowing for timely treatment and a broader range of therapeutic options.

Methods:
Local research ethics board approval was obtained for this study. A standard diagnostic work up was undertaken, then supplemented by both internal and external pathological review of the available tissue sample, including EGFR and ALK mutation testing to clarify the diagnosis.

Results:
The patient, a 49 year old male smoker, initially presented with nausea, vomiting, weight loss and shortness of breath. Imaging revealed an anterior mediastinal mass with hilar, mediastinal, bilateral neck and left supraclavicular region lymphadenopathy. Ultrasound confirmed bilateral adrenal lesions and a solid lesion in the right testicle, but no definitive lung mass was identified. Presentation characteristics were initially thought to indicate a lymphoma or germ cell tumour, however, additional analysis of tissue from a biopsy of the supraclavicular node was more consistent with a poorly differentiated carcinoma suggestive of lung adenocarcinoma, with positive staining for TTF-1 and EMA and negative staining for CK20, CK45, CK30, melanoma markers and thyroglobulin. Molecular testing for EGFR and ALK mutations was then requested, along with external pathology review. Findings from external review confirmed the aforementioned molecular profile and revealed that the tumour was also negative for CDX2, CK5, P63, PAX8, OCT3/4, SALL4 and synaptophysin expression, suggestive of thymic cancer, a teratoma, a germ cell tumour, or metastases from upper gastrointestinal origin. Molecular testing results identified an EGFR exon 21 point mutation, confirming the diagnosis of primary lung cancer. Treatment with afatinib was considered; however, due to the protracted diagnostic window, the patient was ultimately too debilitated to receive therapy.

Conclusion:
The absence of a definite lung mass and the unusual clinical and molecular presentation of this case made primary tumour site identification very challenging. The differential diagnosis was ultimately achieved through molecular testing. It is now well-established that early (reflexive testing) knowledge of EGFR and ALK mutation status, accomplished through molecular profiling, is essential for the appropriate management of patients with adenocarcinoma of the lung. However, this case also highlights the importance of this type molecular characterization in achieving a timely diagnosis.

Background:
During 1998 and 2013 the “Colombian Coffee Zone” (conformed by Caldas, Quindio, and Risaralda states) had an increase of 105 mortality cases of Bronchi and lung malignant tumors, as reported in death certificates.

Methods:
This is an observational and descriptive study that was made in patients at Clinica Oncologos del Occidente in the year 2014 and the Information was taken from the Clinical History Administration System (SAHICO). Thereafter, pending data was collected, by phone calls to patients or patient’s family, according to every case. Patients were interviewed to know their actual performance status and, in case of death, date and basic cause of death was asked.

Results:
SAHICO reported 178 patients with lung cancer. From these patients, 33 did not have a correct diagnosis. Basically they did not have histology report. There were 130 patients with Non-Small Cell Lung Cancer and Small Cell Lung Cancer. The frequency of lung cancer was slightly more common in men; most of the patients were from Risaralda, followed by Caldas. 50% of the patients were 60.7 to 74 years old. The median age for men was 69.1 years old, and 64.1 years old for women. These median ages differences were statistically significant (F=9,121 p value=0,003). And 90.8% of the patients were from urban areas. 85.3% of tumors treated in 2014 correspond to NSCLC, meanwhile 10% were Small Cell lung cancer. Patients who received radiation therapy had a longer survival than patients without any radiations treatment. The survival media in the radiotherapy group was 180.4 days, and 113.2 days for the group without radiation therapy. This difference was significant (Log Rank test: 4.74, p value 0.029). Only 2 patients had both surgery and radiotherapy and had the major survival time, with a media of 331 days. The mean age of the squamous cellular carcinoma patients was 69.8 years old in 64 patients. It was reported a median survival of 120 days with a confidence interval between 78 and 162 days. Only 8 patients with squamous cellular carcinoma had surgery and reported an increase in their survival time. The time median of survival for the surgical patients was 270 days. Meanwhile, this indicator decreased in the non-surgical patients to 109.9 days.

Conclusion:
In general, characteristics of lung squamous cellular carcinoma patients in the Coffee area of Colombia are similar than other regions of the world; incidence in men is only slightly greater than in women, presumably by the early age to start of smoke of the female population and the expose since childhood to others risk factors like biomass combustion smoke. Is clear that patients are detected in an advance stage of disease which has strong influence in prognosis and outcome. Highlights the importance of an integral treatment including all management alternatives and a multidisciplinary equipment of attention for modification of prognosis and survival.

Background:
Long term survivors ( >3years) in advanced NSCLC is steadily increasing from 5 - 10% to 15 - 20%. It is related with the more effective and better treatment given in an individualised manner along with better understanding of the tumour biology. Many factors are also associated with the improved outcome. Our Institute’s 3 years data is analysed in an attempt to find out the favourable factors.

Methods:
Data mining of Stage III & IV non small cell lung cancers treated at RCC, RIMS during 2010 to 2012 are carried out from the patient’s departmental records. Only patients diagnosed and treated at RIMS who survive more than 3 years are included for analysis. Patient characteristics, disease profile & treatment pattern are analysed.

Results:
Out of 196 patients records available- Stage III & IV comprise 160 patients of these 30 patients survived more than 3 years. The analysis shows Male: Female ratio 5:4, mean age 55 years (range 36 to 90 yrs) stage III is 18(60%) stage IV 12(40%). Histologically, Squamous cell Ca. 60% Adeno ca. 24% and small cell 12% and rest others. KPS range from 60% to 90%. Treatment given: 80% received intent to cure with Chemo ± RT. And 20% palliative care only. Long survivors (>3years) 24 patients (16F + 8M) who received intent to treat chemo or chemo+ RT compared to none in supportive care only

Conclusion:
The result shows that females with Histo type adenocarcinoma who received therapy with Chemo + RT +/- targeted therapy with intent to treat are the long survivors according to this study. The study indicates that treatment should be given in a sub set of patients with advanced disease who are responders for increasing meaningful survival.

Background:
Most newly diagnosed advanced lung cancer patients have an initial medical oncology consult as an outpatient. However, occasionally the initial referral occurs as an inpatient. We explored the characteristics of advanced NSCLC patients whose first medical oncology consultation occurred while hospitalized.

Methods:
With ethics approval, we performed a retrospective analysis of all advanced NSCLC patients at our institution whose initial consult occurred while hospitalized, from 2007 to 2012. Demographics, treatment and survival data were collected. This was an exploratory analysis. Multivariate survival analysis was performed using Cox regression models.

Results:
In total, 223 patients were included (baseline characteristics in Table 1). Overall, only 24% received chemotherapy while 72% received some palliative radiotherapy. Median time from diagnosis to chemotherapy was 43 days. Reasons for not receiving chemotherapy included poor performance status (PS) (72%), patient choice (9%), clinical deterioration (6%) or co-morbidities (4%). Factors associated with receiving chemotherapy were good PS (OR 11.11 [95% CI 5.56-25.00], p<0.001), no constitutional symptoms (OR 2.86 [95% CI 1.41-5.88], p=0.004), no leukocytosis (OR 2.38 [95% CI 1.23-4.55], p=0.01), fewer co-morbidities (OR 1.54 [95% CI 1.27-1.89], p<0.001) and younger age (OR 1.09 [95% CI 1.05-1.12], p<0.001). Median OS was shorter in those not receiving chemotherapy (1.7 v 7.1 months, HR 2.76 [95% CI 1.72-4.41], p-value<0.001). Figure 1 shows Kaplan-Meier survival curves. In multivariate analysis, in addition to not receiving chemotherapy, factors associated with shorter OS were PS 3-4, (HR 1.55 [CI 1.03-2.33, p=0.04]), leukocytosis (HR 2.23 [95% CI 1.51-3.28], p-value <0.001) and thrombocytosis (HR 1.52 [1.06-2.18], p=0.02).

Conclusion:
Patients whose first consultation with medical oncologists occurs while hospitalized are an inherently sick population and only a minority receive chemotherapy. The lung cancer community must advocate for earlier diagnosis and referral, so more patients have access to treatment options before a terminal functional decline.

Table 1: Baseline Characteristics

Demographic (N=223)	%
Age in years, median (range)	65 (23-89)
Gender
Male	48
Female	52
Charlson Comorbidity Index total score, median (range)	10 (6-18)
Performance status
0-2	24
3-4	69
Unknown	7
Smoking status
Current	49
Ex	34
Never	9
Unknown	8
Stage at diagnosis
IIIB	10
IV	89
Unknown	1
NSCLC subtype
Adenocarcinoma	45
Squamous cell	23
Large cell	8
Other	23
Dominant presenting symptom
Dyspnea	34
Pain	23
Constitutional symptoms	9
Pneumonia	7
Cough	5
Hemoptysis	3
Other	18
Weight loss
<5%	22
>5%	52
Unknown	25

Figure 1

Background:
Brain metastases are evidenced in 10 to 30 % of NSCLC patients sometime during the disease. The purpose of our research is to identify the clinical pathological characteristics in patients with stage IIIB-IV in relation to the development of brain metastases.

Methods:
590 patients with lung cancer at our institution were analyzed between 2000 and 2013, of which 190 (32,3%) were stage EIIIB and 400 (67,7%) EIV. 76 (12.8%) had brain metastases. The variables included in the analysis of patients with and without brain metastases were: gender, age, histology, smoking status and ECOG. The multivariate logistic regression model was used to identify factors related to brain metastases.

Results:
64 patients out of the total 76 had brain metastases at initial diagnosis and 11 EIIIB developed brain metastasis in relapses. The development of brain metastasis was higher in men compared to women (77.7% vs 22.2%). Over 80% of patients presented ECOG of 0-1. Regarding histology, 60.32% were adenocarcinomas; 30% squamous, and 9.5% undifferentiated. 65% of patients were under 65 years old. 66.6% of patients were former smokers. Patients under 65 years old were at increased risk of developing brain metastases than older patients (HR=0,5-IC95%= 0,6-1,16- p=0,045). Adenocarcinoma histology was associated with an increased number of brain metastases development (OR = 2.42 - 95% CI = 1.84 to 3.00 - p= 0.003).

Conclusion:
Patients who were younger than 65 years old and adenocarcinoma histology, had a statistically significant higher risk of developing brain metastases. Regarding gender, we observed an increased risk in men; however, the differences were not statistically significant.

Background:
The brain is one of the organs where lung cancer often metastasizes. At the time of diagnosis, the central nervous system metastases are present in approximately 10% of lung cancer cases. 80-85% of them are located supratentorially, and 10-15% of supratentorial lesions are located on cerebellar regions. Median survival is 1-2 months from the time of diagnosis without treatment. A general consensus about standard treatment could not be provided in lung cancer with a single brain metastasis; but distant metastases should necessarily be controlled with surgery or stereotactic radiation therapy.

Methods:
74 patients (65 men and 9 women) were included in the study and evaluated retrospectively. They were followed in the department of medical oncology, school of medicine, Uludag University. All the patients had cranial operations for cranial metastases between 2004 and 2012. The ages and the first symptoms of the patients at the time of diagnosis, tumor localizations, surgical procedures, chemotherapy and radiotherapy protocols and histologic subtypes of lung cancer were analyzed. Time from diagnosis of cranial metastases to death was estimated as overall survival.

Results:
The symptoms of the patients at the time of diagnosis were as follows: 21 (28%) headache, 17 (23%) hemiparesis, 18 (24%) more than one neurologic symptoms, 8 (10%) seizure, and 8 (10%) imbalance. The distrıbution of histologic subtypes of patients was as follows: 42 (56%) adenocarcinoma, 17 (23%) squamous cell carcinoma, 14 (14%) small cell carcinoma, and 1 (1%) large cell carcinoma. According to surgical procedures, patients are distributed as follows: 68 (92%) total resection, 4 (5%) subtotal resection, and 2 (3%) stereotactic biopsy. 55 (74%) patients received cranial radiotherapy postoperatively. 15 (20%) patients received radiotherapy for both cranium and lung. 3 (4%) patients did not received radiotherapy. 1 patient’s information about radiotherapy could not be reached. 70 (95%) patients received platinum-based chemotherapy. 4 ()patients did not receive any chemotherapy regimens. Median overall survival was 12 months (1-110 months) in patients with cranial metastases.

Conclusion:
In an article examining brain metastases that were developed postoperatively, 65 patients were evaluated. 5-year survival in this group of patients was 15%. In that study, factors that affect survival positively, were listed as: female gender, adenocarcinoma histologic subtype, presence of limited number of metastases (1-2), no other extra thoracic metastases except brain metastases, stereotactic, radiologic and/or surgical treatment for metastases. However, in the literature it was reported that three cases, whose brain metastases appeared after surgical resection of lung cancer, had overall survival over 12 years with stereotactic radiotherapy. On the other hand, it is obvious that systemic therapy is so important for metastatic patients. The benefits of the combined treatment with surgery were studied by many groups. Although the studies have not identified the prognostic factors for survival exactly and either responded which group of patients could see more benefit from aggressive treatment yet; good results have been taken by adding surgical resection of metastases to combined treatment in especially selected patients.

Background:
Several studies have shown that tyrosine kinase inhibitors and chemotherapy improve the short term and median survival of patients with metastatic adenocarcinoma of the lung (MAL), but the long term survival (LTS) of these patients has not been thoroughly investigated.

Methods:
We performed a univariate retrospective analysis on 174 patients with MAL diagnosed at our institution between 2009 and 2011, and with up to a 5-year follow-up. Most patients received multiple treatment modalities. Overall survival was estimated using the product-limit method and compared using the log-rank test (significant results listed in Table 1); patients alive at last follow-up were censored.

Results:
In our series, 19% (33) of all patients (174) received erlotinib as part of their treatment, and 39%(13) of those receiving erlotinib had epidermal growth factor receptor (EGFR) mutations. Although the 2-year and median survival were superior in patients receiving erlotinib and chemotherapy, neither improved the 5-year survival rate (LTS). Surprinsingly, the 60-months survival rate was higher in the no erlotinib arm (Figure 1). The only treatment modality that significantly improved LTS was surgery. For the patients treated with erlotinib and chemotherapy, regardless of EGFR mutations, all observed deaths occurred within 4 years. Factors associated with LTS were: sex, surgery, and presence of metastatic disease confined to the the lungs.

Conclusion:
In our univariate retrospective analysis, MAL patients who were treated with erlotinib and chemotherapy had improved 2-year and median survival rates compared to patients treated with chemotherapy alone, but had no improvement in LTS. Factors such as: surgery, metastases limited to the lungs only, female sex were associated with LTS in MAL patients, but larger prospective studies are needed to confirm our findings. Our study puts into question the long term survival benefit of tyrosine kinase inhibitors in MAL and suggests a prominent role of surgery in this clinical context. Figure 1 Figure 2

Background:
This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS.

Methods:
Thoracic Oncology Research Program (TORP) Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. Three hundred and sixty four patients included in this analysis had advanced NSCLC and underwent genotype testing by FoundationOne, Caris Molecular Intelligence, and Response Genetics.

Results:
99.4% (159/160) of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor types. However, mutations were not mutually exclusive. For the entire cohort 28% of patients were African Americans; adenocarcinoma was the most commonly tested tumor subtype; 91% of KRAS mutations were detected in smokers; 46% of EGFR alterations and 50% of ALK translocations were detected in never smokers. The majority of ALK translocations were detected in adenocarcinomas.

Conclusion:
Personalized medicine is a significant step forward in the realm of lung cancer treatment. In conjunction with NGS to identify and characterize tumor specific molecular abnormalities, biomarker-driven therapies have improved patients’ overall survival. NGS in this study identified potentially actionable genetic alterations across various tumor histology subtypes, races and smoking status. NGS also provided additional information by uncovering targetable concurrent alterations or alterations of unknown significance at this point in time, but potentially targetable in the future.

Background:
Non-Small Cell Lung Cancer (NSCLC) patients tend to develop brain metastasis (BM) early in the course of the disease, usually within 2 years of diagnosis. BM are an important cause of morbidity and mortality, the study of prognostic factors for its development are invaluable in implementing measures to prevent or decrease the incidence of BM. The aim of this study was to evaluate the prognostic value of certain clinical characteristics in the development of BM in NSCLC patients.

Methods:
We retrospectively analyzed all patients diagnosed with NSCLC at our institution between 2000 and 2013. Demographics, tumor characteristics and metastatic patterns were studied. Median follow up was 45 months. Cox regression was used for multivariate analysis.

Results:
A total of 1062 patients were studied. Of these, 172 (16%) had BM at the time of analysis, with 61 (35%) patients having BM at diagnosis. Median age was 68 years (range, 18-91); median time from diagnosis to BM was 259 days. There were more females than males (64% vs. 36%, p < 0.0001). About NSCLC characteristics, patients with BM were more likely to have upper lobe tumors than all other tumor locations combined (63% vs. 37%, p < 0.0001). 32% of the lung tumors were 5-7cm in diameter and adenocarcinoma represented 68% of all the histologic subtypes. In regards to other distant metastases: 34% of the patients had bone metastasis, 23% adrenal and 17% hepatic. BM were most commonly located in the frontal (41%), parietal (17%) and occipital (14%) lobes. There was a significant survival difference between Stage IV patients with and without BM; patients with BM survived 6.1 months compared with 11.9 months in those without BM (p < 0.0001). In univariate analysis, female sex, histologic grade, upper lobe tumors and high LDH levels were associated with BM. Age < 65 years (HR: 0.60, 95%CI: 0.37-0.95, p < 0.03), T3-4 tumors (HR: 3.4, 95%CI: 2.04-5.64, p < 0.0001), adrenal metastasis (HR: 5.2 95%CI: 2.5-10.7, p < 0.0001) and liver metastasis (HR: 8.6, 95%CI: 4.3-17.2, p < 0.0001) were independent risk factors for the development BM.

Conclusion:
The results of this study pose female sex, tumor histologic grade, tumor location, and LDH levels as important prognosticators of future BM. In addition, younger age, T3-4 tumors, and the presence of adrenal/liver metastases are noted as independent risk factors for BM development. With this information, criteria for the selection of patients as suitable candidates for intra-cranial irradiation, periodic brain imaging studies, and close outpatient follow-up may aid in further prevention of BM, early identification, and timely management.

Background:
The bone is one of the most frequent sites for metastases from non-small cell lung cancer (NSCLC) and bone metastases are diagnosed in 30-40% of patients. They are resulted in skeletal-related events (SREs) that associate with an important morbidity and poor survival. In the current study, clinicopathological factors and SRE-free survival were evaluated for patients with NSCLC with bone metastases.

Methods:
Three-hundred and thirty-five NCSLC patients with bone metastases were retrospectively analyzed, between 2010 and 2013. The effect of clinicopathological factors on SRE and survival were evaluated for all patients with or without SREs.

Results:
Totally, 244 (72.8%) patients developed SREs at the diagnosis or during treatment of disease. Of these, 145 required radiotherapy to the bone or pathological fracture, 59 developed malignant hypercalcemia, 21 developed compression fracture of the vertebrae and 5 required surgical treatment of the bone. There were significant differences between the patients with respect to number of bone metastasis, the presence of palliative radiotherapy and the presence of bisphosphonate therapy. The association of histopathological subtypes and bone metastases was not detected. Patients with multiple bone metastasis had significantly increased SRE when compared to patients with single bone metastasis (p=0.002). Patients with single bone metastasis had a better median SRE-free survival compared with patients multiple bone metastasis (7 vs. 2 months, respectively, p<0.0001). Univariate analysis revealed that performance status (PS), the presence of bone metastasis at diagnosis, number of bone metastasis, SRE, the presence of palliative radiotherapy and bisphosphonate therapy were significant prognostic factors for overall survival (OS). Patients with bone metastasis at diagnosis had a shorter median OS compared with patients developed bone metastasis after diagnosis (8 vs. 18 months, respectively, p<0.0001). The presence of bone metastasis at diagnosis and number of bone metastasis were found to be an independent factors for predicting the occurrence of SRE (p<0.001 and p<0.001, respectively).

Conclusion:
Our results showed that the presence of multiple bone metastases was significantly associated with the development of SRE for NSCLC patients with bone metastases. In addition, bone metastasis at diagnosis is related with poor OS. The determining of additional factors affecting the occurrence of SREs may guide to best treatment for NSCLC patients with bone metastases.

Background:
Approximately 180,000 Americans are diagnosed with non-small cell lung cancer (NSCLC) annually, and more than half have advanced (Stage IIIB/IV) disease. Historically, survival for these patients has been poor. Moreover, even though standard systemic therapies (e.g. platinum-doublet chemotherapy) provide a modest survival advantage, a substantial proportion(~60%) of patients do not initiate or complete treatment. The advent of newer systemic therapies with more favorable effectiveness and toxicity profiles affords opportunities to improve NSCLC outcomes. The objectives of this study were: 1)to quantify survival gains from 1990-2015, ranging from a period when best supportive care(BSC) only was standard, to the present, where multiple cytotoxic and targeted therapies are available, and 2)to project the potential impact of increasing use of modern systemic therapies in clinically appropriate patients.

Methods:
We developed a simulation model to estimate observed and potential survival gains for patients diagnosed with advanced NSCLC in 1990 and 2015. Survival inputs were derived from Phase III clinical trials referenced in National Comprehensive Cancer Network guidelines, and extrapolated to a lifetime horizon by fitting Weibull curves. Proportions of patients receiving available therapies were derived from SEER (for % receiving BSC only) and a commercial treatment registry. Outcomes included one-year survival proportion, mean expected overall survival(OS), expected OS if the proportion receiving systemic therapy is increased by 10% (“Scenario 1”) and 30% (“Scenario 2”) relative to current use, and population-level estimates of total life years. Results were calibrated with SEER overall survival curves. Annual incidence of advanced NSCLC was assumed to be 92,000 in both years.

Results:
In the expected survival analysis, from 1990 to 2015, one-year survival proportion increased by 15.8% and mean per-patient survival improved by 4.3 months (33,412 population life years)(Table 1). In scenarios 1 and 2, the improvement in survival increased to 4.6 months (35,684 population life years) and 5.2 months (40,279 population life years), respectively. Considering the proportion receiving each treatment, and the size of overall survival treatment effects, the majority of the survival gains were attributable to the advent of platinum-doublet chemotherapy (49%), followed by EGFR (35%), VEGF (10%), and ALK (6%) targeted therapies.

Table 1: Advanced non-small cell lung cancer outcomes by year of diagnosis.

Diagnosis Year	Expected: One-Year Survival (%)	Expected: Mean Per-Patient Survival (Months)	Expected: Population Life Years	Scenario 1: Population Life Years with 10% Relative Increase in Proportion Treated	Scenario 2: Population Life Years with 30% Relative Increase in Proportion Treated
2015	29.3%	11.4	87,287	89,559	95,154
1990	13.5%	7.1	53,875	53,875	53,875
Difference	+15.8%	+4.3	+33,412	+35,684	+40,279

Conclusion:
Though survival remains poor in advanced NSCLC relative to other common cancers, meaningful progress in per-patient and population-level outcomes has been realized over the past 25 years. These advances can be improved even further by increasing use of systemic therapies in the substantial proportion of patients who are suitable for treatment, yet currently receive BSC only.

Background:
The OEA[TM] is a clinical support system with a continuous improvement capability. Its objectives are to enable/empower evidence-based decisions/care by disseminating knowledge and expertise to physicians/users tailored to meet the clinical needs of individual patients as if consulting with an expert. Cognitive computing platforms have the potential to disseminate expert knowledge and tertiary level care to patients. This objective is made possible by making available to physicians/providers cognitive computing generated expert recommendations in diagnosis, staging and treatment. The cognitive computing software was trained by MD Anderson experts using currently available consensus guidelines and an iterative feedback process. Here we test the capability of this cognitive computing software program developed at MD Anderson to generate expert recommendations when patients with advanced-stage NSCLC have a targetable molecular aberration.

Methods:
We developed a web based prototype of MD Anderson’s Oncology Expert Advisor (OEA[TM]), a cognitive clinical decision support tool powered by IBM Watson. The Watson technology is IBM’s third generation cognitive computing system based on its unique capabilities in natural language processing and deep QA (question-answer). We trained OEA[TM] by loading historical patient cases and assessed the accuracy of targeted treatment suggestions using MD Anderson’s physicians’ decisions as benchmark. A false positive result was defined as a treatment recommendation rendered with high confidence that was non-correct (less optimal), whereas false negative was defined as a correct or more optimal treatment suggestion listed as a low confidence recommendation.

Results:
In our preliminary analyses, OEA[TM] demonstrated four core capabilities: 1) Patient Evaluation through interpretation of structured and unstructured clinical data to create a dynamic case summary with longitudinal view of the pertinent events 2) Treatment and management suggestions based on patient profile weighed against consensus guidelines, relevant literature, and MD Anderson expertise, which included approved therapies, genomic based therapies as well as automated matching to appropriate clinical trials at MD Anderson, 3) Care pathway advisory that alerts the user for anticipated toxicities and its early identification and proactive management, and 4) Patient-oriented research functionalities for identification of patient cohorts and hypothesis generation for future potential clinical investigations. Detailed testing continues and the accuracy of standard-of-care (SOC) treatment recommendations of OEA[TM], as well as false positivity and negativity rates will be presented in detail at the meeting.

Conclusion:
OEA[TM] is able to generate dynamic patient case summary by interpreting structured and unstructured clinical data and suggest personalized treatment options. Live system evaluation of OEA[TM] is ongoing and the application of OEA[TM] in clinical practice is expected to be piloted at our institution.

Background:
EGFR mutation-positive (EGFR M+) NSCLC is a specific lung cancer subtype characterized by presence of EGFR mutations and sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Common activating mutations (Del19, L858R) account for ~90% of EGFR M+ NSCLC cases. Afatinib, an oral, irreversible ErbB family blocker, improved progression-free survival (PFS) versus standard platinum-based chemotherapy in 1st-line EGFR M+ NSCLC. Afatinib also significantly prolonged overall survival (OS) in the EGFR Del19 mutation subgroup. Erlotinib, a reversible EGFR TKI licensed in the US has also improved PFS in EGFR Del19 mutation subgroup, but not OS. The objective of this study was to assess the cost-effectiveness of afatinib versus erlotinib in the 1st-line treatment of patients with metastatic EGFR Del19 M+ NSCLC in the US healthcare setting.

Methods:
A partitioned survival model was developed consisting of “progression-free”, “progressive disease”, and “death” health states. Patients entered the model in the progression-free state and advanced to progressive disease and death based on the progression-free survival and overall survival curves. The survival curves for afatinib were estimated by fitting parametric models to the empirical data from the LUX-Lung 3 clinical trial. For erlotinib the survival curves were estimated based on hazard ratios that were applied to the afatinib curves. The hazard ratios were derived via a network meta-analysis. Patients incurred treatment-specific drug costs for afatinib and erlotinib until disease progression. Costs to treat grade 3/4 adverse events were applied to each treatment. Resource use from the LUX-Lung 3 trial data and unit costs from published literature and from standard U.S. sources were used to derive the additional, monthly costs of being progression free. Monthly continuing care costs and one-time, end-of-life costs for patients with progressive disease were obtained from published literature. The utility of progression-free disease was obtained from LUX-Lung 3, and the disutility of progressive disease was obtained from the published literature. Disutilities associated with adverse events were also obtained from the literature. The model calculated patient survival (life years) and quality of life adjusted years (QALYs), and total costs per patient. Incremental cost-effectiveness ratios (ICERs) were calculated as the ratio of the difference in cost to the difference in LYs and QALYs. Costs and outcomes were calculated over a 20-year time horizon and discounted at an annual rate of 3%.

Results:
Based on the model, the patients taking afatinib accrued more life years (3.09 vs. 2.46) and QALYs (2.17 vs. 1.72) than patients taking erlotinib. Although the wholesale acquisition cost (WAC) of afatinib was lower than that of erlotinib, the incremental per patient cost was higher with afatinib ($ 32,961) owing to patients spending more time in “progression-free”, and “post-progression” health states in the afatinib group. At an accepted US ICER threshold of $100,000/QALY, afatinib vs. erlotinib had an ICER/QALY gained of $74,345 and cost per LY gained was $52,401.

Conclusion:
Afatinib as a 1st-line therapy for locally advanced or metastatic NSCLC with EGFR exon 19 deletion mutations is a cost-effective alternative to erlotinib according to the commonly accepted cost-effectiveness threshold in the US.

Background:
The RANZCR Faculty of Radiation Oncology Lung Interest Cooperative (FROLIC) surveyed patterns of lung cancer radiotherapy practice in Australasia for both non-small cell (NSCLC)and small cell lung (SCLC) cancer to evaluate current patterns of care and define gaps in optimal care requiring improvement.

Methods:
Radiation Oncologists were surveyed at all 62 departments in Australasia using a web-based survey targeting those treating lung cancer. Questions covered current radiotherapy practice as well as measures of quality

Results:
Of 62 responses received, 57 did treat lung cancer and were eligible for analysis. All Australian states and New Zealand were represented. Sixty-two percent of respondents worked at metropolitan centres, 58% were subspecialists in lung cancer and 60% participate in lung cancer trials. Ninety-four percent discuss lung cancer patients at a tumour board, 74% peer review contours for conventional fractionation and 50% for SABR. Fifty percent used a department protocol for contouring and/or prescription, 39%, an external protocol and 11% had no protocol. For radical conventional radiotherapy, 58% use 4DCT to assess tumour motion, 44% utilise breath hold or respiratory gating, 44% use PET Fusion, 35%, free-breathing CT and 23% PET-CT simulation. In palliative settings, free-breathing CT was most common (81%). For conventional treatment, 98% use 3DCRT, 34% IMRT and 18% VMAT. Image verification was primarily with cone beam CT (86%), KV imaging (72%) and MV imaging (30%). The commonest dose fractionation regime in NSCLC was 60Gy in 30 fractions used in 95% of node-positive and 82% of node-negative disease. 66Gy in 33 fractions and 50-55Gy in 20 had been used by 32% and 30%of respondents respectively. 30Gy/10 fractions was the most frequent palliative regime that had been used (by 76%), followed by 36Gy/12 (72%) . For limited stage SCLC, the majority (61%) treated with 45-50.4Gy in 25-28 fractions while 45Gy/30 twice daily had been used by 48%. In extensive stage SCLC, consolidation chest radiotherapy was used by 63% in complete response, 48% for partial response and 24% would not treat. 46% of departments provided SABR but only half treated central tumours. For peripheral tumours, 80% used 54Gy in 3 fractions and if close to chest wall, 70% used 48Gy in 4 fractions. In fit patients with synchronous solitary brain metastasis and controlled extra-thoracic disease, 37% of respondents would treat both chest and brain definitively, 43% would do so only if chest disease was equivalent to Stage I/II, and 9% would never treat radically. If three brain metastases were present, just 46% would treat definitively. In the setting of an isolated systemic metastasis only, 35% would treat definitively while 61% do not offer definitive treatment in the setting of systemic oligo-metastases.

Conclusion:
A significant proportion of radiation oncologists did not have access to 4DCT for simulation. The majority used 3D image verification and consistently prescribed evidence-based doses. Although protocols were widely used, a significant number did not participate in peer review of contours. The treatment of synchronous oligo-metastatic disease was variable, likely due to a lack of high quality evidence and should be an area of future research.

Background:
Although TAILOR phase 3 trial showed superiority of docetaxel versus erlotinib as second line treatment in NSCLC with wild type EGFR as assessed by direct sequencing, second-line treatment of patients with wild-type status is controversial and EGFR-TKIs are still used as second line treatment.

Methods:
We retrospectively analyzed the results of 2[nd] line treatment with EGFR-TKIs in 25 patients with activating EGFR mutations and 68 patients with wild-type EGFR as assessed by PNA clamping (Panagene®, South Korea), which is more sensitive than direct sequencing.

Results:
There was no significant difference in age, sex, smoking history and histologic subtypes of NSCLC between the two groups. Erlotinib was more frequently used in EGFR wild group (48/68, 71%), while use of gefitinib was significantly higher in EGFR mutation group (15/25, 60%, p=0.003). Progression-free survival (PFS) was significantly longer in EGFR mutation group than EGFR wild group: median PFS was 11.6 months (95% CI 6.2~17.1) in mutation group versus 1.8 months (1.5~2.1) in wild group (log rank p<0.001). PFS was numerically shorter than the 2.4 months (2.1~2.6) of TAILOR trial. Figure 1



Conclusion:
This results show that possibility of survival benefit using second-line EGFR-TKI is very low in patients with NSCLC with wild-type EGFR status, when tested with sensitive EGFR mutation detection technique. Thus chemotherapy should be favored for the second line treatment of patients with NSCLC with wild-type EGFR status.

Background:
Limited data are available on treatment experience in patients with advanced lung adenocarcinoma with unknown EGFR gene status (UN-EGFR-GS). We studied the demographic profile and treatment outcomes of advanced NSCLC patients with adenocarcinoma, which the EGFR gene status was unknown.

Methods:
Retrospective study of patients with UN-EGFR-GS advanced lung adenocarcinoma over a 4-year period at a tertiary care institute in China. Patients diagnosed with stage IIIb or IV were included for analysis during 2009 and 2012.

Results:
In total, 113 patients were included, females and males constituted 46.9% (n=53) and 53.1% (n=60), respectively. Among the 113 patients, 53 were non-smokers and 60 were smokers. The median age was 57.5y(35y-85y). The performance score was 2 in only 12 patients, otherwise was 0 or 1. Majority of patients had stage IV disease (95.6%). Seventy-five patients were advanced stage when diagnosed, and 38 patients were relapsed disease once received surgical resection. Nine patients received adjuvant chemotherapy, which were not relapsed in 6 months after finishing last cycle. The common regimens of first-line treatment were gemcitabine plus platinum (n=36) and pemetrexed plus platinum (n=32). Eleven patients received EGFR-TKIs as first-line treatment. Other drugs included docetaxel, paclitaxel, novelbine and etc. The commonest second-line treatment was oral EGFR-TKIs (n=44). Fifty patients received third-line treatment and 19 received fourth-line treatment. At the end of follow-up (2015-3-30), 91 patients were dead and 22 patients were alive or lost follow up. The median survival of this whole cohort was 20.0m (16.1m-24.0m, 95%CI). The overall survival was not associated with sex (p=0.441), performance status (p=0.809) and smoking (p=0.677). Those patients (29.9m, 95%CI; 18.6m-41.1m) who received surgical resection lived longer than the patients (17.8m, 95%CI; 13.8m-21.8m) who were advanced stage when diagnosed (p=0.01). The overall survival was also not associated with the chemotherapy drugs used in the first-line treatment. The patients (19.0m, 95%CI; 11.4m-26.5m) used pemetrexed plus platinum lived no longer than other regimens (20.5m, 95%CI; 13.4m-27.4m) (p=0.272). In the gemcitabine plus platinum group, the median survival was 19.9m (95%CI; 9.2m-30.6m), which was not longer than other regimens (20.0m, 95%CI; 15.4m-27.4m). The p value was 0.404. We also analyzed the influence of oral EGFR-TKIs on overall survival. Those who had a chance taken EGFR-TKIs lived numerically longer than never; the median survival was 24.8m (19.1m-30.5m, 95%CI) and 16.3m (12.7m-19.9m, 95%CI), respectively. However, the overall difference was not significant (p=0.184).

Conclusion:
The median survival of patients with advanced lung adenocarcinoma with UN-EGFR-GS was 20m. Oral EGFR-TKIs appear to be useful for this group of patients.

Background:
Malignant pericardial effusions are common in lung cancer (LC) and can produce cardiac tamponade (CT). This oncologic emergency requires a high index of suspicion for accurate, prompt diagnosis. To study how CT is diagnosed in LC, we reviewed symptoms, signs and differential diagnoses recorded, and tests obtained, at a tertiary teaching hospital.

Methods:
Records of patients hospitalized with a diagnosis of CT between April 1999 and September 2011 were reviewed, focusing on LC related CT. Extent of disease, treatment history and response, symptoms, vital signs, physical exam and EKG findings recorded by the initial and admitting physicians were recorded, together with differential diagnoses mentioned in the physician notes before radiologic testing. Finally, the radiologic tests used to make or confirm the diagnosis were recorded.

Results:
Of 770 patients with a diagnosis of CT, 57 had malignant CT and 26 had LC. Of these, 7 (27%) were newly diagnosed with cancer at the time of diagnosis of CT. The most common symptom, shortness of breath, was present in 24 (92%) cases. Physical exam findings recorded by physicians are listed in Table 1. EKG findings of low QRS voltage/electrical alternans were present in 3, absent in 3 and were not documented in 20 patients. In only 8 cases (31%) CT was included in the differential diagnosis based on the signs, symptoms and EKG findings at initial presentation. Of these, 3 had a known prior history of pericardial effusion and 3 were newly diagnosed with LC at the time of presentation. Two of these diagnoses were made by oncologists and the other 6 were made by Emergency physicians (ED)/internists. In the remaining 18 cases, the diagnosis was made serendipitously with imaging studies obtained for other reasons. Of these, 5 patients had a known history of malignant pericardial disease and 6 were newly diagnosed with LC. The physician seeing the patient initially was an oncologist in 5 cases and an ED /internist in 13 cases.

	Jugular venous distention	Distant heart sounds	Pulsus paradoxus	Tachycardia	Hypotension
Present	7 (27%)	5 (19.2%)	3 (11.5%)	22 (84.6%)	6 (23%)
Absent	10 (38.4%)	-	4 (15.3%)	4 (15.3%)	20 (77%)
Not recorded	9 (34.6%)	21 (80.7%)	19 (73%)	-	-

Conclusion:
Not including CT in the differential diagnosis of LC patients presenting with dyspnea is common among physicians of all types, including oncologists, internists, and ED. Physicians should include CT in the differential diagnosis of LC patients presenting with dyspnea and tachycardia, especially those with advanced disease, and a careful physical examination will elicit the classic signs in a substantial proportion of patients. Without a high index of clinical suspicion the diagnosis may be delayed or missed.

Background:
Most patients with secondary malignant tracheobronchial tumors have distressing symptoms due to major airway obstruction. However, they are always too frail for curative surgical resection. We choose fibrobronchoscopic cryorecanalization to improve their life quality and analyzed the long time survival outcome.Most patients with secondary malignant tracheobronchial tumors have distressing symptoms due to major airway obstruction. However, they are always too frail for curative surgical resection. We choose fibrobronchoscopic cryorecanalization to improve their life quality and analyzed the long time survival outcome. file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%202.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%201.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%203.tif

Methods:
Clinical records of 14 patients were reviewed retrospectively from December 2005 to January 2013. A temperature from -50℃ to -70℃ was delivered to the central part of the tumor by cryo-probe for 4 to 6 minutes causing destruction of the tumor mass (Cryo-melt method). Subsequently, the edge of tumor was froze for 0.5 to 2 minutes and then tore the lesion piece by piece immediately with the advantage of concretion between the frozen probe tip and the tumor tissue (Cryo-resection method). file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%204.tif

Results:
The rates of dramatic and partial symptomatic alleviation were 57.1% and 28.6% respectively. There were no intraoperative deaths. The median survival was 16.0 months. Overall survival was 64.3% at half year, and 50.0% at 2 years. 2-year survival was significantly correlated to age (less than 60 years 22.2% versus more than 60 years 100%, p=0.011), tumor location (main bronchi 0% versus trachea 77.8%, p=0.003), and cryorecanalization times (one time 33.3% versus two or more times 80.0%, p=0.037). file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%205.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%206.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%207.tif

Conclusion:
Fibrobronchoscopic cryorecanalization is a safe, easily repeatable and effective minimally invasive choice for releasing the airway obstructive symptoms. In addition to high local-regional control rates, a rewarding result of prolonged survive time can also be obtained.

Background:
In the last years, new drugs and strategies have emerged in the management of lung cancer (LC). The French College of General Hospital Respiratory Physicians therefore promoted a prospective multicenter epidemiological study: the ESCAP study. This study was aimed to describe the therapeutic strategies implemented during the first 2-year after diagnosis in patients with LC followed in French General Hospital chest departments. We report below descriptive results for metastatic non-small-cell lung cancer (mNSCLC).

Methods:
For each patient with a LC diagnosed in 2010, a standardized form was completed at diagnosis and following each change in treatment strategy up to at least 2 years after diagnosis.

Results:
53 centers participated in the ESCAP study and included 3,943 patients. Among them, 3,418 patients had a NSCLC. NSCLC was metastatic in 2,003 patients. In patients with mNSCLC, the first therapeutic strategy was chemotherapy alone (56%) followed by palliative chemotherapy plus incidental radiotherapy (35%); 4% of patients died without any implemented therapeutic strategy (see figure). 29% of patients with chemotherapy alone as first strategy died without undergoing any other strategy and 70% had a second strategy (72% chemotherapy alone). 35% of patients with radiochemotherapy died without undergoing any other strategy and 64% had a 2[nd] strategy (73% chemotherapy alone). Figure 1 The most frequent chemotherapy during the first strategy was platinum salts doublet with pemetrexed (39%), followed by platinum salts doublet with paclitaxel (15%). Chemotherapy during the second strategy was second line chemotherapy (67%) or maintenance therapy (25%). EGFR-TKi (34%) and docetaxel (26%) alone were the most frequently prescribed drugs for second line chemotherapy, and pemetrexed (44%) and EGFR-TKi (26%) alone for maintenance therapy.



Conclusion:
The ESCAP study describes the 2-year management of metastatic NSCLC on real-life settings in France. Its preliminary results are consistent with the guidelines of the French National Cancer Institute.

Background:
Inoperable cases are common in T4 lung cancer patients, and their prognoses are mostly poor. Nevertheless, among those who undergo resection, some can achieve long-term survival. We reviewed the validity of surgical treatment for T4 lung cancer at our department.

Methods:
Fifty-six cases of pathologically confirmed T4 lung cancer resection between January 1989 and December 2013 were selected for this study. Cases of nodules in different lobes of the same lung were ineligible. The relationships among the number of infiltrated organs, pN factor, presence or absence of preoperative treatment, histological effect (Ef), and surgical curative rate and prognosis were assessed using statistical techniques.

Results:
The subjects consisted of 53 males and 3 females with an average age of 62.2 years. Depending on the histological types, they were classified as squamous cell cancer (29 cases), adenocarcinoma (16 cases), adenosquamous cancer (7 cases), large cell cancer (1 case), and other cancers (2 cases). Also, there were 37 single and 19 multiple organ infiltration cases, which were classified by infiltrated organ as 16 in the trachea and tracheal bifurcation, 11 in the vertebral body, 10 in the aorta, 10 in the superior vena cava, 9 in the mediastinum, 6 in the left atrium, 6 in the pulmonary artery, 5 in the esophagus, and 2 in the subclavian artery, including duplicated cases. Preoperative treatment was carried out in 22 cases (chemoradiotherapy, 14; chemotherapy, 8), whose histological effect was Ef0-1 in 13 and Ef2-3 in 9. The surgical curative rate was complete resection in 27 and incomplete resection in 29; complete resection was common in those receiving preoperative treatment. There were no death cases within 30 days after the surgery. In all cases, the five-year survival rate was 21.7% and median survival time (MST) was 16.5 months. The five-year survival rate was 27.5% in single organ infiltration compared with 15.8% in multiple organ infiltration (P = 0.08), 27.5% in n0-1 versus 13.8% in n2-3 (P = 0.30), 36.8% with preoperative treatment in contrast to 11.2% without preoperative treatment (P = 0.06), 9.4% in Ef0-1 as opposed to 76.2% in Ef2-3 (P = 0.05), and 37.7% in complete resection in comparison with 7.8% in incomplete resection (P = 0.003). Long-term survival over 5 years was noted in 7 cases (12.5%), 4 of which involved single organ infiltration, n0-1, preoperative treatment, and Ef2-3.

Conclusion:
Single organ infiltration and n0-1 are good surgical indications for T4 lung cancer, and a favorable prognosis can be expected if preoperative treatment and complete resection are performed.

Background:
One of the strongest rationale for maintenance therapy in NSCLC is the fact that exposure to 2nd line therapy is only 40-60% in clinical trials in specialized treatment centers. Even with follow-up intervals of 6 weeks, the 2nd line treatment rate does not seem to increase. We analyzed the exposure of 2nd line therapy as well as OS and PFS in patients with stage IV NSCLC in the subgroups no 2nd line, 2nd line after maintenance and 2nd line without maintenance therapy.

Methods:
All primary lung cancer cases stage IV in the lung cancer center were analyzed based on the documentation files between 2009 and 2013. Patients were followed-up between 1st and 2nd line therapy every 6-8 weeks according to S3 guidelines. Patients with EGFR+, ALK+ or ROS1+ were excluded from the analysis.

Results:
221 patients were diagnosed with NSCLC IV (UICC7), or had systemic relapse of localized disease and were treated with 1st line therapy for metastatic disease. Of these, 160 (72%) received 1st line combination therapy with Carboplatin, 50 (23%) with Cisplatin and 11 (5%) with platin-free single agent therapy. 45 (19%) of all patients received maintenance therapy, most of them with bevacizumab. Of 221 patients, 203 (92%) progressed after 1st line therapy or 1st line and maintenance therapy. 106/163 (65%) of non-maintenance therapy patients received 2nd line therapy, 57 patients (36%) did not. Of 40 patients receiving maintenance therapy and requiring 2nd line therapy, 31 (78%) received 2nd line therapy. Reasons for not obtaining 2nd line therapy were captured and were manifold. Survival analyses showed significant differences regarding overall survival (median survival 21 (maintenance and 2nd line) vs. 13 (1st and 2nd line) months) but no relevant differences regarding progression free survival on 2nd line (median 2 months).

Conclusion:
In a certified lung cancer center and stringent follow-up every 6 to 8 weeks, 1/3 of patients do not receive 2nd line therapy because of various reasons. The application of maintenance therapy raises the chances of receiving 2nd line therapy and increases overall survival whereas progression free survival is not affected.

Background:
Concurrent chemoradiotherapy (CCRT) is considered the standard treatment regimen in patients with inoperable stage III non-small cell lung cancer (NSCLC). Sequential chemoradiotherapy (SCRT) is recommended in patients who are deemed unfit to receive CCRT. As this selection criterion is not very explicit, the ‘personalized’ choice for either CCRT or SCRT is mainly dependent on the multidisciplinary team and treating physician’s judgment. Consequently, this may result in a variation of treatment policies across hospitals/radiotherapy (RT) departments. In this study, we investigated the ratio CCRT/SCRT in eight RT departments in the Netherlands. Furthermore, we explored which patient and disease characteristics determined the choice for SCRT compared to CCRT.

Methods:
Data were derived from the Dutch Lung Radiotherapy Audit (DLRA). Within the DLRA, lung cancer patients undergoing a curative intent treatment are prospectively registered with respect to patient and disease characteristics, diagnostics and treatment. For this study, from eight out of 21 Dutch RT departments, patients with stage III NSCLC undergoing chemoradiotherapy in 2014 were selected. CCRT was defined as ≤ 50 days between the start of chemotherapy and the start of radiotherapy. Furthermore, RT had to start before the end of the last chemotherapy in CCRT. Patients with < 150 days between treatments were scored as undergoing SCRT. Differences in patient and disease characteristics between CCRT and SCRT were tested with independent samples t-tests (for continuous variables) and with chi-square tests (for categorical variables). A multivariate logistic regression model was constructed to determine patient and disease characteristics associated with the choice for SCRT, using a backward selection procedure. Odds ratios (OR) with 95% confidence intervals (CI) are reported.

Results:
In total, 453 stage III NSCLC patients (mean age 65.4 years, 56.5% male) were registered. Of those, 351 (77.5%) patients underwent CCRT and 102 (22.5%) patients received SCRT. The proportion of patients treated with CCRT ranged from 51% to 89% across RT departments. Gender, smoking, gross target volume (GTV), performance score (PS), lung function, Charlson comorbidity index and tumor location were not significantly associated with SCRT in the multivariate model. Conversely, older age (OR 1.05 [95%CI 1.03-1.09]), histology (large cell carcinoma vs adenocarcinoma [OR 0.42 CI 0.19 to 0.97]) and cN-stage (N3 vs N0-1 [OR 5.71 {95%CI 2.10-15.50}]) were significantly associated with SCRT.

Conclusion:
In this selected group of registered NSCLC patients, a large variation was observed in the proportion of stage III NSCLC patients treated with CCRT, ranging from 51% to 89% across RT departments. Surprisingly, PS and comorbidity index (as indicators of a patients’ physical fitness) were not significantly different in CCRT or SCRT patients while age and cN-stage were. Based on the analyzed patient and disease characteristics, it is currently unclear why patients treated with SCRT were not eligible for CCRT.

Background:
Cisplatin [cis-diaminedichloroplatinum-II] is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD[+]) has emerged as a key regulator of cellular energy metabolism and homeostasis. Although a link between NAD[+]-dependent molecular events and cellular metabolism is evident, it remains unclear whether modulation of NAD[+] levels has an impact on cisplatin-induced hearing impairment.

Methods:
To investigate whether augmentation of NAD[+] by NQO1 activation using b-Lapachone (b-Lap) attenuates cisplatin-mediated hearing impairment, male C57BL/6 mice and NQO1 knockout mice on a C57BL/6 background were used. For analysis of the auditory threshold, auditory brainstem response (ABR) was recorded. For biochemical analysis, we measured the enzymatic activity of SIRT1, PARP1, ROS production, NAD+/NADH ratio, mRNA levels of miR-34a and pro-inflammatory cytokines. Immunohistochemistry and western blot analysis were also performed.

Results:
We have demonstrated for the first time that both the protein expression level and the activity of SIRT1 were suppressed by the reduction of intracellular NAD[+] levels in cisplatin-treated cochlear tissue. We also found that the decrease in SIRT1 protein expression and its activity after cisplatin exposure were mediated by the increase in transcriptional activity of p53 for miR-34a expression and PARP-1 activation causing NAD[+]-depletion, respectively. However, the increase in cellular NAD[+] levels by NQO1 activation using b-Lap prevented mice from cisplatin-induced cochlear damage and hearing impairment through the modulation of PARP-1, SIRT1, p53, and NF-kB.

Conclusion:
Considering that b-Lap itself did not attenuate the tumoricidal effect of cisplatin, these results suggest that the direct modulation of the cellular NAD[+] level by pharmacological agents could be a promising therapeutic strategy for enhancing the efficacy of cisplatin chemotherapy without its adverse effects.

Background:
Primary sarcomatoid carcinoma (PSC) accounts for 2% to 3% of all lung cancers. Stage-for-stage, PSC carries a poorer prognosis compared to the more common types of lung cancer. It typically occurs in older heavy smoking men and has a predilection for upper lobe involvement. PSC of the lung was initially described by Virchow in 1865 as a “biphasic” lesion of adenocarcinomatous or squamous cell components along with spindle cell or giant cell elements forming at least 10% of the tumor mass. This description fulfills the current WHO criteria for the diagnosis of PSC. Mutational analysis has revealed a common origin of both elements and it is thought that epithelial-mesenchymal transition (EMT) is the mechanism of that gives rise to this tumor, with the epithelial elements (adenocarcinoma or squamous component) that has undergone a transition to a poorly-differentiated mesenchymal type (sarcomatoid) with the expression of mesenchymal proteins such as vimentin. Efforts to study PSC has been hindered by the rarity of this variant. Aim of the study: To assess the impact of surgery and various systemic therapies on patients with PSC of the lung at the University of Cincinnati Medical Center (UCMC).

Methods:
This retrospective study included all patients identified with a pathologically confirmed diagnosis of PSC of the lung treated at UCMC between the years 2000-2014. Death was considered as the study endpoint. Kaplan-Meier analysis was used to calculate median overall survival (OS) and 95% confidence intervals (CI). Cox model was used to test the chemotherapy effect adjusted for age, sex and surgery, and determine hazard ratios (HR). Data was analyzed using SAS® Version 9.4.

Results:
We identified 21 patients with a diagnosis of PSC of the lung that were eligible for chart review and analysis. The 14 men and 7 women had a median age of 59 (range, 31-84 years). Treatment with systemic chemotherapy showed a trend in improvement in outcome among all stages of disease (p=0.08 and HR 0.04) but chemotherapy was most often used in advanced stages. Female gender demonstrated a trend for improved OS (p=0.1), and older patients demonstrated a better OS (HR=0.849; p=0.041) by a one-year increase in age. The median OS of the patients with PSC treated with systemic chemotherapy was 375 days (95% CI 114-600 days). Patients with early stage disease who were eligible for surgical resection, with or without the addition of systemic chemotherapy had a median survival of 457.5 days (95% CI 206.-1187 days), only slightly different from patients with advanced disease that received systemic chemotherapy. Patients who did not receive systemic chemotherapy had a lower median OS of 256 days (95% CI 98-999 days). Two patients demonstrated EML-4/ALK translocations. The patient with the longest OS of about three years was treated with systemic therapies including cisplatin, gemcitabine, docetaxel and crizotinib.

Conclusion:
Patients with PSC of the lung may benefit from systemic therapy. Larger prospective studies are needed to confirm this benefit especially if used as an adjuvant therapy in early stage disease.

Background:
Pemetrexed is a multitargeted antifolate agent approved for use in the treatment of pleural mesothelioma and non-small cell lung cancer. A recent phase III PARAMOUNT trial has shown that pemetrexed continuation maintenance therapy reduced the risk of disease progression and death compared with a placebo. However, renal toxicities of maintenance therapy of pemetrexed has not been clarified.

Methods:
We retrospectively evaluated a total of 30 patients who had received 4 cycles of induction therapy with pemetrexed with platinum (cisplatin or carboplatin) regimens with or without bevacizumab followed by more than 4 cycles of pemetrexed (± bevacizumab) maintenance therapy. Estimated creatinine clearance at three different time points (before the induction therapy, after the induction therapy, and after the 4 cycles of maintenance therapy) were analyzed. We also investigated factors significantly associated with deterioration in renal function during pemetrexed maintenance therapy using univariate and multivariate logistic regression analyses.

Results:
Significant decrease in the mean value of eCcr could be observed during pemetrexed maintenance therapy in both cisplatin and carboplatin groups. Multivariate analysis revealed that cisplatin administration and poor performance status (PS ≥1) were risk factors significantly associated with eCcr decrease.

Conclusion:
Continuance maintenance therapy of pemetrexed generally could cause renal dysfunction. More attention should be paid to the patients receiving a cisplatin based induction therapy and patients with poor performance status.

Background:
UGT1A1*27 is known that exist together with UGT1A1*28 as linkage disequilibrium and impair the effect of UDP-glucuronosyltransferase (UGT) in basic research, however, poor clinical investigation because of the rare frequency. The aim of this study is to evaluate the effect of UGT1A1*27 gene polymorphism for safety and efficacy in irinotecan therapy.

Methods:
Eligibility criteria were: lung cancer patients; scheduled the dose of irinotecan therapy as single ≥ 80 mg/m[2], combination ≥ 50 mg/m[2], radiation with single ≥ 50 mg/m[2], radiation with combination ≥ 40 mg/m[2]; age ≥ 20 years; performance status 0-2. After informed consents, patients were enrolled and collected the blood to examine UGT1A1*28 and UGT1A1*6 polymorphism and received irinotecan therapy. Examination of UGT1A1*27 were added when founding UGT1A1*28 polymorphism. We planned 111 enrollment for an accrual of 10 patients with UGT1A1*27 gene polymorphism.

Results:
Fifty patients were enrolled in this trial between October 2011 and December 2013. Two patients judged protocol violation. Remaining 48 were evaluated. UGT1A1 gene polymorphisms *28/*28, *6/*6, *28/*6, *28/-, *6/-, -/- observed 0, 1, 1, 7, 17 and 22, respectively. UGT1A1*27 were analyzed in 9 patients including ineligible one patients with *28/*28, however, no UGT1A1*27 gene polymorphism was found and the study was stopped. A total of 153 times of irinotecan therapy were administered with a median of 3 times per one patient: 1 time in 7 patients (15%), 2 times in 9 (19%), 3 in 19 (40%), 4 in 3 (6%), 5 in 1 (2%), and 6 in 9 (19%). Irinotecan were used as combination chemotherapy in 32 (67%) patients, with cisplatin in 12 (25%), carboplatin in 10 (21%), gemcitabine in 9 (19%), paclitaxel in 1 (2%). In remaining 16 patients (33%), only irinotecan single therapy were administered. Radiotherapies were administered concurrently in 23 (48%) patients with median 60 (range 40-61.4) Gy. Febrile neutropenia were observed higher tendency in patients with UGT1A1*6 (32%) and UGT1A1*28 (25%) gene polymorphism compare with wild type (14%) but had no significant difference. Grade 3/ 4 leukopenia and neutropenia were observed in 6 out of 8 patients with UGT1A1*28 gene polymorphism and significant higher compare with wild type (75% vs. 32%, p=0.049; 75% vs. 36%, p=0.039, respectively). The other toxicities have no difference between UGT1A1 gene polymorphism and wild type. There was no pneumonitis and treatment-related death. Tumor response was not evaluated because not included endpoints. Median PFS of 48 patients was 6.8 months and the 1- and 2-year survival rates were 20.8%. Median PFS separated by UGT1A1 gene polymorphisms were 10.1 months in UGT1A1*28 heterozygous, 8.5 months in UGT1A1*6 heterozygous, and 6.8 months in both wild type, respectively. Median OS of 48 patients was 15.7 months and the 1- and 2-year survival rates were 57.7% and 40.3%, respectively. Median OS separated by UGT1A1 gene polymorphisms were not reached in in UGT1A1*28 heterozygous, 16.4 months in UGT1A1*6 heterozygous, and 12.3 months in wild type, respectively.

Conclusion:
UGT1A1*27 gene polymorphism was not found in our methods. Further investigation might be warranted in patients with UGT1A1*28 wild type.

Background:
There are no demonstrated predictive molecular markers for pemetrexed. The aim of this study is to explore and evaluate whether thyroid transcription factor 1 (TTF1) protein expression can be a predictive biomarker of clinical activity for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC).

Methods:
123 patients with advanced nonsquamous NSCLC treated with pemetrexed-based chemotherapy as first-line, maintenance, second or later-line therapy were retrospectively reviewed. Then we chosen patients who had undergone assay of immunohistochemical expression of TTF1 in their tumor tissue sample, and we analyzed for their clinicopathological features, expression of TTF1 and clinical outcomes. Analysis of TTF1 expression was done according to the routine clinical practice of our center.

Results:
Immunohistochemical analysis of TTF1 expression was only performed in 51 of the 123 patients reviewed. Of these 51 patients, 36 were men and 15 women, 7 (13,7%) had never smoked and 44 (86,3%) were former or current smokers. Median age was 65 (range 39-79). Performance status (PS) distribution: 0 (25,4%), 1 (62,7%), 2 (7,8%), 3 (3,9%). Predominant histology type was adenocarcinoma (78,4%), followed by large cell carcinoma (13,7%) and not otherwhise specified-NOS (7,8%). 36 patientes had TTF1-positive tumors (70,5%), and 15 TTF1-negative ones (29,5%). The types of tumor tissue sample in which TTF1 assay was undergone were the following: endobronquial biopsy (43,1%), percutaneous biopsy (33,3%), fine needle aspiration puncture (17,6%), citology (0,5%). TTF1 positive tumors shown a higher disease control rate (DCR) for pemetrexed-based chemotherapy (60,5% vs 39,5%, p=0,05). Median progresión free survival (PFS) and overall survival (OS) in the whole group was 5,55 and 23,95 months respectively. TTF1-positive tumors had significant longer PFS (6,96 vs 3,64 months; p=0,0156) and a nonsignificant trend of longer OS (24,27 vs 13,66 months; p=0,581) to pemetrexed-based chemotherapy than patients with TTF1-negative tumors.

Conclusion:
TTF1 protein expression was associated with better clinical outcomes. TTF1 positive tumors shown a significant association with better PFS and a nonsignificant trend of better DCR and OS in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TTF1 expression should be further studied.

Background:
The mass-spectrometry based serum test VeriStrat® (VS) was developed using samples from non-small cell lung cancer (NSCLC) patients (pts) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs); VS was shown to be prognostic in several tumors and predictive of differential overall survival (OS) benefit for erlotinib vs. chemotherapy (CT) in 2[nd] line for NSCLC. We investigated the role of VS in pts receiving Cisplatin (CDDP) or Carboplatin (CBDCA) plus Pemetrexed (P) as 1[st] line for advanced, non-squamous NSCLC.

Methods:
VeriStrat classification was available for 55 eligible pts, who were classified as VS Good (VSG) or VS Poor (VSP); VS testing was done blinded to clinical data. Progression-free survival (PFS) and OS were analyzed by Kaplan-Meier method and compared using log-rank p-values; Cox models were used in multivariate analysis. Association with categorical variables was analyzed by Fisher’s exact test.

Results:
36 (65%) pts were classified as VSG and 19 (35%) as VSP. In the overall population, median PFS was 6.1 months (mo) for VSG vs.1.3 mo for VSP (hazard ratio (HR) 0.39 [0.21-0.70], p=0.001 ); adjusted HR (AHR) 0.43 [0.21-0.91], p=0.026). Median OS was 10.6 mo for VSG vs. 3.1 mo for VSP (HR 0.26 [0.14-0.50], p<0.001; AHR 0.20 [0.09-0.47], p<0.001). A similar relationship was found in both treatments: In CBDCA-P median PFS in VSG and VSP was 3.9 mo and 1.6 mo respectively (HR 0.34 [0.14-0.81], p=0.011); median OS was 10.0 mo in VSG and 2.0 mo in VSP (HR 0.26 [0.11-0.61], p=0.001). In CDDP-P median PFS was 6.6 mo in VSG and 1.2 mo in VSP (HR 0.52 [0.20-1.33], p=0.161), median OS was 12.3 mo in VSG, 3.5 mo in VSP (HR 0.25 [0.09-0.70], p=0.005).When compared within VS groups, no statistically significant differences between CBDCA-P and CDDP-P was found either for PFS (VSG: p=0.471, VSP: p=0.493) or OS (VSG: p=0.319, VSP: p=0.429). VS was significantly associated with disease control rate (p=0.003) and objective response (p=0.021).

Population (N°)	Median PFS (months)		Hazard ratio, p	Median OS (months)		Hazard ratio, p
	VSG	VSP		VSG	VSP
Overall (55)	6.1	1.3	0.39 [0.21-0.70] p=0.001	10.6	3.1	0.26 [0.14-0.50] p<0.001
CBDCA-P (30)	3.9	1.6	0.34 [0.14-0.84] p=0.011	10.0	2.0	0.26 [0.11-0.61] p=0.001
CDDP-P (25)	6.6	1.2	0.52 [0.20-1.33] p=0.161	12.3	3.5	0.25 [0.09-0.70] p=0.005

Conclusion:
VeriStrat has prognostic significance in platinum-based CT: overall, VSP pts have significantly shorter PFS and OS than VSG pts. In each VS group, CDDP-P and CBDCA-P showed similar behavior. Further research is needed to find alternative treatments to improve outcomes for VSP pts. ClinicalTrials.gov Identifier: NCT02055144.

Background:
BACKGROUND: The Paramount trial demonstrated a significant survival benefit with pemetrexed continuation maintenance therapy for non-squamous NSCLC. This retrospective work aims to study predictive factors for a long duration of maintenance therapy and its toxicities.

Methods:
METHOD: All patients who received pemetrexed maintenance between 1st January 2009 and 1st July 2013 in Centre Léon Bérard (France) were included. Patients were classified in two groups: “long maintenance” if they received ≥ 5 cycles of maintenance with pemetrexed and “short maintenance” if they received ≤ 4 cycles. We retrospectively collected data about patients (age, gender, smoking status, PS), histological subtype, number of metastatic sites, number of induction and maintenance cycles, response to induction chemotherapy, bevacizumab use, reason for discontinuation, and toxicities. Proportions of patients or disease characteristics in each group were compared with univariate test (Fisher exact and Wilcoxon).

Results:
RESULTS: 65 patients were included, 33 in “short maintenance” group and 32 in “long maintenance” group, with 60% male and a mean age of 61.13 (±7,78). 55% of patients had ≥ 2 metastatic sites with PS 0, 1 or 2 in 21%, 67%, and 13% out of patients, respectively. Induction cycles were initiated with cisplatin in 71% and carboplatin in 29% of patients; median number of induction cycles was 4 [3-6]. 39% of patients achieved partial response to induction chemotherapy and 61% stable disease. Median number of maintenance cycles was 4 [1-28]. 19 patients (29%) received bevacizumab in combination to pemetrexed during induction and maintenance therapy. Maintenance discontinuation was due to progressive disease in 61%, toxicity in 19% and local treatment in 16% of patients, respectively. Significant predictive factors of a long duration of maintenance therapy were female gender (27% vs 53%; p=0.044) and ≥ 2 metastatic sites (42% vs 70%; p=0,046). Age, smoking status, histological subtype, response to induction therapy, bevacizumab use, and PS were not significantly related to maintenance duration. Grade 3-5 adverse events occurred in 20 patients (31%) including 5 treatment-related deaths (8%) (including 4 infectious-related deaths). There was a similar rate of grade 3-5 toxicities in both groups. Toxicities were mainly infectious (n= 13; 65%) including 4 febrile neutropenia. Predictive factors of grade 3-5 toxicities were age > 70 years (35% vs 9%; p=0.026) and carboplatin use (50% vs 20%; p=0,020). At the end of the study, maintenance therapy was ongoing in 3 patients. Among the 62 other patients, 81% received subsequent systemic therapy with a similar duration of treatment between “short” and “long” maintenance groups.

Conclusion:
CONCLUSION: Univariate analysis identified female gender and ≥2 metastatic sites as only predictive factors for a long duration of pemetrexed maintenance therapy. Patients with single metastasis frequently stopped maintenance treatment for administration of local therapy. Predictive factors for severe toxicities were age > 70 years and carboplatin use whereas addition of bevacizumab to pemetrexed did not result in an increase of toxicity.

Background:
Pemetrexed/platinum is one of the standard treatment regimens for patients with advanced non-squamous non-small cell lung cancer(NSCLC). The aim of this study was to examine the association between survival of lung cancer patients treated with pemetrexed/platinum and clinical factors.

Methods:
The medical records of advanced or relapsed non-squamous NSCLC patients treated with pemetrexed/platinum at our hospital between January 2010 and December 2013 were reviewed. Basic characteristics, histological subtypes of NSCLC, driver mutation status, TTF1 staining status and status of treatment with taxane were evaluated for association with the survival from pemetrexed/platinum started day to deaths.

Results:
Two hundreds nine records were reviewed. The median age was 62 (28-79), 60% were male, 40% were never smoker, 89% had an ECOG PS0-1 and 11% had a PS 2-3. The median value of CEA and CYFRA were 10.5 ng/ml and 3.0 ng/ml, respectively. 93% were diagnosed as adenocarcinoma and 7% were diagnosed as other subtypes (large, adenosquamous, sarcomatoid and not otherwise specified). 79% (81/102) had a positive TTF1 staining. 26% had EGFR mutation, 7% had ALK fusion and 11% had KRAS mutation. 36% of patients were received bevacizumab with pemetrexed/platinum. 35% of patients were treated with cisplatin. The response rate of pemetrexed/platinum was 34.8%. Median overall survival was 537days. 65% of patients were treated with taxane and the response rate was 15.0%. In multivariate analysis, poor PS(HR 1.33; p=0.027), others in histological subtypes (HR2.00; p=0.047) and K-RAS mutation(HR 2.74; p=0.021) correlated significantly with a shorter overall survival and low CYFRA(≤3.0ng/ml, HR 0.55; p=0.002) correlated significantly with a longer overall survival.

Conclusion:
High CYFRA, KRAS mutation and others in histological subtypes may be associated with shorter overall survival treated with pemetrexed/platinum in non-squamous NSCLC. The development of effective treatment regimens for such patients is needed to improve their outcomes.

Background:
Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies. Tissue inhibitor of metalloproteinases 1 (TIMP1) and EGFR regulates extracellular matrix catabolism and promotion of cell growth and anti-apoptotic activity in NSCLC.

Methods:
Forty nine patients with heavily treated metastatic NSCLC were enrolled from March 2011 to November 2014. Thirty-three (67%) had never been exposed to bevacizumab and 16 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1 (treatment was repeated every 3 weeks). In all patients the mutational status of KRAS and EGFR, as well as TIMP1 and EGFR expression was evaluated.

Results:
The median age was 60 years (range, 44-78 years), 57% was male and 75% had ECOG 0-1. The median follow-up was 13.2 months and twenty-three patients had received >3 prior lines. The ORR was 32% (95%CI 22% to 39%) and thirteen patients (26%) achieve stable disease. Median progression-free survival (PFS) rate was 4.4 months (95%CI 2.8-8.3) and median overall survival (OS) rate was 18.0 months (95%CI 16.2-30.7). Nine patients harbouring EGFR mutations had a long-lasting, partial response (>5 months after at least 4 prior lines). Major toxicity was myelosuppression (grade 3 neutropenia occurred in 32% of patients and thrombocytopenia in 8.3%). Three patients experienced febrile neutropenia, one patient suffered grade 4 diarrhoea, and non-haematological toxicity was usually mild. Shorter OS was found in patients with a higher expression of TIMP1 mRNA (P=0.0001) but not according to the expression of EGFR (P=0.14).

Conclusion:
Irinotecan plus bevacizumab resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients with advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations and low expression of TIMP1.

Background:
Increased expression of cyclooxygenase-2 (COX-2) is common in non-small cell lung cancer (NSCLC), and is therefore a potential target for treatment. However, phase III trials have failed to demonstrate beneficial survival effects of adding COX-2 inhibitors to standard chemotherapy. We investigated whether COX-2 expression in tumor and stromal cells had any predictive impact on the effects of celecoxib, a selective COX-2 inhibitor.

Methods:
In a previously published multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and WHO performance status 0-2 were randomized to receive celecoxib 400 mg b.i.d. or placebo up to one year in addition to a two-drug platinum-based chemotherapy regimen. In a subset of 122 patients, archive tumor tissue was available for further analyses. Immune stainings for COX-2 expression were undertaken. Intensity and extent of positively stained cells in tumor and stroma cells were scored on a 0 to 3 scale, and the product of these scores was used as a co-variable in the predictive analysis.

Results:
An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue showed no survival differences between the celecoxib or placebo arms (HR 0.99; 95% CI 0.79-1.24 and HR 0.89; 95% CI 0.62-1.28, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stroma cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 0.96; 95% CI 0.60-1.54 and HR 0.66; 95% CI 0.38-1.16). The p-value for interaction effect between COX-2 score in tumor or stroma cells and celecoxib effect on survival was 0.48 and 0.25, respectively.

Conclusion:
In this subgroup analysis of patients with advanced NSCLC treated in a randomized trial, we could not detect any significant interaction between COX-2 expression in tumor or stroma cells and outcome of celecoxib treatment in addition to standard chemotherapy.

Background:
To evaluate the efficacy and safety of weekly intravenous Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) for the patients with advanced non-small-cell lung cancer (NSCLC) who have failed prior multilines treatments, and to investigate the association of status of secreted protein, acidic and rich in cysteine (SPARC) expression and clinipathological factors with clinical outcome.

Methods:
We retrospectively analyzed the efficacy and toxicities of NAB-paclitaxel monotherapy in treating 84 patients who had progression disease after at least two lines standard chemotherapy from May 1, 2011 to June 31, 2014. All patients were treated with NAB-paclitaxel 130mg/m2 on days 1 and 8 of a 21-day cycle. Radiologic tumor assessment was performed every 6 weeks or when the patient’s symptoms deteriorated obviously. We also detected the SPARC status expression (by immunohistochemistry) in 35 patients who had tumor tissue available. 76 of 84 patients had EGFR mutation status. The date of last follow-up was March 31, 2015.

Results:
Of these 84 patients, 76 patients had complete follow-up data, 5 patients lost of follow-up for overall survival, and 3 patients couldn’t tolerate the continuous NAB-paclitaxel therapy due to serious adverse events and had only the evaluation of safety data.. EGFR mutation were found in 22 of 76 patients and their median PFS and OS were 4.4 months and 11.5months. The median treatment line of weekly NAB-paclitaxel therapy was 4 line (range: 2~7 line). The median follow-up interval time was 11.2 months. The objective response rate (ORR) and disease control rate (DCR) (N=81) were 14.8% (12/81) and 67.9% (55/81), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95% CI: 2.8~5.0 months) and 11.0 months (95%CI: 7.6~14.4 months), respectively. Pearson’s correlation analysis showed that previous treatment with Solvent-based Paclitaxel or Docetaxel didn’t affect the response to NAB-paclitaxel. However, the patients who reached disease control after previous Solvent-based Paclitaxel or Docetaxel presented better DCR than the patients who failed to previous Solvent-based Paclitaxel or Docetaxel (DCR: 77.1% vs 47.6%, p=0.040) (by Fisher’s Exact Test). Cox regression analysis showed that ORR was related with both PFS and OS. The common adverse events (N=84) included leukopenia (36.1%), neutropenia (29.2%), peripheral neurotoxicity (23.6%), et al. The main grade 3/4 toxicities included neutropenia (9.7%) and leukopenia (6.9%). 3 patients had discontinued chemotherapy due to drug induced lung injury, serious fatigue and serious anorexia, separately. In this study, no association between SPARC expression and efficacy was observed.

Conclusion:
Advanced NSCLC patients who have experienced multiline chemotherapy with disease progression could benefit from weekly NAB-paclitaxel therapy with good safety and clinical outcome. It seemed that SPARC expression could not predict efficacy to NAB-paclitaxel.

Background:
In the JMEN trial (Ciuleanu et al., Lancet 374:1432-1440, 2009), patients with advanced non-squamous non-small cell lung cancer (NSCLC) derived a benefit from pemetrexed maintenance therapy after platinum-based initial therapy by extending survival, delaying disease progression, and maintaining overall quality of life (QoL). However, fatigue was the most common physician-reported toxic effect in the pemetrexed treated group. We conducted a post-hoc analysis to investigate the dynamic change of fatigue in overall population and East-Asian (EA) patients treated on the JMEN trial.

Methods:
This analysis was performed in the overall safety population (N=656) and the EA subgroup safety population (N=152) mainly from China, Taiwan, and Korea including squamous and non-squamous NSCLC patients. The Common Terminology Criteria for Adverse Events (version 3.0) was used for summary of the AE incidence rates by cycle and AE severity reported by investigator. The Lung Cancer Symptom Scale (LCSS) was used to evaluate patients’ QoL. Worsening of fatigue was defined as an increase of 15 mm or more from baseline on a 100 mm scale in LCSS reported by the patients. The percentage of patients with worsening fatigue was also summarized by cycle. The time to worsening of fatigue symptom was analyzed using Kaplan-Meier method and Cox proportional model.

Results:
In the EA population drug-related fatigue (grade 1-4) occurred more frequently in pemetrexed arm compared with placebo arm (30.4% vs 16.0%, p=0.075). The grade 3/4 drug-related fatigue was rare in both arms (1 event reported in each arm). For both overall and EA populations, the fatigue incidence by cycle during the maintenance treatment with pemetrexed did not increase during subsequent cycles (Figure 1A, B). The percentage of patients who experienced worsening of fatigue based on the patients-reported LCSS scores was also comparable between the two arms in the overall and EA populations (Figure 1C, D). EA Patients in the pemetrexed arm experienced a numerically longer median time to worsening of fatigue compared to EA patients in the placebo arm, although the difference is not statistically significant (5.95 months vs. 3.91 months, HR= 0.84, 95% confidence interval [CI]: 0.51-1.37, p= 0.471). Figure 1



Conclusion:
These analyses suggest that despite a higher incidence of grade 1/2 drug-related fatigue compared with placebo, pemetrexed maintenance treatment for EA patients with advanced NSCLC will not impair patient-reported QoL.

Background:
Platinum-based doublet chemotherapy is still mainstay in treatment of advanced non-small-cell lung cancer (NSCLC). There was no molecular determinant for guiding platinum-based chemotherapy. Excision repair cross-complementing group 1 gene (ERCC1) is important for platinum-induced DNA adduct repair and ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism and has been known for the dominant molecular determinant of gemcitabine efficacy. We assessed whether selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in patients with advanced NSCLC.

Methods:
Eligible patients were randomly assigned 1:1 to experimental arm and control arm. The experimental arm consisted of gemcitabine/carboplatin (GC) if ERCC1 and RRM1 were low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received docetaxel/carboplatin (DC). All chemotherapy regimens were to be continued for maximum 4 cycles every 3 weeks or unacceptable toxicity. ERCC1 and RRM1 mRNA expression were measured by quantitative real-time PCR in formalin-fixed paraffin-embedded (FFPE) tissue. The trial was powered for an 80% improvement in overall response rate (ORR, P0=0.25, P1=0.45, α=0.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study was prematurely terminated after the futility analysis of 42 PFS events, which showed a low conditional probability (conditional power=0.14) of a statistically significant outcome.

Results:
A total of 56 patients (n=26 in experimental arm, n=30 in control arm) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (64.3%) and ECOG performance status 0 to 1 (96.4%). EGFR mutation was documented in 8 patients (4 in experimental arm, 4 in control arm). Among 26 patients in the experimental arm, mRNA expression of ERCC1 and RRM1 ranged from 0.18 to 2.81 (median, 0.69) and 0.22 to 16.65 (median, 0.66), respectively. Based on mRNA expression levels, 19 (73.1%) patients were assigned to GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to VD. The median number of chemotherapy cycles delivered was 3.7 in experimental arm and 3.5 in control arm. The ORRs were 26.9% in experimental arm and 40.0% in control arm, which were not statistically significant (P=0.58). With a median follow-up of 30.1 months, median PFS was 4.6 months in experimental arm and 5.1 months in control arm (hazard ratio [HR] 1.27; 95% CI 0.69-2.31; P=0.43). Median OS was 18.2 months in experimental arm and was 12.6 months in control arm (HR 0.71; 95% CI 0.32-1.53; P=0.38). The occurrence of grade 3 or higher neutropenia (69.2% vs. 93.4%, P=0.02) and febrile neutropenia (3.8% vs. 23.3%, P=0.04) was significantly more common in control arm. There was no treatment-related death.

Conclusion:
ERCC1 and RRM1 expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

Background:
Renal impairment increases with age and can impact treatment decisions. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C) in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062). In a subgroup analysis of this phase III trial, nab-P/C demonstrated promising efficacy and was well tolerated in patients with or without renal impairment (Langer et al. Clin Lung Cancer. 2015;16:112-120). This analysis examined outcomes of patients in the phase III trial stratified by age and renal function.

Methods:
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1 in combination with C AUC 6 on day 1 every 21 days (randomized 1:1). Treatment continued until disease progression. Baseline renal function (creatinine clearance [CrCl]) was assessed in a central lab. ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test.

Results:
Treatment with nab-P/C resulted in improved outcomes compared with sb-P/C in patients with mild renal impairment, regardless of age (Table). nab-P/C also consistently demonstrated greater treatment effect compared with sb-P/C for ORR and similar or better PFS and OS in patients ≥ 60 years, regardless of renal function. In patients with either mild renal impairment or normal renal function, the toxicity profiles in each treatment arm were similar to those of the intent-to-treat population.

Conclusion:
These results suggest that, in general, clinical outcomes in patients with advanced NSCLC and mild renal impairment are better with nab-P/C vs sb-P/C, regardless of age. It should be noted that these were small subset analyses and results should be interpreted with caution. Figure 1

Background:
Chemotherapy-induced thrombocytopenia (CIT) has seriously hindered the application of anti-cancer drugs. Thrombopoietic factors such as recombinant human interleukin-11(rhIL-11), thrombopoietin and its derivative(recombinant human thrombopoietin, rhTPO) are routinely administrated for CIT. But there is no randomized study to compare rhTPO with rhIL-11 on efficacy and safety of thrombocytopenia prophylactic treatment before. This is the first randomized, open-label, multicenter, phase Ⅲ study to compare them in China. We tried to investigate the efficacy and safety of prophylactic administration with rhTPO or rhIL-11 to prevent CIT in advanced non-small-cell lung cancer(NSCLC) patients.

Methods:
From June 2009 to February 2015, 71 patients with advanced NSCLC who were receiving the first-line platinum-based chemotherapy suffered severe thrombocytopenia(the nadir of platelet counts＜50×10[9]/L, confirmed by two times of blood routine in different days) during prior chemotherapy cycle. They were randomized to rhTPO arm or rhIL-11 arm in the following chemotherapy cycle, and the chemotherapy regimens and drug doses were consistent in the prior and following cycle (GC Gemcitabine 1000-1250 mg/m[2], D1 and D8; Carboplatin dosing by AUC value=5, D1; Q3W) or GP (Gemcitabine 1000-1250 mg/m[2], D1 and D8; Cisplatin 75 mg/m[2], D1; Q3W). 49 patients (34 males, 15 females) were enrolled rhTPO arm and 22 patients (14 males, 8 females) were enrolled rhIL-11 arm. There were no statistical difference between two arms in terms of gender[34 males(69.4%) vs.14 males(63.6%),P＞0.05], age(58.5±9.3 yrs vs. 60.3±7.5 yrs, P＞0.05), and the nadir of platelet counts during prior chemotherapy cycle(31.4±13.1×10[9]/L vs. 28.6±12.8×10[9]/L, P＞0.05). rhTPO (15000U/d) was injected subcutaneously on the 2[nd], 4[th], 6[th], 9[th ]Day after the initiation of chemotherapy, and IL-11(3mg/d) was injected subcutaneously per day from Day 9 to Day15 after the initiation of chemotherapy. Blood routines were conducted to test before chemotherapy initiation and the 3[th], 5[th], 7[th], 9[th], 11[th], 13[th], 15[th], 17[th], and 21[th] day after chemotherapy. Toxicity and efficacy were monitored.

Results:
In the following chemotherapy cycle there were no statistical difference between rhTPO arm and rhIL-11 arm on the following indexes: the nadir of platelet counts(66.6±43.1×10[9]/L vs. 53.8±40.6×10[9]/L, P＞0.05) , the maximum platelet counts (219±132×10[9]/L vs. 240±151×10[9]/L, P＞0.05) , duration of platelet counts less than 50×10[9]/L[Median (95%CI): 4.0(3.0-5.0) days vs. 4.5(3.0-6.0) days, P＞0.05], time of platelet count recovered to 75×10[9]/L [Median(95%CI): 2(2-3) days vs. 3(0-4) days, P＞0.05] and to 100×10[9]/L[median(95%CI): 4(3-6) days vs. 4.5(3-8) days, P＞0.05]. Drug-related adverse events in rhTPO arm were less than that of rhIL-11 arm (5 cases(10.2%) in rhTPO arm, 7 cases(31.8%) in rhIL-11 arm, P<0.05).

Conclusion:
Although there is no statistical difference on efficacies, prophylactic administration of rhTPO is safer and more convenient than that of rhIL-11 in advanced NSCLC patients. This is an interim analysis. More data is still waiting.

Background:
The Victorian Lung Cancer Registry is a clinical quality registry designed with the aim of improving the quality of care delivered to Victorians with lung cancer by collecting and assessing management, treatment and outcome data on all new cases of lung cancer.

Methods:
The establishment of the Victorian Lung Cancer Registry Pilot Project commenced with the appointment of a Steering Committee to provide project governance. Review of current literature and evidence-based national and international clinical practice guidelines was undertaken by an expert working group. Included data items were epidemiologically sound, reproducible and valid. The data set enables the capture of identified quality indicators designed to describe the structural quality, process quality and indicators of outcome in lung cancer management. Case ascertainment is derived from institutional ICD-10 coding and participant consent occurs via an “opt-off” system. Follow up and outcome measures are collected at baseline, 6 and 12 months after diagnosis capturing survival, treatment and quality of life. Institutional recruitment was designed to sample from metropolitan public, metropolitan private and regional hospitals.

Results:
Data was collected on 690 patients from 1 July 2012 to 31 June 2013 from 8 Victorian Hospitals (3 public and 3 private metropolitan and 2 regional). Evidence of distress screening was available for 27% of subjects. Diagnosis was confirmed < 28 days from referral in 66% of cases across institutions. A statement of ECOG status was available in 45% of cases and clinical TNM staging in 49% prior to treatment. A record of multidisciplinary team meeting presentation was available in 59% of cases. First treatment was initiated < 42 days from diagnosis in 76% of cases. Curative surgery was provided for 28% of subjects, curative chemotherapy <5% and curative radiotherapy < 5%.

Conclusion:
The evaluation of registry outcomes at governance, administrative and clinical levels may identify targets for quality and service improvement and further define safety measures. The comparison of performance outcomes across institutions and sectors may drive competitive recruitment to improve measures on a longitudinal basis.

Background:
Cancer of the prostate and lung are most commonly diagnosed in the elderly. Aberrant female sex hormone signaling has been well-described in NSCLC. The impact of androgen deprivation therapy (ADT) on non-small cell lung cancer (NSCLC) outcome has, however, not been well studied.

Methods:
We employed the linked SEER-MEDICARE database to assess the potential impact of ADT on NSCLC. We analyzed data from patients diagnosed with NSCLC between 1985 and 2005 and registered in the SEER-MEDICARE database. Patients were categorized into three groups: prostate cancer diagnosis followed by NSCLC (PL), NSCLC followed by prostate cancer (LP) and NSCLC only (L). Demographic and survival outcomes were compared between these groups. The impact of sequence of cancer diagnosis and ADT on survival post NSCLC diagnosis was assessed within the PL group using logistic regression model. Cox proportional hazards models were employed to estimate the effect of ADT and stage of prostate cancer on survival with adjustment for significant prognostic factors.

Results:
A total of 417630 patients were included in this analysis; male/female (56.4%/43.6%); Race: White (84.0%), Black (9.0%), Asian (2.1%), Hispanic (1.0%), others (3.0%); Stage: I (17.4%), II (2.9%), III (33.6%) and IV (46.1%). The majority of the patients were in the L group (96.3%), followed by PL (2.9%) and LP (0.8%). Patients in the LP group had the best 12-month survival rates (84.5%), followed by L (44.4%) and PL (40.1%). Analysis within the PL group showed an inverse correlation between stage of prostate cancer diagnosis and interval of time to NSCLC diagnosis: 54.8, 54.1, 62.1 and 59.3 months for stage I, II, III and IV prostate cancer, respectively. Prostate cancer patients exposed to ADT had a shorter interval to lung cancer diagnosis (48.3 vs. 52.7 months; p < 0.001). On multivariate analysis, patients exposed to ADT had a higher median survival (10 months vs. 9 months; p < 0.001) and reduced risk of death (HR:1.11; 95%CI:1.05-1.18), p <0.001).

Conclusion:
ADT therapy for prostate cancer was associated with improved survival for subsequent NSCLC diagnosis. Our result supports systematic exploration of ADT as a treatment strategy for NSCLC.

Background:
Metastatic non-small cell lung cancer (NSCLC) remains an incurable disease. Sacher et al reviewed phase III studies in first-line advanced/metastatic NSCLC conducted from 1981 to 2010. Although trends in study outcomes were assessed, design and stratification factors have never been analyzed.

Methods:
The recently published list of phase III trials by Sacher et al (JCO 2014;32:1407-11) was reviewed thoroughly. Eligible trials for this study must have been published in the English literature between 1981 and 2010. Trials that included a substantial number of previously treated NSCLC patients were excluded. Maintenance studies after first-line chemotherapy were also excluded. Characteristics in each decade were determined for sample size, number of trials, region, rate of meeting accrual goal, primary endpoint, type of phase III, interim analysis, allocation method, and stratification factors (SFs). Any p-value of less than 0.05 was considered significant for statistical analysis.

Results:
A total of 162 studies were considered to meet the criteria. The number of studies and median sample size increased from 29 and 133 in 1980s to 46 and 181 in 1990s to 87 and 407 in 2000s, respectively. Primary endpoint was reported more frequently in recent decades; 24% of studies in 1980s, 83% in 1990s, 99% in 2000s. Non-overall survival endpoints were frequently chosen in European and Asian studies. Interim analysis was planned for 3% in 1980s, 20% in 1990s, 33% in 2000s. Allocation method was rarely reported throughout the three decades (0% in 1980s, 22% in 1990s, 28% in 2000s). The median number of SFs increased significantly from one in 1980s to three in 2000s (see Table). Performance status (PS), stage, and institution have been most frequently selected, and at least one of the three factors was used in most of the studies (84%) in 2000s. There are many other SFs that were used infrequently. More details will be presented. Table: SFs in first-line phase III NSCLC trials. All others; stratification factors other than PS, stage, and institution. The median number of SFs increased significantly (one way ANOVA, p=0.003).

	1981-1990	1991-2000	2001-2010	Total
No. of studies	29	46	87	162
Median no. of SFs	1	2	3	2
PS	14(48%)	21(46)	48(55)	83(51)
Stage	2(7)	22(48)	63(72)	86(53)
Institution	2(7)	17(37)	37(43)	56(35)
PS or Stage	15(52)	29(63)	6(7)	113(70)
PS, Stage, or Institution	16(55)	32(70)	73(84)	121(75)
Not reported or None	12(41)	13(28)	13(15)	38(23)
All others	1(3)	1(2)	1(1)	3(2)

Conclusion:
This study reports extensive details in design of phase III trials for first-line NSCLC that have been published over three decades. We found increases in sample size and reporting primary endpoint, whereas allocation method remains underreported. Although PS, stage, and institution are the most frequently selected, choice of SFs remains inconsistent across studies. Our report provides researchers with valuable information for future studies.

Background:
Molecular targeted therapy based on tyrozine kinase inhibitors (TKI), directed at epidermal growth factor receptor (EGFR) is one of the novel effective agents in management of advanced-stage NSCLC. However several candidate predictors have been extensively studied, apart from activating EGFR gene mutations, no reliable biochemical or molecular predictors of response to erlotinib have been validated. The aim of our retrospective study was to evaluate the association of baseline serum albumin with outcomes in a large cohort of patients with advanced-stage NSCLC treated with erlotinib.

Methods:
Clinical data of 457 patients with locally-advanced (IIIB) or metastatic stage (IV) NSCLC treated with erlotinib were analysed. Serum samples were collected and the measurement was performed one day before the initiation of erlotinib treatment.

Results:
Before the treatment initiation, low albumin was (<35 g/l) measured in 37 (8.1%) patients and normal albumin (≥ 35 g/l) was measured in 420 (91.9%). The median PFS and OS for patients with low serum albumin was 0.9 and 1.9 months compared to 1.9 and 11.4 months for patients with normal serum albumin (p=0.001 and p<0.001). The multivariate Cox proportional hazards model revealed that EGFR mutation status (HR=2.50; CI: 1.59-3.92; p<0.001) and pretreatment serum albumin (HR=1.73; CI: 1.21-2.47; p=0.003) were significant independent predictive factors for PFS, whereas EGFR mutation status (HR=3.14; CI: 1.70-5.81; p<0.001), stage (HR=1.48; CI: 1.09-2.02; p=0.013), ECOG PS (HR=1.77; CI: 1.37-2.29; p<0.001) and pretreatment serum albumin (HR=4.60; CI: 2.98-7.10; p<0.001) were significant independent predictive factors for OS.

Conclusion:
The results of the present retrospective study indicate that pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients treated with erlotinib. Based on the present study results, measuement of serum albumin is an objective laboratory method feasible for estimation of prognosis of patients with advanced-stage NSCLC. This study is supported by Ministry of Health, Czech Republic - conceptual development of research organization Faculty Hospital in Pilsen - FNPl, 00669806 and by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund.

Background:
We conducted a systematic review of data from patients reported in the TULUNG registry (data cut-off 26-Jan-15). The TULUNG registry is Czech national oncology registry which prospectively collects data from all NSCLC patients treated with new targeted therapies in Czech Republic since 2008.

Methods:
Analysis was performed on a group of patients with non-squamous NSCLC with good performance status (PS 0-2), treated with bevacizumab. Since 2008 bevacizumab has been used for treatment in 193 patients (full record criteria met). 10 patients with incomplete records were not included to the review

Results:
In this group of patients 35.8% were female; the median age at bevacizumab treatment initiation was 60 years (range 29-83). The majority of patients were smokers and ex-smokers (37.8% and 34.7% respectively) and 91.7% of tumors were adenocarcinomas by histology. 91.7% patients were at the metastatic stage at the initiation of bevacizumab treatment, 6.2% of patients were in stage IIIb and only 2.1% of patients in stage IIIa (UICC6). The performance status was distributed between ECOG PS0 and PS1 mainly (40.9% PS0 and 58% PS1)at the initiation of the bevacizumab treatment. Majority of patients received bevacizumab treatment in the first line (96.4%). Two main chemotherapy regimens were used; carboplatin+paclitaxel (68.4%) and cisplatin+gemcitabine (9.8%). In this group of 193 patients analyzed, bevacizumab therapy was terminated in 152 (78.8%) patients at data cut-off. The most frequent reasons for termination were disease progression, in 55.9%, termination of treatment according to plan in 8.6% and death, in 7.9% of patients. Treatment with bevacizumab is ongoing in 41 (21.2%) patients. In 152 of patients with terminated treatment, the median duration of treatment was 15.6 weeks (95% CI 0.3 – 51.3). Response assessment showed CR in 0.7%, PR in 40.8% and SD in 35.5% of patients. Median progression free survival was 6.9 months (95% CI 5.8 – 8.1), median overall survival 16.7 months (95% CI 11.7 – 21.7). 1-year survival from bevacizumab treatment initiation was 67.9%. Adverse events were reported in 9.8% of patients, the most frequently reported adverse events were thromboembolic events (5.2%) and neutropenia (1.6%). Tromboembolic events were observed in 10 patients, none of these was fatal. We didn´t observe any severe episode of bleeding event.

Conclusion:
Therapy with bevacizumab in non-squamous NSCLC was active and very well tolerated. In eligible patients, only 7 patients (4.6%) had to discontinue bevacizumab therapy due to safety reasons. In patients with completed bevacizumab therapy 77.0% disease control rate was reached with a median survival of approximately 16.7 months from initiation of first line therapy with bevacizumab.

Background:
Maintenance therapy (MT) after platinum doublet chemotherapy has been shown to improve progression-free survival (PFS) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC), whereas optimal strategies for MT, such as continuation or switch maintenance, have yet to be determined. ATLAS trial adopted a combination maintenance strategy design in which both EGFR-positive and -negative NSCLC patients received platinum doublet chemotherapy at the choice of investigators plus bevacizumab (Bev) followed by Bev with either erlotinib (Erl) or a placebo as a maintenance therapy. The trial demonstrated that Erl plus Bev was favorable for PFS, but not for either OS or toxicity, when compared with placebo plus Bev. The aim of this phase II study was to clarify the effects and safety of a fixed induction regimen: carboplatin (Cb)/pemetrexed (PEM)/Bev followed by Bev plus Erl as a maintenance therapy in non-squamous (nonSq)-NSCLC patients with wild-type (WT) EGFR.

Methods:
All eligible patients (pts) had treatment-naive nonSq-NSCLC (stage IIIB, IV, or postoperative recurrent) with WT EGFR. Cb (AUC 5), PEM (500 mg/m[2]) and Bev (15mg/kg) were administered on Day 1 every three weeks for four-to-six cycles and maintenance therapy with Bev (15mg/kg) once every three weeks plus continuous Erl (150mg/body) was administered until occurrence of either disease progression or unacceptable toxicity. The primary endpoint was PFS at 6 months (mo). The secondary endpoints included OS, tumor response, toxicity, and quality of life (QOL).

Results:
From September 2011 to June 2014, 51 pts were enrolled. Fifty pts were evaluated for the efficacy and safety of the treatment. The median follow-up duration was 14.3 months (range: 1.1-30.7). The median age was 64 years (range: 36-74); male/female=27/23 (54/46%); ECOG PS 0/1=28/22 (56/44%); Stage IIIB/IV/recurrent=5/41/4 (10/82/8%); adenocarcinoma/NSCLC=48/2 (96/4%). The median cycles of the induction/maintenance therapy were 4 (range: 1-6)/4 (range: 1-20). Twenty-nine pts (58%) received the MT. Overall response rate was 48.0% (95% CI: 34.8-61.5%), and disease control rate was 86% (95% CI: 73.8-93.0%). Six-month PFS rate was 59.5% (95% CI: 45.0-72.6%). Median OS and PFS were 18.4 mo (95% CI: 11.9-24.9 mo) and 6.5 mo (95% CI: 5.8-7.2 mo), respectively. CTCAE Grade (Gr) 3/4 hematological toxicities were neutropenia (48%/3.4%), anemia (18%/3.4%) and thrombocytopenia (22%/0%). The most frequent Gr 3/4 non-hematological toxicities were anorexia (14%/3.4%), hypertension (10%/3.4%), malaise (6%/3.4%), nausea (6%/0%) and rash (0%/10%). There were two interstitial lung diseases (Gr1), one gastrointestinal perforation (Gr4), and one treatment-related death due to ventricular fibrillation. QOL results are still under analysis.

Conclusion:
Cb/PEM/Bev followed by maintenance Bev/Erl was effective and well tolerated in NS-NSCLC pts with WT EGFR.

Background:
ARCHER 1042 (NCT01465802) was a randomized patient (pt) blinded trial that explored prophylactic interventions to minimize select dermatologic adverse events of interest (SDAEI) and diarrhea associated with D, an irreversible small molecule PanHER inhibitor.

Methods:
In Cohorts I (CI) and II (CII) pts with advanced NSCLC, ≥1 prior chemo, ECOG 0–2, were randomized (pt blinded) in CI to (a) D 45 mg daily (QD) plus placebo (pbo) (D+pbo) or (b) D 45 mg QD plus doxy 100 mg twice daily x 4 wks (D+doxy) and in CII assigned to D 45 mg QD plus probiotic (prob) and topical alclometasone (alclo) (D+prob+alclo). Primary endpoints in first 8 wks included: all grade (G) and G≥2 SDAEI and PRO (Skindex-16) (CI, CII) and CII G and G≥2 diarrhea and PRO (modified Mucositis Daily Questionnaire). Plasma samples were collected to confirm that exposure of D is not altered with doxy treatment.

Results:
As of August 25, 2014, 112 pts randomized to Cohort I D+pbo vs. D+doxy (median age 66 years, 53% male) and 59 pts to CII D+prob+alclo (median age 66 years, 66% male) were evaluable (>6 wks treatment). Median relative dose intensity (RDI) of D in the first 8 wks was 82.74% for D+doxy compared with 79.76% for D+pbo and 75.00% for D+prob+alclo. Figure 1 PRO Skindex scores improved with prophylactic doxy, but not alclo; prophylactic probiotic was not associated with improved CTCAE or PRO. Plasma exposure of D was similar when administered either with pbo or doxy.



Conclusion:
These preliminary data suggest prophylactic doxy improves ≥G2 Select Dermatologic AEs with improved D RDI and less need for dose discontinuations. The prophylactic effect observed with doxy cannot be attributed to altered exposure of D. In contrast, prophylactic topical corticosteroids had no effect on rash or diarrhea.

Background:
In industrialized countries, the age of approximately 50% of patients at diagnosis of non-small cell lung cancer (NSCLC) is >70 years old. Exploration of an optimal treatment strategy for elderly patients with NSCLC as either a first-line or second-line therapy is required. Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is an effective treatment for patients with NSCLC, especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second or third-line erlotinib monotherapy in elderly patients with EGFR-wt advanced or recurrent NSCLC.

Methods:
Eligibility criteria included: patients aged ≥70 years with pathologically or cytologically proven NSCLC; measurable tumor sites according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1; an Eastern Cooperative Oncology Group performance status of 0–2; no activating EGFR gene mutations (exon 18, 19, 20 and 21); history of 1–2 regimens of systemic chemotherapy; stage IIIB or IV NSCLC, or postoperative recurrence; treatment naïve to EGFR-TKI; and appropriate organ function. EGFR gene mutation analysis was performed by using invasive signal amplification reaction with a structure-specific 5’ nuclease and a polymerase chain reaction (PCR) product (PCR-invader). Patients received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile.

Results:
This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range, 70–84 years), and six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0, and 11 (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% (95% confidence interval [CI]: 0–17.1) and DCR was 56.3% (95% CI: 33.2–76.9). The median PFS and OS were 1.7 months (95% CI: 1.3–2.2) and 7.2 months (95% CI: 5.6-8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which was improved by following steroid therapy.

Conclusion:
In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second-line therapy.

Background:
This multicenter, randomized phase II trial investigated the efficacy and safety of docetaxel plus bevacizumab and S-1 plus bevacizumab in the second-line treatment of non-squamous (non-Sq) non-small-cell lung cancer (NSCLC).

Methods:
Patients with non-Sq NSCLC who experienced disease progression after prior platinum-based chemotherapy with or without bevacizumab were randomly assigned (1:1) to receive docetaxel 60 mg/m[2] plus bevacizumab 15 mg/kg (DB) once every 3 weeks or S-1 40 mg/m[2] orally twice daily on days 1–14 plus bevacizumab 15 mg/kg (SB) on day 1 every 3 weeks until disease progression. The primary endpoint was progression-free survival (PFS).

Results:
Ninety patients were randomized. The median PFS was 3.9 months (95% confidence interval [CI] = 3.0–6.5) in the DB arm and 3.5 months (95% CI = 2.9–5.9) in the SB arm. The objective response rate was significantly higher in the DB arm than in the SB arm (22.2% vs. 2.2%; P = 0.004), whereas the disease control rates of the arms were identical (62.2% vs. 62.2%; P = 1.00). Patients receiving DB were more likely to have ≥grade 3 neutropenia (93.4% vs. 4.4%) and febrile neutropenia (33.3% vs. 0%) than SB-treated patients. In the DB arm, PFS and overall survival were significantly longer among bevacizumab-naïve patients than among bevacizumab-experienced patients (median PFS: 7.4 months vs. 2.8 months; P < 0.001; and median OS: 27.4 months vs. 11.7 months; P = 0.002).

Conclusion:
DB and SB produced modest PFS benefits in the second-line treatment of patients with advanced non-Sq NSCLC. Because of the toxicity of DB and the low response rate of SB, neither regimen warrants further investigation, excluding DB in bevacizumab-naïve patients with advanced non-Sq NSCLC.

Background:
This study aimed to explore the safety and effectiveness of anti-angiogenesis agent Endostar combined with neo-adjuvant chemotherapeutic therapy in the treatment of non-small cell lung cancer (NSCLC) patients in phase ⅢA (N2).

Methods:
From April, 2011 to December, 2013, a total of 30 patients diagnosed as NSCLC in phase ⅢA (N2) by pathology or assistant examinations were selected in the randomized, control and open clinical study treated with NP combined with Endostar or single NP neo-adjuvant chemotherapeutic therapy. Control group was treated with neo-adjuvant NP chemotherapy for 2 weeks, on which basis trial group was added with Endostar for 2 weeks. Clinical efficacy was evaluated 3 weeks and surgery was performed within 4 weeks after 2-cycle treatment. The primary end points were response rate (RR), clinical benefit rate (CBR) and tumor regression rate (TRR) as well as peri-operative clinical indexes and safety. The secondary end points included disease-free survival time (DFS) and overall survival time (OS).

Results:
In the 26 patients with evaluable efficacy, trial group and control group were 50.0% and 40.0% in RR (P＝1.0), 87.5% and 64.0% in CBR (P＝0.76), 19.7% and 7.1% in TRR (P＝0.036), 12.0 months and 10.0 months in total DFS (P＝0.44) and 16.0 months and 14.0 months in OS (P＝0.39), respectively. however, there was no significant difference between two groups in all clinical indexes and hematological and non-hematological toxicities in all degrees (P＞0.05).

Conclusion:
Endostar combined with NP chemotherapy are markedly higher than single NP neo-adjuvant chemotherapy in RR, CBR, TRR, DFS and OS without increasing the therapeutic toxicities. In addition, there is no significant difference between two groups in peri-operative clinical indexes, indicating that Endostar combined with NP chemotherapy are safe and effective in treating patients with NSCLC in ⅢA (N2).

Background:
Erlotinib is active in tumors with an EGFR mutation. Capecitabine, a thymidylate synthetase inhibitor, has shown some activity in advanced lung cancer (ALC). The combination of erlotinib and capecitabine has not been studied in ALC.

Methods:
We conducted a phase 1b trial, using a standard 3+3 dose escalation design to define the maximum tolerated dose (MTD) and safety of the combination of erlotinib and capecitabine, given on a 3-weekly cycle in 2[nd] line patients unselected for EGFR status. DLT was any grade≥2 toxicity. After MTD was defined in the 2[nd] line patients, we planned expansion of the trial to 1[st] line patients for further dose escalation. Dosing levels are listed in Table 1. Toxicity was assessed using CTCAE v3.0, response rate was assessed using RECIST 1.1, and survival assessed using Kaplan-Meier method.

Results:
We recruited 40 patients with adenocarcinoma. 55% were male, with median age of 67 years (range 38-84). 65% were ex-smokers and 28% were current smokers. Performance status was ECOG 1 in 65% and 2 in 35% of patients. 85% of patients had received platinum-doublet chemotherapy for 1[st] line ALC, with 10% having maintenance pemetrexed. One patient had an EGFR mutation. Dose escalation stopped at level 3 in 2[nd] line patients with expansion to 6 patients due to dose limiting toxicities (DLTs) of grade (G) 2 creatinine rise, G2 anemia, G3 atrial fibrillation, and G3 pneumonia in 2/6 patients. The MTD was thus at level 2 that was also expanded to 6 patients, confirming safety. First line patients were then recruited at MTD but resulted in DLTs in 3/4 patients with G3 troponin rise, G2 rash, and G2 bilirubin rise in 2 patients. Hence the 1[st] line approach was abandoned. The MTD in 2[nd] line patients was further expanded for toxicity and activity. The overall response rate was 3% with a disease control rate of 34%. A partial response was seen in 1 patient with EGFR mutation of 11.3 months duration. The median progressive free survival was 1.6 months (95%CI 1.4 – 3.5) and the median overall survival was 6.1 months (95%CI 5.1 – 12.5).

Conclusion:
The MTD for capecitabine is 750mg/m[2] bd days 1–14 and erlotinib 100mg od on a 3-weekly cycle. The addition of capecitabine does not improve the efficacy of erlotinib in unselected ALC. This combination could be explored further in ALC selected for EGFR mutation. Table 1: Patient disposition.

Dose escalation	No. of pts	No. of pts with DLTs
Level 1 - Erlotinib 100mg od, Capecitabine 500mg/m[2], bd, days 1-14	3
Level 2 - Erlotinib 100mg od, Capecitabine 750mg/m[2], bd, days 1-14	3 + 3
Level 3 - Erlotinib 100mg, od, Capecitabine 1000mg/m[2] bd, days 1-14	3 + 3	2
1[st] line ALC at level 2	4	3
Dose Expansion
2[nd] line ALC	21

Background:
Concurrent chemoradiotheray is the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC), but often accompanying with high toxicities and poor tolerability. Radiosensitization of EGFR tyrosine kinase inhibitors (TKI) has been proved in preclinical studies, and the safety of TKI combined with thoracic radiotherapy has also been evaluated in several phase II trials.

Methods:
Patients with previously untreated, non-metastasis NSCLC, EGFR wild-type, Easter Cooperative Oncology Group performance status of 0-2 and acceptable organ function were eligible. The prescribed radiation dose was 60-70Gy, and both three dimensional conformal and intensity-modulated radiation therapies were allowed. TKI was administrated concurrently with thoracic radiotherapy. The primary endpoint was local-regional control; second endpoints included progression-free survival, overall survival and treatment-related toxicities.

Results:
Between 2012.1 and 2015.3, 12 eligible patients were recruited into this study, with an median age of 65 years (range 47 ~ 82 years)， 1 female and 11 males. One of them was stage Ⅳ, two of them were stage Ⅱ and nine of them were stage Ⅲ. During the process of treatment, 2 (16.7%) of patients developed grade Ⅱ radiation pneumonitis and 9 (75.0%) developed level Ⅰ~Ⅱ hematological toxicity. Patients were followed up with a median follow-up time of 13 months (6~35months) and the last follow-up time was 2015.3. The results showed that 1-year and 2-year overall survival rates were 76.2% and 57.1%, respectively. 1-year and 2-year local recurrence-free survival rates (LRFS) were 62.2% and 62.2%, respectively. 1-year and 2-years PFS rates were 55.0% and 55.0% (see table), respectively.

Conclusion:
The preliminary results showed that concurrent thoracic radiotherapy and EGFR-TKI were safe and effective in NSCLC patients with wild-type EGFR. This trial is on going.

Background:
PF-06439535, a potential biosimilar to bevacizumab, is a humanized monoclonal IgG1 antibody that targets the vascular endothelial growth factor. This study (B7391001) compared the pharmacokinetics (PK) of PF-06439535 to bevacizumab sourced from the US (bevacizumab-US) and EU (bevacizumab–EU), and the PK of bevacizumab-EU to bevacizumab–US in healthy male volunteers.

Methods:
In this double-blind study, 102 healthy males, aged 21-55 years, were randomized 1:1:1 to receive a single 5 mg/kg intravenous dose of PF-06439535, bevacizumab-US, or bevacizumab-EU. One subject discontinued before dosing. Assessments for PK were conducted for 71 days, with extended safety and immunogenicity assessments up to 100 days postdose. PK similarity was achieved if 90% confidence intervals (CIs) for the test-to-reference ratios of the maximum concentration (C~max~), the area under the concentration-time curve (AUC) from time 0 to the last quantifiable time point (AUC~T~), and AUC from time 0 extrapolated to infinity (AUC~0-∞~) were within 80.00%–125.00%.

Results:
Ninety-seven subjects were eligible and included in the PK analysis. The demographics of the PK eligible subjects were comparable among the 3 treatment groups. The 3 study drugs exhibited similar PK parameters (Table 1). For the comparisons of PF-06439535 to bevacizumab-EU or bevacizumab-US, and of bevacizumab-EU to bevacizumab-US, the 90% CIs for the ratios of C~max~, AUC~T~, and AUC~0-∞~ were all within 80.00%–125.00% (Table 2). Treatment-related adverse events were reported in 15.2%, 25.7%, and 18.2% of subjects in the PF-06439535, bevacizumab-EU, and bevacizumab-US treatment arms, respectively. Table 1: Mean (±SD) PK Parameter Estimates

Parameters (units)	PF-06439535	Bevacizumab-EU	Bevacizumab-US
N	32	33	32
C~max~ (µg/mL)	142.9 ± 20.3	137.0 ± 20.5	130.0 ± 18.2
AUC~T~ (µg•hr/mL)[a]	40840 ± 6411	41010 ± 6711	38920 ± 4566
AUC~0-∞~ (µg•hr/mL)	43080 ± 7103	43830 ± 8326	41450 ± 5350

[a]AUC~T~ was ≥80% of the corresponding AUC~0-∞~ in all 97 PK eligible subjects. Table 2: Comparisons of Pharmacokinetic Exposure Parameters between Test and Reference Products

Comparison (Test to Reference)	Parameters, units	Test[a]	Reference[a]	Test/Reference Ratio (%)	90% CI for Ratio
PF-06439535 to bevacizumab-EU	C~max~, µg/mL	141.5	135.5	104.42	98.36–110.84
	AUC~T~, µg•hr/mL	40330	40490	99.62	93.69–105.93
	AUC~0-∞~, µg•hr/mL	42490	43100	98.58	92.16–105.44
PF-06439535 to bevacizumab-US	C~max~, µg/mL	141.5	128.9	109.79	103.38–116.60
	AUC~T~, µg•hr/mL	40330	38660	104.32	98.06–110.97
	AUC~0-∞~, µg•hr/mL	42490	41120	103.33	96.55–110.58
Bevacizumab-EU to bevacizumab-US	C~max~, µg/mL	135.5	128.9	105.15	99.05–111.62
	AUC~T~, µg•hr/mL	40490	38660	104.71	98.48–111.34
	AUC~0-∞~, µg•hr/mL	43100	41120	104.82	98.00–112.12

[a]Adjusted geometric means

Conclusion:
This study demonstrates PK similarity of PF-06439535 to both bevacizumab-US and bevacizumab-EU, and of bevacizumab-EU to bevacizumab-US. The safety profile was similar in the 3 treatment groups with no significant safety findings reported.

Background:
Treatment strategies for advanced non-squamous (sq) non-small cell lung cancer (NSCLC) are divided by EGFR mutations. However, there has been no previous report about efficacy of cytotoxic agents separated by EGFR mutations. In addition, the influence of the EGFR mutations on the maintenance therapy with pemetrexed (Pem) or bevacizumab (Bev) has not been elucidated. We planned two studies designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem and Bev maintenance therapy for non-sq NSCLC patients without or with activating EGFR mutation.

Methods:
We undertook two multicenter, open-label, single-arm, phase II studies. Patients with wild type EGFR or with EGFR mutation (exon 19 deletions or exon 21 point mutation) entered CJLSG0909 or 0910, respectively. Patients received Pem 500mg/m[2], Cb AUC 6, and Bev 15mg/kg day1, every 3 weeks, 4 to 6 cycles (induction therapy). Patients who had achieved disease control received Pem+Bev maintenance therapy until progressive disease or unacceptable adverse event. Key inclusion criteria were stage IIIB, IV, or recurrent disease after surgery, no prior chemotherapy, age 20 to 74. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were the disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. (Unique trial Number; UMIN000003736/UMIN000003737)

Results:
In CJLSG0909, 50 patients received induction treatment. They had a median age of 64 years and were predominantly men (40 [80%]) with adenocarcinoma (47 [94%]), stage IV (40 [80%]), and a performance status (PS) of 1 (40 [80%]). The median of induction therapy was 5 cycles. Thirty-five (70%) patients received maintenance therapy, and the median of maintenance therapy was 5 cycles. Partial response was observed in 25 patients with a ORR of 50.0% (95% confidence interval, 33.7–62.6%). Stable disease was observed in 21 patients and the DCR was 92%. Median PFS was 6.8 months and median OS was 19.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (40 [80%]), thrombocytopenia (12 [24%]), anemia (8 [16%]), nausea (4 [8%]), anorexia (3 [6%]), ALT elevation (3 [6%]), AST elevation (2 [4%]), vomiting, periodontal, hemoptysis, thrombosis and proteinuria (1 [2%]) respectively. In CJLSG0910, 30 patients received induction treatment. They had a median age of 65.5 years and were predominantly women (17 [57%]) with adenocarcinoma (29 [97%]), stage IV (27 [90%]), and a PS of 0 (23 [77%]). The median of induction therapy was 6 cycles. Twenty-five (83%) patients received maintenance therapy, and the median of maintenance therapy was 8.5 cycles. Partial response was observed in 15 patients with a ORR of 50.0% (95% confidence interval, 33.9–66.1%). Stable disease was observed in 15 patients and the DCR was 100%. Median PFS was 10.0 months and median OS was 41.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (14 [47%]), thrombocytopenia (6 [20%]), anemia (6 [20%]), diarrhea (2 [7%]), nausea, anorexia, amylase elevation (1 [3%]) respectively.

Conclusion:
These studies suggested that chemotherapy with Pem+Cb+Bev, including Pem+Bev maintenance therapy is candidate for first line therapy in non-sq NSCLC patients regardless of the activating EGFR mutations.

Background:
HER2 has long been recognized as an oncogenic driver in some breast and gastro-esophageal cancers. More recently, somatic mutations in HER2 have been reported in 1-2% of patients with lung adenocarcinoma, and the promise of HER2 as a treatment target in lung cancer has been suggested using anti-HER2 small molecules and antibodies.

Methods:
Here we report the outcomes of three patients with metastatic lung adenocarcinoma with HER2 mutations being treated with HER2 targeted therapies at a single institution.

Results:
The first patient is a 65yo Caucasian woman, minimal smoking history, with stage IIIA lung adenocarcinoma who then developed recurrent metastatic disease mainly in the liver after completing definitive chemoradiotherapy. She progressed through three lines of chemotherapies, with near replacement of liver with tumor. At that time she was found to have HER2 exon 20 insertion mutation (A775_G776 insSVMA) and was started on vinorelbine and trastuzumab. The main side effect was fatigue, which was tolerable. She achieved radiographic stable disease with 13% reduction of her liver metastasis as her best response by RECIST v1.1 for 6 months and significant clinical improvement before progression of disease in all sites. The second patient is a 60yo Caucasian woman, former smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with extensive bony disease. She was treated with carboplatin, paclitaxel, bevacizumab, and an investigational anti-Met therapy with initial mild decrease in lung mass and nodules after one month, then mild progression for 14 months. She was taken off trial then and started on vinorelbine and trastuzumab, and so far shows no measurable growth after 5 months on therapy. The third patient is a 35yo Asian woman, non-smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with malignant pleural effusions, bilateral lung and brain lesions, and extensive lymph node involvement. She was treated with carboplatin, pemetrexed, and bevacizumab first followed by pemetrexed and bevacizumab maintenance, with initial mild improvement then progression after 4.5 months. She was then treated with erlotinib with rapid progression within 1 month. She was then treated with afatinib 40mg daily based on the HER2 mutation, improved disease after 2 months with best response 21% reduction, then progression after 3 more months (5 months total of clinical benefit). She was then started on vinorelbine and trastuzumab. Treatment was interrupted due to one new brain lesion requiring stereotactic radiation treatment. She has shown partial response with best response of 31% on the latest imaging done 4 months after starting therapy.

Conclusion:
From our single institution experience, HER2 targeted therapy can provide disease control for patients with metastatic HER-2 mutated NSCLC that has progressed on previous therapies. Our results are consistent with the study by Mazières et al. Vinorelbine was dosed as 25 mg/m2 and trastuzumab as 2 mg/kg every 1 week (with 4mg/kg first loading dose) or 6 mg/kg every 3 weeks. All three patients were able to tolerate therapies well with no significant toxicities nor cardiac toxicity.

Background:
Angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) are among the most common medications in the treatment of hypertension and diabetes. These drugs are under evaluation as a means to mitigate radiation pneumonitis/fibrosis likely mediated by anti-inflammatory and endothelial effects. Their collateral impact on oncological outcomes is unknown. We retrospectively evaluate the effect of ACEi and ARB usage on pathological response during preoperative platinum-based concurrent chemoradiotherapy (CCRT) with high-dose radiotherapy (≥59.4 Gy) in a cohort of patients with stage III non-small cell lung cancer (NSCLC).

Methods:
Between June 2000 and December 2009, 79 patients with stage III NSCLC (AJCC 7[th] ed.) were treated with preoperative CCRT at our institution. Data on ACEi/ARB usage during CCRT and pathological response was available for 72 patients. The primary end-point was pathological complete response (pCR), in both the primary site and involved lymph nodes. X[2] analysis was to assess distribution of categorical variables, Kaplan-Meier survival analysis with log rank test for univariate and Cox regression multivariate (age, gender, race, stage, RT dose and chemotherapy regimen) analysis of overall survival (OS) and freedom-from recurrence (FFR) was performed.

Results:
The median age at diagnosis was 56 years (range, 38-78) with 56% males, 74% Caucasians and 96% smokers. Stage distribution was IIIA (72%), IIIB (28%), T1/2 (54%), T3/4 (46%), N0/1 (14%) and N2/3 (86%). The median radiation dose was 66.6 Gy (range 59.4-69.6 Gy) with the most common CCRT regimen being carboplatin-paclitaxel (54%). At a median follow up of 3.8 years for all patients and 6.8 years for surviving patients, the median OS and FFR of the entire cohort were 4.9 years (95% Confidence Interval (CI): 3.5-6.5) and 3.1 years (95% CI: 1.3-4.9), respectively with overall pCR rate of 44%. During CCRT, 11 patients (15%) were taking ACEi/ARB and 61 patients (85%) were not taking ACEi/ARB. No statistical differences were seen in the distribution of baseline variables between the two cohorts. None of the patients developed acute radiation pneumonitis in the time interval between radiotherapy completion and surgery (median 55 days; range, 33-105 days). The pCR rate without and with ACEi/ARB was 46% vs 36% (p=0.56). The median FFR without and with concurrent ACEi/ARB use was 3.1 years vs. not reached, p = 0.35, while the corresponding median OS values were 4.8 years and 5.5 years, p = 0.59, respectively. On multivariate analysis, an improved OS was associated with younger age (HR: 0.39, 95%CI: 0.2-0.8, p<0.01), an improved FFR was associated with lower stage (HR: 0.3, 95%CI: 0.15-0.76, p<0.01) and Caucasian race (HR=0.37, 95% CI: 0.15-0.88, p=0.02), with no impact of ACEi/ARB use on either outcome.

Conclusion:
The use of ACEi/ARB did not have any apparent influence the rates of pCR in this small cohort of advanced stage NSCLC patients treated with trimodality therapy following preoperative platinum-based CCRT with high-dose radiotherapy. As the role of these drugs in mitigating radiation pneumonitis continues to be evaluated, simultaneous assessment of lack of a negative impact on disease outcomes needs to be validated in larger, prospective analyses.

Background:
Circulating Tumor Cells (CTCs) have been shown to be a useful prognostic tool in several cancers. Non-small-cell-lung cancer (NSCLC) lacks validated prognostic biomarkers and, thus, this study aimed to explore the sensitivity and clinical significance of the detection of CK19mRNA (+) CTCs in NSCLC patients.

Methods:
Peripheral blood was obtained from 642 patients with previously untreated stage IIIB/IV NSCLC and from 455 patients after the completion of 1[st] line chemotherapy. RNA extracted from the Calu-3 and ARH-77 cell lines was used as positive and negative controls, respectively. The detection of CK19mRNA-positive cells was performed using an RT-qPCR assay.

Results:
The analytical detection limit of the method was found to correspond to 0.42 Calu-3 cell equivalents/5μg RNA. One hundred and sixty seven (26.0%) patients had detectable CK19mRNA (+) CTCs at baseline; the detection of CK19mRNA (+) CTCs post chemotherapy was associated with significantly decreased PFS and OS (PFS: 2.6 vs 3.8 months, p=0.008; OS: 5.7 vs 10.0 months, p=0.006). Multivariate analysis revealed that gender, performance status and the detection of CK19mRNA (+) CTCs post chemotherapy emerged as independent factors associated with reduced PFS (HR=1.350, p=0.010) and OS (HR=1.608; p=0.001).

Conclusion:
Detection of peripheral blood CK19mRNA (+) CTCs post chemotherapy is an adverse prognostic factor correlated with poor clinical outcome in patients with stage IIIB/IV NSCLC.

Background:
The median overall survival time for patients with stage IV non-small cell lung cancer (NSCLC) is 4 months, and 1- and 5-year survival is less than 16% and 2%, respectively. NSCLC is usually treated with surgery followed by radiation and treatment with platinum-based regimens or in some cases Tyrosine Kinase Inhibitors (TKIs). Unfortunately, long-term prognosis with platinum-based therapies is poor, and TKI resistance has emerged as a significant unmet medical need. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks at N[7] of guanine. It has previously demonstrated activity against NSCLC in NCI-sponsored preclinical and clinical trials and is approved for treatment of lung cancer in China (Approval No. Guoyao Zhunzi H45021133); however, it is currently not widely known or used for the treatment of NSCLC.

Methods:
not applicable

Results:
Recent preclinical data suggest that VAL-083 may be a therapeutic option for drug-resistant NSCLC. VAL-083 has superior activity to cisplatin in both in vitro and in vivo models of NSCLC, including TKI-resistant NSCLC. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrates significant superadditivity (p<0.05) and synergism (CI < 1) for both combinations in NSCLC cell lines A549, H1975 and H460. When tested in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 (10 mg/kg) was superior to cisplatin (4 mg/kg) in tumor growth delay. Mice were treated with a single IP injection of either cisplatin, VAL-083 or VAL-083 followed immediately by cisplatin. Combination treatment of with cisplatin produced a more than additive effect by delaying growth 8.65 days. In another in vivo model using NSCLC cell-line A549 in Rag2mice, VAL-083 was given as part of a combination treatment with cisplatin. Tumour growth delays of 11, 18 and 25 days were observed for 2 mg/kg cisplatin in combination with 2, 2.5 or 3 mg/kg VAL-083, respectively, while no significant tumour growth delay was observed between untreated and Cisplatin (2 mg/kg). The median survival time was increased by 2 days for cisplatin alone, while the combination of VAL-083 (2 mg/kg, 2.5 mg/kg and 3 mg/kg) with cisplatin (2 mg/kg) increased survival by 17 days, 17 days, and 14 days, respectively.

Conclusion:
The preclinical data strongly suggest VAL-083 as a potential treatment for drug-resistant NSCLC. A planned open-label phase IV (post market) clinical trial will investigate the activity of VAL-083 in relapsed or refractory NSCLC assessed by objective response rates, complete and partial response rates and stable disease. VAL-083 will be dosed in accordance with the approved label (40 mg/day) and the results will provide guidance to treating physicians under the context of VAL-083’s current approval in China, as well as serve as proof of concept for expanded development in the rest of the world.

Background:
Abemaciclib, a cell cycle inhibitor selective for CDK4/6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. Combinations of abemaciclib showed greater activity compared with monotherapy in KRAS-mutant NSCLC preclinical models. Primary aim of study NCT02079636 was safety/tolerability of combination therapy with abemaciclib; secondary aims included pharmacokinetics and antitumor activity.

Methods:
In this open-label 3+3 dose-escalation study with expansion cohorts, eligibility included stage IV NSCLC, measurable or nonmeasurable disease (RECISTv1.1), ECOG PS ≤1, and 1-3 prior therapies. Abemaciclib was combined with pemetrexed (Part A, nonsquamous, 500 mg/m[2] IV day 1), gemcitabine (Part B, 1250 mg/m[2] IV days 1 and 8), ramucirumab (Part C, 10 mg/kg IV day 1, or 8 or 10 mg/kg IV days 1 and 8) (Q21), or LY3023414 (dual PI3K-mTOR inhibitor) (Part D, 100 mg, 150 mg or 200 mg orally Q12H). In escalation, patients were dosed continuously until progression with abemaciclib at 100 mg (Part D), 150 mg or 200 mg orally Q12H.

Results:
As of February 27, 2015, 70 patients (Parts A-C) received ≥1 dose; 15 patients at 150 mg and 55 patients (including all 39 patients in expansion) at 200 mg Q12H abemaciclib. The MTD was established at 200 mg Q12H abemaciclib for Parts A-C. See Table 1 for treatment-emergent adverse events (TEAEs). Stable disease was observed in 13/23 patients in Part A; 7 unknown, 4/24 patients in Part B; 10 unknown, and 7/23 patients in Part C; 12 unknown. In Parts A-C, 18/70 (26%) patients started ≥4 cycles (Part A=9, Part B=3, Part C=6). Three confirmed PRs were observed: Part B, 1 patient with squamous histology (unknown mutation status), Part C, 1 patient with nonsquamous histology (KRAS mutation positive; EGFR mutation negative), and 1 patient with squamous histology (unknown mutation status). Updated analyses will be presented including Part D and longer term follow-up for Parts A-C through approximately June 2015. Table 1. TEAEs related to treatment (≥20% in ≥1 part)

% All grades (% Gr3/4)	Part A (n=23)	Part B (n=24)	Part C (n=23)
Diarrhea	65 (4)	50 (17)	52 (9)
Fatigue	57 (9)	63 (8)	17 (4)
Nausea	35 (0)	50 (4)	48 (9)
Neutropenia	61 (61)	50 (33)	17 (4)
Anemia	57 (26)	33 (17)	9 (0)
Thrombocytopenia	39 (9)	38 (8)	17 (13)
Decreased appetite	30 (0)	25 (0)	22 (0)
Vomiting	9 (0)	21 (0)	35 (0)
Blood creatinine increased	30 (0)	8 (0)	17 (4)
Leukopenia	30 (22)	17 (8)	9 (4)

Conclusion:
Abemaciclib combined with single-agents with acceptable toxicity. Safety findings observed in Parts A and B are consistent with AEs expected when combining myelosuppressive compounds with abemaciclib, resulting in an increased myelosuppressive effect. In Part C, safety findings are consistent with those of single-agents. Tumor responses were observed in Parts B and C.

Background:
Although the anaplastic lymphoma kinase inhibitor (ALKi), crizotinib achieves high responses in patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC), disease progression within 1 year can occur, with the brain/central nervous system (CNS) as a common site of progression and relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than crizotinib in enzymatic assays and crosses the blood-brain barrier with good CNS penetration in preclinical studies. In the pivotal phase 1 study (NCT01283516), ceritinib was highly active in ALK+ NSCLC patients (regardless of prior crizotinib exposure) and achieved intracranial responses in 7 of 14 patients with measurable baseline brain lesions. The adverse events profile in these patients was similar to that of the full study population.

Methods:
This international, prospective, phase 2, open-label study is designed to evaluate the antitumor activity of ceritinib in patients with ALK+ NSCLC metastatic to the brain or leptomeninges (ASCEND-7; CLDK378A2205). Eligible patients must have ALK+ (centrally assessed) NSCLC metastatic to the brain and ≥ 1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients must be neurologically stable ≥ 1 week prior to study drug administration and will be allocated to 1 of 5 arms depending on prior treatment:

Arms 1-4 (patients with active* brain metastases, without leptomeningeal carcinomatosis [LC])	Prior ALKi treatment	No prior ALKi treatment
Prior whole brain radiotherapy (WBRT)	Arm 1	Arm 3
No prior WBRT	Arm 2	Arm 4
Arm 5: patients with LC with or without evidence of active lesion at baseline

*Lesion free of local treatment (stereotactic or WBRT) or lesions in unequivocal progression after radiotherapy. Oral ceritinib 750 mg/d will be dosed on a continuous schedule and study assessments are consistent across arms. The primary and key secondary objectives are to evaluate overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial responses for all patients and for each of arms 1–4; overall survival and safety for all patients and for each of arms 1–5; and ceritinib pharmacokinetics in all patients. Enrollment is ongoing.

Results:
This study is in the activation phase.

Conclusion:
This study will demonstrate the efficacy of ceritinib in ALK+ NSCLC brain metastases and leptomeningeal metastases, in both WBRT-naive patients and prior irradiated patients.

Background:
Plinabulin (P) is a microtubule-depolymerizing agent that inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. It also could activate anti-tumor immunity via inducing maturation of dendritic cells. Pinabulin at 30 mg/m2 given on days 1 and 8 was studied in a randomized phase 2 study in combination with docetaxel 75 mg/m2. Despite the fact that ITT overall survival (OS) was not statistically different between both arms, duration of response was notably longer in DP compared to D, 12.7 months vs 1.5 month in the 30 cohort ( p=0.049). Nivolumab (Nivo) is the first PD-1 inhibitor approved by the FDA in metastatic squamous NSCLC, based on results of a phase III trial showing that patients receiving Nivo lived, on average, 3.2 months longer than patients receiving standard ChRx. Microtubule-depolymerizing agents are known to induce dendritic cell maturation and synergize with immune checkpoint inhibitors in immune competent cancer models. Therefore we hypothesize that combining plinabulin with nivolumab will enhance the immune response which will in turn lead to a higher response rate (RR) and longer OS in patients with metastatic squamous NSCLC.

Methods:
This is a phase I open-label, dose escalation study of plinabulin in combination with nivolumab (PNivo) in patients with metastatic squamous NSCLC that have progressed through one line of platinum-containing ChRx. The primary objectives are safety and tolerability of combination therapy to define the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and/or RP2D for PNivo. The secondary objective is the efficacy of PNivo in terms of RR, progression free survival and OS in the expanded cohort. Plinabulin will be escalated from the biologically active dose of 13.5 mg/m2 using a “3+3” design. At the MTD or highest dose level in this study, the cohort will be expanded as applicable to ensure a total of 9 subjects are treated at the RP2D. Correlative studies to investigate pharmacodynamical effects will be performed. Main inclusion criteria are histologically documented metastatic squamous NSCLC with measurable disease, EGFR/ALK and ROS-1 negativity, ECOG status 0 to 2, preserved organ and marrow function. Main exclusion criteria are untreated brain metastases, concurrent radiation and systemic therapy within 21 days of the first dose of study drug.

Results:
not applicable

Conclusion:
not applicable

Background:
Treatment of elderly patients with non-small cell lung cancer (NSCLC) is challenging due to comorbidities and reduced tolerability; as a result, these patients often receive suboptimal treatment. In addition, 5-year survival rates are lower in elderly than in younger patients with NSCLC. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly increased median overall survival (OS) vs solvent-based paclitaxel plus C in a subset of patients ≥ 70 years of age with advanced NSCLC (19.9 vs 10.4 months; HR 0.583; P = 0.009; Socinski et al. Ann Oncol. 2013;24:314-321). However, 55% of elderly patients treated with nab-P/C required dose reductions and 84% had dose delays, primarily due to adverse events, including myelosuppression. In the open-label, multicenter phase IV ABOUND.70+ trial, the safety and efficacy of 2 different schedules of first-line nab-P/C treatment will be evaluated prospectively in elderly patients with advanced NSCLC.

Methods:
Approximately 284 patients with NSCLC ≥ 70 years of age who are not candidates for curative surgery or radiation therapy will be randomized 1:1 to nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus C AUC 6 on day 1 every 21 days or the same nab-P/C dose every 21 days followed by a 1-week break. Key eligibility criteria include histologically/cytologically confirmed locally advanced or metastatic NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and absence of preexisting peripheral neuropathy (PN) grade > 2. Patients will be stratified by ECOG performance status (0 vs 1) and histology (squamous vs nonsquamous). ClinicalTrials.gov identifier NCT02151149.

Key Endpoints
Primary	Percentage of patients developing either PN grade ≥ 2 or myelosuppression grade ≥ 3
Secondary	Safety Progression-free survival OS Overall response rate
Exploratory[a]	Healthcare resource utilization throughout the study Changes in quality of life

[a] Additional exploratory endpoints may be defined in the statistical analysis plan if applicable.

Results:
TPS Abstract Section NA

Conclusion:
TPS Abstract Section NA

Background:
Patients with advanced non-small cell lung cancer (NSCLC) progressing after 1[st] line platinum containing doublet chemotherapy +/- targeted therapy for EGFR mutations and EML4-ALK fusion genes have limited therapeutic options. Extracellular components such as hyaluronan (HA) make up the tumor microenvironment (TME) and may limit access of chemotherapeutic agents to the cell as a result of increased interstitial pressure and decreased blood flow. PEGPH20 (PEG) decreases HA and restores blood flow. In animal models of NSCLC, PEG + docetaxel (Doc) significantly prolonged survival compared to Doc alone. These results are consistent with results in previous studies in pancreatic adenocarcinoma (PDA). In a Phase 1b trial of the combination of PEG + gemcitabine in Stage IV pts with PDA whose tumors were HA-high pts had higher ORR, PFS and OS compared to pts with HA-low tumors.

Methods:
This is an ongoing Phase 1b/2 open-label, randomized study of the addition of PEG to docetaxel (PDoc) compared to docetaxel (Doc) in pts with Stage IIIB/IV NSCLC having been treated with at least 1[st] line platinum containing chemotherapy. The Phase 1b portion of the study will determine the maximum tolerated dose (MTD), dose limiting toxicity and recommended Phase 2 dose for two schedules of PEG; one given every 21 days with Doc and the second dosed 2X per week with Doc. Up to 40 subjects are expected to be enrolled in the Phase 1b dose escalation. Once MTDs are determined the second portion of the Phase 1b will accrue approximately 10 patients whose tumors are HA-high to determine which schedule will go forward in Phase 2. The Phase 2 will randomize 188 patients in a 1:1 fashion to receive PDoc or Doc stratified by histology and prior targeted therapy. The primary endpoint of the Phase 2 portion is PFS. This is the first clinical trial evaluating PEGPH20 in NSCLC. The trial is currently accruing to the dose finding portion of the Phase 1b. ClinicalTrials.gov Identifier: NCT02346370

Results:
not applicable

Conclusion:
not applicable

Background:
Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.

Methods:
The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.

Results:
not applicable

Conclusion:
not applicable

Background:
Ramucirumab, a human IgG1 monoclonal antibody, binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2, preventing binding of VEGF-A, C and D. Ramucirumab in combination with docetaxel has demonstrated improvement in overall survival, progression free survival (PFS), objective response rate and disease control rate in 2nd line treatment of NSCLC patients in the phase III REVEL study, which included non-squamous and squamous cell carcinoma patients. Although erlotinib is recognized as one of the standard of care options in the frontline treatment of patients whose tumors harbor an Epidermal Growth Factor Receptor (EGFR) mutation, it is hypothesized that the duration of disease control would be greater when an antiangiogenic agent such as ramucirumab is added to erlotinib. This global phase Ib/III trial will assess safety, tolerability and efficacy (phase III) of the combination of ramucirumab with erlotinib in previously untreated stage IV NSCLC patients harboring activating EGFR mutations. The trial is planned to be conducted in ~120 sites in the Americas, Europe, and Asia and is currently open for enrollment. (RELAY, NCT02411448)

Methods:
In part A (phase Ib) approximately 12 patients (6 Japan + 6 US/EU) will receive ramucirumab (10mg/kg on day 1) every two weeks + erlotinib (150 mg/day). DLT assessment will be performed after patients complete four weeks of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every two weeks with erlotinib until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS. There are 3 planned interim analyses that will evaluate safety, futility and efficacy, respectively. Other secondary endpoints include overall survival, objective response rate, disease control rate, duration of response, safety and quality of life.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Despite advances in targeted therapy, treatment options for metastatic NSCLC progressing after initial therapy remains limited. HSP90 is an ATP-dependent molecular chaperone that plays a vital role in protein stabilization. Some HSP90 client proteins are key regulators in cell proliferation and survival. Many mutant oncoproteins are more dependent on HSP90 for proper folding and stability compared to their wildtype counterparts. AUY922 potently inhibits HSP90, showing preclinical activity in a wide range of cancer cell lines, including NSCLC (1). Phase I clinical trials established 70 mg/m[2] as the dose for further development (2). A single agent phase II trial demonstrated clinical activity of AUY922 in NSCLC, particularly molecular subsets with driver mutations in the known HSP90 client proteins, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (3). Pemetrexed is a folate antimetabolite chemotherapeutic approved for use in advanced non-squamous, NSCLC. In pre-clinical models, mRNA for dihydrofolate reductase (DHFR), a target of pemetrexed, reliably decreased in response to AUY922 exposure (1). These findings suggest that the combination of AUY922 and premetrexed in NSCLC is worthy of investigation.

Methods:
Adult patients with previously treated stage IV non-squamous, NSCLC, measureable disease per RECIST 1.1, ECOG performance status < 2, and life expectancy > 3 months are eligible for this open label phase Ib clinical trial (NCT01784640). A standard 3 x 3 design will evaluate 3 cohorts, all with pemetrexed at the standard 500 mg/m[2] dose, plus: AUY922 40 mg/m[2], 55 mg/m[2], and 70 mg/m[2] qwk. Enrollment of the 70 mg/m[2] qwk cohort has been open since November 2014 and is currently ongoing. After the optimal dose for further evaluation is determined, an additional 20 patients will be enrolled at that dose. This expansion phase will focus on patients with EGFR mutations and ALK gene rearrangements. The primary endpoint is safety and tolerability of AUY922 combined with pemetrexed in patients with previously treated non-squamous NSCLC. [Funding by Novartis, K23CA149079, Wolfen Family, One Ball Matt Memorial Golf Tournament]. References 1) Garon EB et. al. Mol Cancer Ther. 2013 2) Sessa C et. al. Clin Cancer Res. 2013 3) Garon EB et. al. ASCO 2012

Results:
Not applicable

Conclusion:
Not applicable

Background:
Tumor Treating Fields (TTFields) are a novel, non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and effective in glioblastoma patients. Local treatment options for patient with brain metastases (BM) are limited to neuro-surgery (NS), stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) or a combination thereof. In patients treated with NS or SRS, intracranial recurrence remains high, since the rest of the brain is not treated. The addition of WBRT, can improve intracranial control either alone or when added to SRS but at the risk of severe neurocognitive and other complications. Thus, new therapeutic options are needed, particularly ones that allow for greater intracranial control while minimizing the risk of neurocognitive and other adverse events.

Methods:
The METIS Clinical Trial 240 patients with 1-10 BM from NSCLC will be randomized in a ratio of 1:1 to receive SRS followed by either TTFields or supportive care alone. Patients are followed-up bimonthly until 2[nd] intracerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 1[st] intracerebral progression. Objectives To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints Time to intracerebral progression (primary); time to first/second intracerebral progression for patients with 1-4 and 5-10 BM; 2, 4, 6, 8, 10, 12-month first/second intracerebral progression rate; intracerebral progression free survival; overall survival; time to neurocognitive failure; rate of decline in cognitive function; neurocognitive failure-free survival; radiological response; safety (secondary). Treatment Continuous TTFields at 150 kHz will be applied to the brain using the NovoTTF-100M System within 7 days of SRS. The System is a portable medical device allowing normal daily life activities. The device delivers alternating electric fields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations This is a prospective, randomized, multicenter study for 240 patients. The trial is designed to detect an increase in the time to intracerebral progression from 7.7 to 13.4 months (hazard ratio 0.57). This sample size assessment takes into consideration a competing risk (death prior to intracerebral progression) of 0.08252 per month in both treatment arms. The competing risk is based on a predicted median overall survival of 8.4 months mainly due to systemic disease progression. The trial has 80% power at a two sided alpha of 0.05. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) with the competing risk taken as loss to follow up (patients will be censored at time of death if it occurs prior to intracerebral progression).

Results:
not applicable

Conclusion:
not applicable

Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.

Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.

Results:
not applicable

Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.

Background:
Many patients with advanced non-small cell lung cancer (NSCLC) often present with poor performance status (PS), and there is no clear consensus on how best to treat these patients. Despite an increased risk of toxicity resulting from standard chemotherapy, patients with NSCLC and a poor PS can clinically benefit from platinum-doublet therapy. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) in patients with NSCLC and an ECOG PS 0-1 significantly improved the overall response rate (ORR) compared with solvent-based paclitaxel plus C (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). In the single-arm, open-label, multicenter phase II ABOUND.PS2 study, the safety and efficacy of first-line nab-P/C followed by nab-P monotherapy will be evaluated in patients with locally advanced/metastatic NSCLC and an ECOG PS of 2.

Methods:
During the induction part of the study, approximately 50 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1 and 8 plus C AUC 5 IV on day 1 every 21 days. Patients without disease progression may proceed to the monotherapy part of the study in which they will continue to receive nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days until progression or unacceptable toxicity. Key eligibility criteria include histologically/cytologically confirmed stage IIIB/IV NSCLC, no prior chemotherapy for metastatic disease, ECOG PS of 2, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov number NCT02289456.

Key Endpoints
Primary	The percentage of patients who discontinue treatment during the induction part due to treatment-emergent adverse events
Secondary	Safety Progression-free survival Disease control rate Overall survival ORR
Exploratory	Healthcare resource utilization throughout the study Changes in physician-reported ECOG PS and patient-reported quality of life Summary of Charlson Co-Morbidity Index at baseline Correlation between patient- and physician-reported ECOG PS during treatment Correlation between patient- and physician-reported Karnofsky PS at baseline

Results:
This is a TPS abstract Results = NA

Conclusion:
This is a TPS abstract Results = NA

Background:
Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.

Methods:
An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.

Results:
not applicable

Conclusion:
not applicable

Background:
Platinum-based chemotherapy with or without maintenance therapy is the standard of care for treatment-naive non-small cell lung carcinoma (NSCLC) that lacks EGFR sensitizing mutations and ALK translocations. The PD-1 pathway is frequently used by tumors to evade an immune response. Pembrolizumab (MK-3475), an anti–PD-1 monoclonal antibody, has demonstrated manageable toxicity and promising antitumor activity in patients with treatment-naive NSCLC enrolled in the phase 1b KEYNOTE-001 study. In this study, a relationship between increased tumor PD-L1 expression and improved pembrolizumab antitumor activity was observed. KEYNOTE-042 (ClinicalTrials.gov identifier NCT02220894) is a randomized, open-label, international, phase 3 study designed to compare the efficacy and safety of pembrolizumab with those of platinum-doublet chemotherapy as first-line therapy for PD-L1–positive advanced NSCLC.

Methods:
Eligibility criteria include age ≥18 years, advanced NSCLC without EGFR sensitizing mutations or ALK translocation, no prior systemic chemotherapy, PD-L1 expression in ≥1% of tumor cells, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Patients are randomly assigned in a 1:1 ratio to a 200-mg fixed dose of pembrolizumab every 3 weeks (Q3W) or investigator’s choice of carboplatin AUC 5 or 6 plus paclitaxel 200 mg/m[2] Q3W or carboplatin AUC 5 or 6 plus pemetrexed 500 mg/m[2] Q3W. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), region (East Asia vs non-East Asia), and PD-L1 expression (strong [staining in ≥50% of tumor cells] vs weak [staining in 1%-49% of tumor cells], as assessed by immunohistochemistry at a central laboratory). Pembrolizumab will be continued for 35 cycles or until disease progression, intolerable toxicity, or investigator decision; treatment may be continued beyond initial radiographic disease progression in eligible patients. Discontinuation of pembrolizumab is permitted for patients who experience a complete response confirmed on a follow-up scan performed ≥4 weeks after initial observation. Chemotherapy will be given for a maximum of 6 cycles and may be followed by optional pemetrexed 500 mg/m[2] Q3W maintenance therapy in patients with nonsquamous histology. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter and graded per NCI CTCAE v4.0. Response will be assessed every 9 weeks per RECIST v1.1 by independent central review. Patients will be followed for survival every 2 months. Primary end point is overall survival in the PD-L1–strong-positive stratum; secondary end points are progression-free survival in the strong-positive stratum and progression-free and overall survival in all patients. Enrollment is ongoing and will continue until approximately 1240 patients have been allocated to study treatment.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Treatments that improve overall survival (OS) in advanced NSCLC are urgently needed. Docetaxel (DOC) is recommended as 2[nd]-line chemotherapy for advanced NSCLC, with a median OS of 7-8 months. The chaperone protein clusterin (CLU) is upregulated in NSCLC and other cancers in response to anticancer therapies. Custirsen (OGX-011) is a second-generation antisense oligonucleotide that inhibits CLU expression, enhances chemotherapeutic activity, and in vivo has reversed DOC resistance. In early phase studies in metastatic castration resistant prostate cancer (mCRPC), custirsen plus DOC was well tolerated and showed encouraging results. In a phase 3 mCRPC study (SYNERGY), 50% of patients defined as poor prognosis had survival benefit from custirsen when added to 1[st]-line DOC.

Methods:
ENSPIRIT was initiated September 2012. Eligible patients in this phase 3, multinational, open-label trial have failed 1 prior line of platinum (PT)-based therapy, have an ECOG of 0-1, and adequate bone marrow, renal, and liver function. Randomization is 1:1, with stratification by gender, NSCLC histology, best response to 1[st]-line PT therapy (response/stable disease vs progression), and ECOG score. Patients receive 21-day cycles of DOC (75 mg/m[2] IV day 1) or DOC plus custirsen (640 mg IV/wk, preceded by 3 doses during a 9-day loading period) until progressive disease, unacceptable toxicity, or withdrawal. The primary efficacy measure is OS. Two interim analyses are planned for stopping the trial based on inadequate evidence of clinical benefit or futility; the first futility analysis was completed in August 2014. A recent amendment changed the hypothesized hazard ratio for the primary analysis from 0.80 to 0.75 (power remains at 90%), resulting in a required sample size of 700 patients (instead of original 1100). In addition, the second futility has a more rigorous criterion for stopping due to survival futility and is to occur earlier than originally planned. The study will not be stopped early for efficacy. The aim of the ENSPIRIT amendment is to assess for a more clinically relevant survival benefit when adding custirsen to 2[nd]-line DOC or terminate the trial early for survival futility.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Patients with squamous cell (SCC) non-small cell lung cancer (NSCLC) may be at risk of poorer outcomes and have fewer treatment options than those with other histologies. Furthermore, no randomized studies have demonstrated the benefit of maintenance therapy in these patients. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) demonstrated a 68% improvement in the overall response rate (ORR; 41% vs 24%; P < 0.001) and a trend toward improved overall survival (OS; median, 10.7 vs 9.5 months; HR 0.890; P = 0.310) compared with solvent-based paclitaxel plus C in a subset of patients with advanced SCC NSCLC (Socinski et al. Ann Oncol. 2013;24:2390-2396). An exploratory analysis of the phase III trial demonstrated that therapy with nab-P/C beyond 4 cycles of first-line treatment was effective in the subset of patients with SCC NSCLC who did not progress (from the time of randomization, median progression-free survival [PFS] and OS were 6.8 and 13.8 months, respectively), and no new safety signals were noted (Socinski et al. IASLC 2013 [abstract 3438]). In the open-label, multicenter phase III ABOUND.sqm trial, the efficacy and safety of nab-P maintenance therapy after nab-P/C induction therapy will be evaluated in patients with advanced SCC NSCLC.

Methods:
During the induction part of the study, approximately 540 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus IV C AUC 6 on day 1 every 21 days. Patients with a complete response (CR), a partial response (PR), or stable disease (SD) will be eligible for maintenance. In the maintenance part of the study, approximately 260 patients will be randomized 2:1 to nab-P 100 mg/m[2] on days 1 and 8 every 21 days plus best supportive care (BSC) or BSC alone until disease progression. Patients will be stratified by disease stage (IIIB vs IV), response to induction therapy (CR/PR vs SD), and ECOG performance status at the end of induction (0 vs 1). Key eligibility criteria include histologically or cytologically confirmed stage IIIB/IV SCC NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov identifier NCT02027428.

Key Endpoints
Primary	PFS from randomization into the maintenance part of the study
Secondary	Safety OS from randomization into the maintenance part of the study ORR during the induction and maintenance parts of the study
Exploratory	Correlation between pretreatment tumor characteristics and response to treatment Association between changes in tumor characteristics and acquisition of resistance to therapy at the time of treatment failure during maintenance Correlation between genetic polymorphisms and treatment efficacy and/or toxicity Healthcare resource utilization during the maintenance part of the study Changes in quality of life

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Patients harboring epidermal growth factor receptor (EGFR)-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) invariably develop acquired resistance (AR). The mechanisms of AR are unknown in 30–40% of patients. In pre-clinical studies, insulin-like growth factor (IGF) signaling has been implicated in AR to EGFR TKIs in the absence of other known mechanisms including T790M mutation. It is hypothesized that an EGFR TKI combined with an IGF inhibitor can overcome this resistance. BI 836845 is a fully human, affinity-optimized, IGF ligand-neutralizing antibody. BI 836845 binds to IGF-1 and IGF-2 and neutralizes growth-promoting signaling. Preliminary results from two Phase I studies have shown a tolerable safety profile. This trial was designed to evaluate the safety and anti-tumor activity of BI 836845 combined with afatinib in patients with EGFR-mutated NSCLC progressing following prior treatment with reversible or irreversible EGFR TKIs.

Methods:
This is an open-label, dose-escalation trial in Korea, Taiwan and Singapore (NCT02191891; Study 1280.16) consisting of a dose confirmation part (Part A) followed by an expansion part (Part B). Eligible patients are aged ≥18 years with advanced and/or metastatic NSCLC progressing during continuous treatment with single-agent EGFR TKI ≤30 days immediately prior to study treatment, with documented presence of an activating EGFR mutation and lacking an EGFR T790M mutation (confirmed by central testing in Part B). Patients with prior afatinib treatment at a dose below the assigned dose level (Part A only) or <30 mg/day (Parts A and B), or disease progression on an insufficient dose of EGFR TKI immediately prior to study in the investigator’s opinion, or >2 (Part A) or >1 (Part B) prior EGFR TKI treatment regimens for relapsed or metastatic NSCLC are excluded. Part A follows a 3+3 design to determine the MTD and/or recommended Phase 2 dose (RP2D) of BI 836845 combined with afatinib (starting dose: BI 836845 1000 mg/week intravenous infusion over 60 minutes plus oral afatinib 30 mg/day administered in 4-week courses). Patients receive continuous treatment until disease progression, intolerable adverse events (AEs), consent withdrawal or non-compliance with the study protocol. Patients are entered sequentially into escalating/de-escalating dose tiers to determine the MTD based on the occurrence of dose-limiting toxicities (DLTs) during Course 1 (3–6 patients per cohort); 6 additional patients will be enrolled in an extension cohort at the R2PD. Part B consists of two separate expansion cohorts of patients previously treated with irreversible EGFR TKIs (e.g. afatinib, dacomitinib; Cohort 1) and those previously treated with reversible EGFR TKIs (gefitinib or erlotinib; Cohort 2). In each cohort, 18 patients will be treated with the RP2D determined in Part A. Primary endpoints are the MTD and DLTs during Course 1 (Part A) and the objective response assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Part B). Secondary endpoints include disease control, time to objective response, duration of objective response, and pharmacokinetic parameters. AEs are evaluated according to Common Terminology Criteria for AEs (CTCAE) v4.03. All analyses will be descriptive and exploratory.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Plinabulin (BPI-2358) is a marine derived tubulin binding agent, which inhibits existing tumor vasculature and directly induces cancer cell apoptosis via the Ras-JNK pathway. Additional effect of inducing dendritic cell maturation is also observed. Phase 1/2 randomized clinical trial of Docetaxel + Plinabulin (DP) compared to Docetaxel (D) alone failed to show improvement in OS in an ITT analysis. The median OS was 8.6 months in DP, and 7.5 months in D arm. (HR 0.97, P=0.90). However, post hoc subset analysis showed improvement in OS in patient with pulmonary tumors >3 cm regardless of number of prior therapy for metastatic disease. In this population, OS was 11.47 (7.13, 16.73) months vs. 7.10 (4.06, 10.60) in DP vs D arm (HR 0.76 and P=0.36). Mechanistically it is postulated that those patients are more dependent on angiogenesis. This phase 3 protocol is designed to test the hypothesis generated from the subset analysis.

Methods:
This is a randomized phase 3, open label clinical trial comparing DP at 75 mg/m2 of D on day1 and 30 mg/m2 of P on days 1 and 8 to D alone at 75 mg/m2 on day 1 in a 21-day cycle. Randomization stratified by ECOG performance status and region. Study population: patients with metastatic with non small cell lung cancer ( NSCLC), who has failed one line of chemotherapy and have at least one lung lesion larger than 3 cm. Primary endpoint of the study is to compare overall survival (OS) between two arms. Secondary endpoints are Progression free survival (PFS), overall response rate (ORR), duration of response (DOR), and adverse event profile. Planned number of subjects 550 (440 from China and 110 from the US). Primary outcome analysis is planned after 434 death events which will provide a 0.85 power to detect a statistically significant treatment effect using a two-sided log-rank test at a significance level of α = 0.05.

Results:
Not applicable, trial in progress.

Conclusion:
not applicable

Background:
Epigenetic changes due to promoter hypermethylation have been shown to cause loss of tumor suppressor gene (TSG) function in NSCLC. Significant toxicity and lack of tumor selectivity have been the main limitations of systemic demethylating agents. We previously showed that aerosolized 5-Azacytidine (Aza) was superior to systemic administration in prolonging the survival of mice with carcinogen-induced lung cancer. These results suggest that inhaled Aza could inhibit lung cancer initiation and progression in subjects with chronic airborne carcinogen exposure. Thus, we designed the first phase I study of aerosolized Aza to determine the minimum effective dose of inhaled Aza required to induce relevant TSG re-expression in the bronchial epithelium of patients with advanced NSCLC.

Methods:
This is a phase I study following a 6+6 dose escalation and de-escalation design. Patients with advanced NSCLC, who have received at least one prior standard chemotherapy or targeted therapy, with ECOG PS 0-1, and adequate baseline bone marrow reserve, pulmonary reserve, and organ function are eligible. This study has received IRB and FDA approval as of 01/2015. Patients will be treated with inhaled Aza daily (20-minute inhalation) x 5 days per week once every 2 weeks. Based on our toxicity studies in mice, the recommended starting dose is 15 mg/m[2] . Dose escalation will proceed if <33% subjects in a given cohort experience pre-defined dose limiting toxicity (DLT) defined as grade 2 or higher pulmonary toxicity, grade 4 anemia, neutropenia, thrombocytopenia or any grade 3 or higher non-hematologic toxicity. The primary objective of the study is to determine the minimum effective dose of inhaled Aza required to induce re-expression of 5 relevant candidate TSGs (p16, H-Cad, OPCML, SFRP-1, and RASSF1A) that are silenced in the bronchial tissue of 20-50% heavy smokers with lung cancer. This will be determined in the bronchial epithelium of patients with advanced NSCLC in pre and post treatment biopsies. Secondary objectives include determining changes in global methylation patterns in the bronchial epithelium, and changes in methylation patterns in the exhaled breath. Clinical trial information: NCT02009436. Supported by NIH CA154755

Results:
not applicable

Conclusion:
not applicable

Background:
Integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is widely used for lymph node staging in patients with non-small cell lung cancer (NSCLC). However, FDG-PET/CT has certain limitations. If N0 cases staged by FDG-PET/CT were reliable, anatomy resection and systematic lymph node dissection might be avoided. And prediction of occult nodal metastasis could allow selection of candidates for preoperative cervical mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration. This study defined risk factors for occult nodal metastasis in patients with NSCLC patients who were diagnosed as clinical stage I by preoperative integrated FDG-PET/CT.

Methods:
We retrospectively reviewed the records of 423 NSCLC patients who underwent surgical resection from April 2007 to March 2015 at the department of Thoracic Surgery, Sagamihara Kyodo Hospital. No preoperative mediastinoscopy was carried out in this group and all underwent curative intent surgical resection. The following patients were excluded from the present study: those who were diagnosed as clinical stage IIA/IIB/IIIA by preoperative integrated FDG-PET/CT (n = 101), patients who underwent limited resection (wide-wedge resection or segmentectomy; n = 62), patients who received neo-adjuvant chemotherapy or radiotherapy (n = 1), and patients with preoperative integrated FDG-PET/CT was not performed (n = 20). The remaining 239 patients who were diagnosed as clinical stage I NSCLC were identified. They underwent surgical resection with systematic lymph node dissection. The prevalence of occult nodal metastasis in patients as clinical stage I was analyzed according to clinicopathological factors such as gender, age, smoking status, history of lung disease, serum carcinoembryonic antigen (CEA) level, concurrent diabetes, histopathological type, grade, tumor side, tumor localization, primary tumor location (central, non-central), tumor size (cm), pleural invasion, standardized uptake value (SUV) max of primary tumor. Risk factors for occult nodal metastasis were defined by univariate and multivariate analysis.

Results:
Occult nodal metastasis was detected in 12.5% (30/239) of the patients. N1 involvement was identified in 5.0% (12/239) of the patients and N2 disease was identified in 7.5% (18/239). An optimal cut-off value of primary tumor SUVmax for occult nodal metastasis was identified as 3.0 by the receiver operator characteristic (ROC) curve, the sensitivity and specificity were 90.0% and 42.1% respectively. In univariate analysis, the following were significant predictors of occult nodal metastasis: adenocarcinoma (P = 0.023), tumor size >3cm (P = 0.002), pleural invasion (P = 0.034) and SUVmax of primary tumor >3.0 (P = 0.018). In multivariate analysis, the following were independent predictors of occult nodal metastasis: adenocarcinoma (P = 0.006), tumor size >3cm (P = 0.013), and SUVmax of primary tumor >3.0 (P = 0.033).

Conclusion:
The present study demonstrated that adenocarcinoma, tumor size >3 cm, and SUVmax of primary tumor > 3.0 are risk factors for occult nodal metastasis in patients with NSCLC who were diagnosed as clinical stage I by preoperative integrated FDG-PET/CT.This study may provide some aids to pre-therapy evaluation and decision-making.

Background:
It has been common that patients with previous cancer treatment history undergo curative resection of non-small cell lung cancer (NSCLC); however, the impact of multiple cancer history on outcome after surgery remains unclear.

Methods:
We conducted a retrospective study by using data from patients who underwent curative surgical resection for NSCLC between 1998 and 2011 at our institution. Data recorded for analyses were: age, gender, clinical and pathological stages of NSCLC, mode of surgical resection, comorbidities, pre-treatment serum CEA level, smoking history, and previous cancer history (organ, histologic type, number of cancer treated). The chi-square test and Wilcoxon test were used to analyze the factors between groups (ie, cases with previous cancer history versus those without cancer history). The Kaplan-Meier method was used to estimate survival rates. The log-rank test was applied to compare the survival rates between the groups. A p value less than 0.05 was considered as statistically significant.

Results:
In the study, 229 out of 923 cases (24.8%) had previous cancer treatment history. In the 229 cases, 194 had single cancer treatment history, 30 had double cancer treatment history, and 5 had triple cancer treatment history. Types of cancer treated were: colorectal cancer (n=51), lung cancer (n=30), hepatocellular carcinoma (n=25), breast cancer (n=16), esophageal cancer (n=15), renal cell cancer (n=12), cancers of head and neck (n=11), and others (n=56). There were significantly increased rate of having cancer treatment history in the later study period (2005-2011) compared to a rate in the earlier study period (1998-2004)(30% versus 15%, p<0.01). When comparing to patients without previous cancer history, those with previous cancer history were significantly older (69.1 versus 66.4 years, p<0.01), and had higher smoking history rate (75.1% versus 64.7%, p<0.01). On the other hand, the proportion of stage I NSCLC was significantly higher in cases with previous cancer history than those without previous cancer history (95.2% versus 74.4%, p<0.01). All cases with triple cancer treatment history had clinical and pathological stage I NSCLCs. The survival outcome after surgical resection was significantly better in cases without previous cancer treatment history than those with cancer treatment history (5-year survival rates; 79% versus 75%). In those with cancer treatment history, cases with 2 or more cancers treated had worse outcome than those with only one cancer treated before lung cancer resection (5-year survival rates; 69% versus 76%).

Conclusion:
Although the previous cancer treatment history and the number of cancers treated affected the outcome of patients who underwent curative lung cancer resection, the 5-year survival rate of 75% was achieved in the population. In those with previous cancer history, lung cancer tends to be found in early stage because of the periodical check-up for previous cancers. Therefore, surgical resection of newly detected NSCLC can be a viable option, if the previously treated cancer(s) are well controlled and the new lung cancer is deemed resectable.

Background:
There is little evidence reagrding the impact of blood loss volume during operation on long term survival. Using a large-scale multicenter database for NSCLC, we sought to investigate the prognostic value of blood loss volume.

Methods:
We collected a cohort of resected NSCLC patients from a multi-institutional registry in China (7 centers, 2001-2008) to examine the relationship between blood loss volume and overall survival (OS). According to clinical significance and expertise, blood loss volume was divided into two groups, <200 or ≥200. OS was calculated with the Kaplan-Meier method and univariate comparison between groups was performed using the log-rank test. Cox regression served as a multivariate technique.

Results:
A total of 5,762 cases were available. The mean blood loss volume was 218.4±197.2 mL, median value was 200 mL (0-5000mL). Patients who had less than 200mL blood loss during the operation had more favorable prognosis than those with blood loss of 200mL or more (median OS, 98.8 vs. 76.0 months; HR 0.756, 95% CI 0.691 to 0.829). After adjusting for sex, age, histology, T stage, N stage and operation type (complete VATS, assisted VATS and thoracotomy), blood loss volume remained an independent prognostic factor (HR 0.791, 95% CI 0.716 to 0.874). The volume of blood loss directly correlated with operation time (r=0.21, P<0.001), drainage days (r=0.17, P<0.001), days of ICU stay (r=0.11, P<0.001), drainage volume (r=0.05, P=0.04), and potentially the number of stations examined (r=0.03, P=0.06).

Conclusion:
We revealed that blood loss volume during surgery is a significant adverse prognostic factor for long-term survival. Patients with blood loss volume greater than 200mL require more attention on the recovery strategy. In addition, blood loss volume might be a comprehensive reflection of surgical trauma, and might serve as a marker for evaluating the adequacy of patient’s physical condition for receiving adjuvant chemotherapy.

Background:
After proposal of a new histologic classification of lung adenocarcinoma from the IASLC/ATS/ERS in 2011, the 2015 WHO classification of lung cancer new defines the new subtypes of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The former shows a lepidic growth pattern without invasion (BAC) and the latter a lepidic growth pattern with <= 5mm invasion. Atypical adenomatous hyperplasia (AAH) and AIS（previously, bronchioloalveolar carcinoma）are categorized as preinvasive lesions of adenocarcinoma. Recent studies have shown that patients with AIS and MIA had nearly 100% disease-free survival (DFS), if complete resection was achieved, though the details of the surgical procedures were not mentioned.

Methods:
We reviewed 93 patients with AAH, AIS or MIA, enrolled from among 629 lung adenocarcinoma patients who underwent resection at our hospital from 2007 to 2014. We retrospectively investigated clinical features, pathological findings and the presence of epidermal growth factor (EGFR) mutations, as well as the surgical procedures of wedge resection, segmentectomy and lobectomy. The results were compared with clinical outcomes.

Results:
The patients ranged in age from 40 to 82 years (median 66) and included 40 males and 53 females. Synchronous or metachronous multiple primary lung carcinomas were documented in 15 (16%) patients, who had undergone resections of one to four lesions. Seven of 15 patients had combined lesions of AAH, AIS and MIA, and 8 of 15 had invasive adenocarcinoma combined with AIS or MIA. The total numbers of resected lesions were 7 AAHs, 28 AISs, and 70 MIAs. The diameters of the AAH, AIS and MIA were 4 to 10 mm (median 7), 5 to 20 mm (median 8) and 4 to 23 mm (median 11), respectively. In gene analysis for each lesion, the EGFR mutations were detected in one of five AAH lesions (20%), in eight of 28 AIS lesions (28%) and in 34 of 67 MIA lesions (50%). It was confirmed that both tumor size and the frequency of EGFR mutations gradually increased in the direction from AAH to MIA. As for surgical procedures, we performed 1) wedge resection for 5 AAH lesions, 12 AIS lesions and 22 MIA lesions, 2) segmentectomy with N1 lymph node sampling for 1 AAH, 6 AIS and 15 MIA and 3) lobectomy with N2 lymph node dissection for 1 AAH, 10 AIS and 33 MIA. None of the cases had lymph node metastasis pathologically and all were p-Stage IA. The median follow-up duration from the date of surgery was 31 months (1.7-86 months). Two patients with MIA died 22 and 29 months after surgery due to other malignancies, but none of the patients experienced recurrence and the 5-year DFS rate was 100%. Of 70 MIA lesions, 37 (53%) were removed by wedge resection or segmentectomy.

Conclusion:
AAH/AIS/MIA lesions were related to multiple primary lung carcinomas. Gradual malignant progression from AAH to AIS to MIA was verified. Although accumulation of further cases and long-term follow-up are needed, a subset of these lesions might be treated by wedge resection or segmentectomy.

Background:
This study aimed to determine homeostasis and tumor factors for 5-year survival (5YS) of non-small cell lung cancer (LC) patients (LCP) (T1-4N0-2M0) after complete en block (R0) lobectomies/pneumonectomies (LP).

Methods:
We analyzed data of 665 consecutive LCP (age=57.5±8.3 years; tumor size=4.4±2.4 cm) radically operated and monitored in 1985-2015 (m=575, f=90; lobectomies=423, pneumonectomies=242, combined LP with resection of trachea, carina, atrium, aorta, VCS, vena azygos, pericardium, liver, diaphragm, ribs, esophagus=180; only surgery-S=524, adjuvant chemoimmunoradiotherapy-AT=141: CAV/gemzar + cisplatin + thymalin/taktivin + radiotherapy 45-50Gy; T1=237, T2=248, T3=125, T4=55; N0=419, N1=130, N2=116, M0=665; G1=163, G2=199, G3=303; squamous=377, adenocarcinoma=243, large cell=45; early LC=132, invasive LC=533. Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.

Results:
Overall life span (LS) was 2114.8±1685 days and cumulative 5YS reached 69.6%, 10 years – 61.2%, 20 years – 43.1%. 415 LCP lived more than 5 years without cancer (LS=3041.4±1472.5 days). 194 LCP died because of LC (LS=559.6±373.5 days). AT significantly improved 5YS (65.1% vs. 34.3%) (P=0.00001 by log-rank test) only for LCP with N1-2. Cox modeling displayed (Chi2=290.78, df=13, P=0.000) that 5YS of LCP significantly depended on: phase transition (PT)“early-invasive LC” in terms of synergetics, PT N0-N12, histology, G, blood cell subpopulations, cell ratio factors (ratio between blood cells subpopulations and cancer cells-CC), prothrombin index, heparin tolerance, recalcification time, glucose, AT (P=0.000-0.035). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT N0-N12 (rank=1), PT “early-invasive LC” (rank=2), lymphocytes (3), segmented neutrophils (4), tumor size (5), AT (6), T1-4 (7), ESS (8), prothrombin index (9), glucose (10), thrombocytes/CC (11), healthy cells/CC (12), lymphocytes/CC (13), erythrocytes/CC (14). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).

Conclusion:
5YS of LCP after radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, hemostasis system and AT.

Background:
In Japan, photodynamic therapy (PDT) has been recommended for the treatment of centrally located early lung cancers (CLELC). With recent advances in the diagnosis lung cancer, we continually attempt to expand the indications of PDT, not only for CLELC but also for peripheral type lung cancer. PDT for peripheral lung cancer could be one of the desirable treatment options for patients without surgical indication such as poor pulmonary function. To perform PDT for peripheral lung nodules, it is necessary to use a thin and flexible laser fiber that can sufficiently reach the peripheral lung parenchyma. In this study, we evaluated the feasibility and efficacy of a plastic laser fiber for peripheral PDT.

Methods:
A plastic fiber (cylindrical light diffuser Model RD [Medlight, Switzerland]) was used as a laser fiber for peripheral PDT. The laser output and the light irradiation distribution of the RD cylindrical light diffuser were measured and compared with those of the Panasonic cylindrical probe currently used for PDT. NPe6-PDT was performed for peripheral pig lung. One week after PDT, the pigs were dissected and the lung was removed. The efficacy of NPe6-PDT was evaluated by the pathological findings.

Results:
The mean difference in laser output and the laser source output was 17.7±1.6% for the Panasonic cylindrical fiber and 11.6±3.1% for the RD cylindrical light diffuser. For the light irradiation distribution, the RD cylindrical light diffuser was able to produce more uniform irradiation than the Panasonic cylindrical fiber. The pathological findings showed necrotic tissue and infiltration of lymphoid cells at the laser irradiation area. Around the necrotic tissue, thickening of the alveolar walls and obstruction of the vessels due to thickening of the vascular endothelium were observed.

Conclusion:
The cylindrical light diffuser Model RD showed comparable laser irradiation to the Panasonic cylindrical fiber. The animal experiment showed the effect of PDT in peripheral lung. We conclude that PDT for peripheral lung using the new fiber is feasible and could become one treatment option for peripheral lung cancer.

Background:
The purpose of this study is to evaluate the correlation between histological invasiveness and computed tomography (CT) value and size in pure ground glass nodules (GGNs) to determine optimal “follow-up or resection” strategies.

Methods:
Between 2001 and 2014, 78 resected pure GGNs were evaluated retrospectively. Maximum diameter and CT value of pure GGNs were measured using a computer graphics support system.

Results:
All GGN with a maximum diameter ≦10mm and CT value ≦-600 Hounsfield units (HU) were noninvasive lesions, while 21 of 26 (81%) with a maximum diameter >10 mm and CT value >-600 HU were invasive lesions. With respect to a correlation between each histological type and pure GGN with a maximum diameter ≦10 mm and CT value ≦-600 HU, the specificity was 90% and the sensitivity and negative predictive value were both 100% in atypical adenomatous hyperplasia (AAH), while the specificity was 58% and the sensitivity and positive predictive value were 0% in minimally invasive and invasive adenocarcinoma.

Conclusion:
In establishing follow-up criteria for pure GGNs at a maximum diameter of ≦10mm and CT value of ≦-600HU, unnecessary surgery for AAH and therapeutic delay for invasive adenocarcinoma can be avoided.

Background:
Lung cancer is the commonest cause of cancer death in the world. Recent research has suggested reducing the length of the diagnostic and staging pathway from 30 to 14 days may improve survival. University Hospital of South Manchester (UHSM) is a regional cancer centre in Manchester Cancer, a large cancer network in the North of the United Kingdom. Manchester Cancer diagnoses over 2000 lung cancers every year and UHSM is responsible for the diagnostic and staging pathways for over 200 lung cancer patients per year locally. We anticipate that an efficient patient journey will involve an “investigation day” where patients undergo the majority of the necessary investigations in a single visit/overnight stay. The results of this work may assist in planning the infrastructure required.

Methods:
Prospective data was collected on all patients referred to the rapid access chest clinic (suspected lung cancer) at UHSM from November 2014 to February 2015. Specifically, the investigations each patient underwent in their pathway, both for diagnosis/staging and physiological tests to determine appropriate treatment were recorded.

Results:
Results are presented in table 1.

	n (%)
Total number of patients	264
Number with lung cancer	73 (28%)
PET-CT	67 (25%)
Bronchoscopy	45 (17%)
Diagnostic EBUS	29 (15%)
Staging EBUS	29 (15%)
Mediastinoscopy	0 (0%)
Percutaneous CT-guided lung biopsy	25 (9%)
Neck USS & biopsy	6 (2%)
Liver biopsy	1 (1%)
MR (brain, spine, adrenal, liver)	10 (4%)
Bone biopsy	1 (1%)
Bone scan	2 (1%)
Spirometry	109 (41%)
Diffusion studies	69 (26%)
Differential perfusion scan	6 (2%)
Shuttle walk	41 (16%)
CPET	17 (6%)
Echocardiogram	29 ( 11%)

Conclusion:
Approximately one-third of new referrals to this lung cancer clinic are subsequently diagnosed with lung cancer. Reliable and rapid access to PET-CT, specialist bronchoscopy services and cardiorespiratory physiology testing is paramount for streamlining patient pathways. To realise our aspirations of an “investigation day” we estimate a need for 4 PET-CT slots, 4 lung function slots (with capability of spirometry, diffusion studies and shuttle walk), 8 bronchoscopy / EBUS slots and 2 CT-guided biopsy slots per week to serve our lung cancer population.

Background:
In patients undergoing lung resection, infectious complications are diagnosed when clinical and radiological evidences are observed. Therefore, early detection of complications may benefit patients and could lead cost reduction. C-reactive protein (CRP) measurements persistently high may indicate complications after surgical resection. Our aim is to define the expected variability of CRP after pulmonary resections which have not progressed to clinical or surgical complications.

Methods:
Retrospective Cohort of patients with neoplastic lung disease treated by anatomic pulmonary resection, between January-2010 and June-2014, which had not developed postoperative complications. A CRP curve was built with data until the fifth postoperative day (POD). Surgical and clinical data was collected to look for predictors of CRP values. Statistical analysis was made with median and confidence interval, T-test for median comparison and logistic regression for predictors.

Results:
We analyzed 220 medical records, 100 patients were excluded because lack of data and 50 due to complication development. Seventy patients were included. The median age was 65 years (from 14 to 89). Forty-one were male (58%). Ten patients (14,8%) had Diabetes, 1 (1,42%) hepatopathy and 1 (1,42%) renal failure. Sixty-one patients (87,14%) underwent lobectomy, 8 (11,42%) pneumonectomy and 1 (1,42%) segmentectomy. There were 48 (68,57%) open thoracotomy and 22 (31,42%) video assisted thoracotomy. The histologic type of tumor was 33 (47,14%) adenocarcinoma, 14 (20%) spinocellular carcinoma, 3 (4,28%) benign diseases and 20 (28,57%) others. The median CRP were 12,85 mg/dl (CI-5,44) preoperative; 76,82 mg/dl (CI-8,49) first day, 156,36 mg/dl (CI-17,91) second , 132,35 mg/dl (CI-17,62) third, 103,24 mg/dl (CI-16,29) forth and 94,11 mg/dl (CI-14,32) fifth. Logistic regression pointed that patients operated by videothoracoscopy (VATS) approach are associated with are associated with lower increase of CRP levels (p=0,002). Other studied factors as age, sex, type of surgery, comorbidities and histology fail to predict CRP level.

Conclusion:
It was observed that CRP peak occurs in the second POD. From the third to the fifth POD, there was a drop of CRP levels, however, it does not returne to the preoperative baseline. The VATS approach induces smaller increases in CRP

Background:
Malignant pleural effusion or dissemination is not an indication for surgery or poor prognosis. However, cases that are positive for intraoperative pleural effusion may have better prognosis. We retrospectively examined cases that were positive for intraoperative pleural effusion.

Methods:
We retrospectively investigated the data of 96 patients with primary lung adenocarcinoma who underwent surgery between 2010 and 2013 at the Department of Thoracic Surgery of the Ayabe City Hospital. A total of 11 patients (11.5%) were positive for intraoperative pleural effusion. We compared the data between these patients and the patients who were negative for intraoperative pleural effusion.

Results:
The mean patient age was 72 years (range, 57–83 years); 4 patients were men and 7 were women. The median time from diagnosis to surgery was 89 days (range, 39–1610 days). The median tumor size was 42 mm (range, 15–90 mm). All cases were clinical N0 tumors. Regarding the surgical technique, 2 patients underwent exploratory thoracotomy, 4 underwent wedge resection, and 5 underwent lobectomy. The following pathological findings were obtained. Pleural invasion was pl1 in 1 patient, pl2 in 6, and pl3 in 2. Five patients showed lymphatic vessel invasion (Ly+), 4 patients showed vascular invasion (V+), and 3 patients showed the presence of micropapillary patterns (MPPs). One patient was positive for an EGFR mutation. Five patients had received adjuvant chemotherapy. The overall 4-year survival rate was 72.7%. The patients with E(+) showed a significantly higher extent of Ly+, pleural invasion (pl2), and MPPs (P < 0.05 for all).

Conclusion:
Primary lung adenocarcinoma with intraoperative findings of malignant pleural effusion tend to show Ly+, vascular invasion, and MPPs.

Background:
Atrial fibrillation (AF) after pulmonary resections for lung cancer, although transient in most cases, occurs in up to 30% following lobectomy and up to 65% after pneumonectomy and might, in turn, lead to serious adverse events including stroke, myocardial infarction and death. Different preventive measures have been investigated, however because of paucity of evidence from randomized studies, straightforward recommendations are still uncertain. We aimed to perform a Bayesian-framework mixed treatments comparison (network) meta-analysis of both randomized controlled- (RCTs) and observational studies, to investigate the net-relative benefit of diverse drugs in prevention of atrial fibrillation following pulmonary resections for lung cancer.

Methods:
We screened Medline, Google Scholar, EMBASE and Cochrane CENTRAL registries for randomized and observational studies comparing drugs to each other and/or to placebo. Studies with post-operative AF as prespecified end-point were retrieved for detailed abstraction. Primary outcome was assessed at longest available follow-up.

Results:
Overall 15 studies (13 RCTs) were identified, enrolling N=1753 patients. Beta-blockers, Atrial Natriuretic Peptide and Flecainide were associated with significant relative reduction in odds of postoperative AF, OR (2.5-97.5% CrI) of 0.34 (0.02-0.92); 0.35 (0.00-0.94) and 0.11 (0.00-0.46) respectively; Digoxin was found to increase these odds. Addition of observational data allowed for identification of Amiodarone as another potentially preventive treatment OR (2.5-97.5% CrI) 0.28 (0.03-0.69). Bayesian posterior probability curves revealed the ranking among treatments with Flecainide, beta-blockers, ANP and Amiodarone being associated with the highest probability to reduce the odds of AF, magnesium and calcium blockers with virtually no effect and digoxin found inferior to placebo. Figure 1



Conclusion:
Beta-blockers and Flecainide are effective in reducing the incidence of postoperative AF in patients after pulmonary resections which is not the case with digoxin; data on remaining treatments are sparse and preclude drawing definite conclusions.