Virtual Library

Abstract:
The cancer anorexia-cachexia syndrome (CACS) is a significant clinical problem, affecting upwards of half of all patients with cancer, and causing at least 20% of deaths in the general cancer population. An international expert consensus grouprecently defined cancer anorexia-cachexia as “a multifactorial syndrome characterized by an ongoing loss of skeletal mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [1]. Its impact is particularly significant in lung cancers, where it is present in 60% of patients at diagnosis; in all stages of NSCLCa patients, 5 kg of weight loss reduced survival rates by more than 40%. Systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and body weight reduction [2,3]. CACS is associated with fatigue and a reduction in physical functioning, quality of life (QoL), tolerance and response to anticancer therapy, and survival [1,4,5,6]. The condition is further compounded by its under-recognition, with CACS often present even in the absence of weight loss and at times obscured by obesity [5]. CACS may be preceded by muscle loss and may be exacerbated by anticancer therapies. It is the final common pathway in people with advanced cancer leading to death unless some other process supervenes. The most prominent feature of CACS is its nonresponsiveness to existing treatment approaches, which have included unsuccessful use of nutritional supplements, appetite stimulants, 5-hydroxytryptamine-3 (5-HT3) antagonists and cyclooxygenase-2 (COX-2) inhibitors [2]. American guidelines are aimed at the delivery of optimal nutrition management [7], with those of organizations such as the National Comprehensive Cancer Network lacking specific guidance on pharmacologic treatments [8]. The European Palliative Care Research Collaborative (EPCRC) offers clinical guidance on drug treatments for cancer cachexia [9], but is limited in available advice due to the lack of widely effective and safe agents. There is a vast unmet medical need for this debilitating syndrome. While CACS continues to be an issue that impacts many cancer patients, headway is being made in the development of drugs that can significantly improve quality of life. Some investigational agents have shown potential in completed Phase II or III studies of patients with CACS. During this session we will review recent clinical trial evidence for these agents. Other developmental headway is being made in rapid identification of people at risk for CACS and/or requiring treatment, and point of care clinical decision support to optimize treatment approach. The use of aggregating clinical, biological and patient-reported data and development of specific predictive models are leading to personalized symptom control. In totality, the industry is making progress in the treatment of CACS, and there continues to be vast opportunity to further improve in the future. 1 Fearon K, Strasser F, Anker SD et al.Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12(5), 489–495 (2011). 2 Suzuki H, Asakawa A, Amitani H, Fujitsuka N, Nakamura N, Inui A. Cancer cachexia pathophysiology and translational aspect of herbal medicine. Jpn. J. Clin. Oncol. 43(7), 695–705 (2013). 3 Dodson S, Baracos VE, Jatoi A et al. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu. Rev. Med. 62, 265–279 (2011). 4 Kumar NB, Kazi A, Smith T et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr. Treat. Options Oncol. 11(3–4), 107–117 (2010). 5 Fearon K, Arends J, Baracos V.Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10(2), 90–99 (2013). 6 Ross PJ, Ashley S, Norton A et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br. J. Cancer. 90(10), 1905–1911 (2004). 7 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J.P.E.N. J. Parenter. Enteral. Nutr. 33(5), 472–500 (2009). 8 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Palliative Care 2013. www.nccn.org/professionals/physician_gls/pdf/palliative.pdf (Accessed 14 November 2013). 9 European Palliative Care Research Collaborative. European Clinical Guidelines: Clinical practice guidelines on cancer cachexia in advanced cancer patients with a focus on refractory cachexia 2010.

Abstract:
An international consensus group has defined cancer cachexia as “a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment”.[1] Fifty percent of patients with lung cancer have muscle wasting at diagnosis and this muscle loss increases throughout their disease course. Metabolic changes associated with cachexia lead to decreased protein stores, altered metabolism, and impaired immunity which clinically can be associated with anorexia and fatigue, weakness, and decreased physical performance. Cancer patients with muscle wasting are less able to tolerate chemotherapy, have worse treatment outcomes, loss of independence and overall shorter survival. Effective prevention and treatment strategies are needed. Although muscle wasting is central to the process of cachexia, our clinical diagnostic criteria are largely based on weight. Standard definitions for cancer cachexia include either weight loss > 5% of body weight or a body mass index (BMI) of < 20 kg/m[2] with 2% weight loss. More exact measurements of muscle and muscle wasting can be made through imaging techniques assessing lean body mass (LBM). Dexascan has been used to evaluate LBM, but is not routinely used in clinical practice currently. A very promising technique involves the use of standard computerized tomography in conjunction with a software program which accurately delineates skeletal muscle from adipose tissue, with excellent correlation with other techniques.[2] Application of this technique to a large population of patients with advanced lung and GI cancer has demonstrated a high prevalence of muscle wasting (sarcopenia) in patients with a BMI <20, but also documents a prevalence of sarcopenia of 40-60% in patients with normal BMI. At least 20% of patients with an elevated BMI also have muscle wasting (sarcopenic obesity). Studies in this population with sarcopenia regardless of baseline weight have shown increased toxicity of chemotherapy treatments, shorter time to tumor progression and decreased overall survival. Despite the frequency and severity of cancer cachexia, broad based accepted clinical practice guidelines are limited. The European Palliative Care Research Collaborative consensus recommendations[3 ]include enteral nutritional therapy, nutritional counseling, physical therapy, and psychotherapeutic interventions for quality of life benefit. However, specific pharmacologic therapies, to date, have had little established benefit. For example, Megesterol stimulates appetite and weight gain in some patients, but without an increase in muscle mass, and has significant toxicity regarding venous thromboembolic events. The most effective strategy would be effective anticancer therapy. However, in advanced cancer where our treatments may only be partially effective or ineffective, toxicities are frequent and add to the overall wasting syndrome. Improved biologic understanding of muscle wasting has led to new therapeutic approaches that are under development. One category of agents interferes with biologic signaling and cytokines that may lead to muscle atrophy, including myostatin/activan inhibitors, anti-TNFa and anti-IL6 agents, among others. Several of these agents are in early phase clinical trials. A second approach has been to target pathways that directly stimulate hypertrophy of muscle. Two of these agents have been studied in phase 3 trials in advanced lung cancer patients, enobosarm and anamorelin. Enobosarm, a selective androgen receptor modulator, has been developed to have direct action on muscle, but without androgenic effects on prostate or virilization. Phase 2 trials have shown a clear increase in LBM and physical function, leading to two randomized phase 3 trials in patients with advanced lung cancer receiving chemotherapy. These studies have shown a clear impact on improvement in LBM in both trials, but an inconsistent effect on function as measured by stair climb power between the 2 studies.[4] As predicted by the mechanism of action, no change in appetite or body weight was noted. A second approach for muscle hypertrophy is Anamorelin, a ghrelin receptor agonist. Ghrelin stimulates appetite, increase in body weight and body mass and metabolism. Randomized phase 3 trials of Anamorelin in advanced lung cancer patients have demonstrated an increase in body weight, along with LBM, but no improvement in functional assessment as measured by hand grip strength.[5] Quality of life improvements have also been seen in the study population with Anamorelin. Clinical trial results of both enobosarm and Anamorelin will be reviewed and compared in more detail, as well as potential implications for future development of these and other agents, leading to more effective therapeutic interventions for patients with cancer cachexia in the future. References Ferron K, et al. Lancet Oncol. 12:485-495, 2011. Prado C, et al. Lancet Oncol. 9:629, 2008. European Palliative Care Research Collaborative, 2011, www.epcrc.org. Crawford, J. J Clin Oncol 32:5s, 2014 (suppl; abstr 9618). Temel J, Abernethy A, et al. ASCO Proceedings, Abstract 9500, 2015.

Abstract:
With the adoption of reimbursement for lung cancer screening in eligible beneficiaries both by third party payers and Medicare, smoking cessation becomes a strategic partner to reduce lung cancer mortality. In the present paradigm, Medicare will require screening programs to meet criteria of the American College of Radiology (or equivalent body) for radiologists, CT scanner platforms, and facilities; to satisfy specific patient eligibility criteria and shared decision-making; and to submit all screening data to a CMS-approved registry. Among the requirements is that the imaging facility or screening program make available smoking cessation interventions for current smokers. There are two basic approaches for this: [a] partnering in a transdisciplinary program that includes primary care, subspecialty care, and imaging in which counseling, shared decision-making, and smoking cessation programs are integrated and typically provided by the clinicians; or [b] building these services into an integrated screening facility with delivery by a qualified health care provider working in concert with the imagers. Some hybrid models have been described. Ultimately, the choice of approach is largely dependent upon institutional culture, institutional resources, and degree(s) of decentralization of the screening program. This session will introduce the benefits and liabilities of each approach as well as implications for costs

Abstract:
Lung cancer screening with computed tomography has demonstrated a significant reduction in mortality (1) leading to the recommendation for annual low-dose CT (LDCT) screening for lung cancer for adults between 55 and 80 years old who are at high risk for lung cancer because of their age and extensive smoking history. In addition to lung cancer screening having public health benefit for early detection of lung cancer, lung cancer screening programs may also represent a “teachable moment” for reaching smokers and promoting cessation through the delivery of evidence-based tobacco cessation treatment (2). Since the advent of lung cancer screening programs, there has been much interest in the impact of lung cancer screening on smoking behaviors. Ostroff and colleagues (3) first published the observation that 25% of current smokers seeking lung cancer screening reported smoking cessation one-year following enrollment in a lung cancer screening program Since then, several observational studies have reported cessation rates ranging from 6.6% to 42% following enrollment in lung cancer screening programs (4-11). However, a more recent systematic review of clinical trials and cohort studies examining smoking behaviors among individuals undergoing LDCT for lung cancer screening concluded that lung cancer screening per se does not change smoking behaviors leading to the conclusion that further research is needed to develop and evaluate cost-effective models for delivery of tobacco treatment in lung cancer screening protocols (12). A recent survey of lung cancer screening sites examined the organizational priority, practice patterns and perceived barriers associated with tobacco treatment (13). To facilitate the integration of tobacco treatment within lung cancer screening programs, a greater understanding of the barriers associated with implementation is needed. Thus, the presentation objectives are to: 1) Establish the rationale for integration of tobacco dependence treatment in lung cancer screening programs; 2) Examine patterns and predictors of smoking cessation among lung cancer screening program enrollees; 3) Examine current organizational priority, practice patterns and perceived barriers associated with tobacco treatment delivery; 4) Review opportunities and challenges of integrating tobacco dependence in lung cancer screening protocols. This presentation will provide a blueprint for developing and implementing evidence-based tobacco treatment services within the context of lung cancer screening program. 1. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. The New England journal of medicine. 2011;365(5):395-409. Epub 2011/07/01. PMID: 21714641. 2. Poghosyan H, Kennedy Sheldon L, Cooley ME. The impact of computed tomography screening for lung cancer on smoking behaviors: a teachable moment? Cancer nursing. 2012;35(6):446-75. Epub 2012/01/03. PMID: 22209869. 3. Ostroff JS, Buckshee N, Mancuso CA, Yankelevitz DF, Henschke CI. Smoking cessation following CT screening for early detection of lung cancer. Preventive medicine. 2001;33(6):613-21. Epub 2001/11/22. PMID: 11716658. 4. Ashraf H, Tonnesen P, Holst Pedersen J, Dirksen A, Thorsen H, Dossing M. Effect of CT screening on smoking habits at 1-year follow-up in the Danish Lung Cancer Screening Trial (DLCST). Thorax. 2009;64(5):388-92. Epub 2008/12/05. PMID: 19052048. 5. Clark MM, Cox LS, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Effectiveness of smoking cessation self-help materials in a lung cancer screening population. Lung cancer (Amsterdam, Netherlands). 2004;44(1):13-21. Epub 2004/03/12. PMID: 15013579. 6. Cox LS, Clark MM, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Change in smoking status after spiral chest computed tomography scan screening. Cancer. 2003;98(11):2495-501. Epub 2003/11/25. PMID: 14635086. 7. MacRedmond R, McVey G, Lee M, Costello RW, Kenny D, Foley C, et al. Screening for lung cancer using low dose CT scanning: results of 2 year follow up. Thorax. 2006;61(1):54-6. Epub 2006/01/07. PMCID: PMCPMC2080704. 8. Schnoll RA, Miller SM, Unger M, McAleer C, Halbherr T, Bradley P. Characteristics of female smokers attending a lung cancer screening program: a pilot study with implications for program development. Lung cancer (Amsterdam, Netherlands). 2002;37(3):257-65. Epub 2002/09/18. PMID: 12234693. 9. Taylor KL, Cox LS, Zincke N, Mehta L, McGuire C, Gelmann E. Lung cancer screening as a teachable moment for smoking cessation. Lung cancer (Amsterdam, Netherlands). 2007;56(1):125-34. Epub 2007/01/02. PMID: 17196298. 10. Townsend CO, Clark MM, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Relation between smoking cessation and receiving results from three annual spiral chest computed tomography scans for lung carcinoma screening. Cancer. 2005;103(10):2154-62. Epub 2005/04/13. PMID: 15825210. 11. van der Aalst CM, van den Bergh KA, Willemsen MC, de Koning HJ, van Klaveren RJ. Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch-Belgian randomised controlled lung cancer screening trial. Thorax. 2010;65(7):600-5. Epub 2010/07/16. PMID: 20627916. 12. Slatore CG, Baumann C, Pappas M, Humphrey LL. Smoking behaviors among patients receiving computed tomography for lung cancer screening. Systematic review in support of the U.S. Preventive Services Task Force. Annals of the American Thoracic Society. 2014;11(4):619-27. Epub 2014/04/08. PMID: 24701999. 13. Ostroff J, Borderud S, Copeland A, editors. Readiness and capacity of US lung cancer screening sites to deliver tobacco dependence treatment. Healthography: American Public Health Association 142nd Annual Meeting & Expo; 2014; New Orleans, LA.

Abstract:
SCLC constitutes about 15% of all lung cancers and occurs almost exclusively in smokers. Clinical features of SCLC include rapid growth and the early development of metastases. The vast majority of SCLC patients present with either locally advanced or metastatic disease. Owing to high metastatic potential of SCLC, a careful mediastinum staging, along with brain, bone and abdomen imaging, is indicated to identify patients amenable to curative approaches. Traditionally, SCLC patients have been divided into limited stage (LS), defined as tumor confined to the ipsilateral hemithorax and regional nodes, and extensive stage disease, defined as tumor beyond these boundaries. In 2007, the International Association for the Study of Lung Cancer (IASLC) recommended TNM staging for SCLC similarly to NSCLC, and this change was incorporated in 2010 into the AJCC/UICC 7[th] edition. Chemotherapy remains the mainstay of treatment in all SCLC patients. The current standard of care for LS-SCLC patients includes 4 cycles of chemotherapy consisting of cisplatin and etoposide. Carpoplatin can be substituted to cisplatin if contraindicated or in patients with poor tolerance to cisplatin. In LS-SCLC patients chemotherapy should be accompanied by thoracic radiotherapy. The metaanalysis of randomized studies comparing chemotherapy with or without radiotherapy showed apparently increased local tumor control and increased overall survival in favor of combined treatment (relative risk of death 0.86 [95% CI, 0.78 to 0.94; p=0.001], corresponding to a an absolute benefit of 5.4% at 3 years), at the expense of slightly increased early toxicity.[1] Radiotherapy concurrent to chemotherapy is preferred to sequential approach, despite higher incidence of severe pneumonitis and oesophagitis.[2 ]Early introduction of radiotherapy (with 1 or 2 cycle of chemotherapy) may increase treatment outcome.[3 ]A critical factor in chemoradiation for LS-SCLC is a short time from to the start of any therapy to the end of radiotherapy.[4] The optimal dose of radiotherapy for patients with LS-SCLC remains a matter of debate. Hyperfractionated radiotherapy including 45 Gy in 3 weeks (1.5 Gy twice daily) has been shown to be superior to 45 Gy in 5 weeks (1.8 Gy daily),[5 ]and is currently used as an alternative to standard regimens (60-70 Gy, 2 Gy daily). The volume of thoracic radiotherapy should be defined based on CT or (whenever possible) PET/CT scan, obtained within 4 weeks before treatment, and on CT scan obtained in the therapeutic position at the time of radiotherapy planning. The target to be irradiated should include all gross disease present at the time of radiation planning (postchemotherapy volume), and all nodal regions involved at the time of initial diagnosis (prechemotherapy volume). The use of traditional larger fields including also elective nodal sites is currently not recommended. With more effective therapy of LS-SCLC and a decreased risk of a thoracic relapse, the brain has emerged as one of the main sites of relapse, with a cumulative incidence at 2 years higher than 50%. Owing to limited penetration of cytotoxic drugs through the blood-brain barrier, the brain is considered a pharmacologic sanctuary site. This observation led to the development of prophylactic cranial irradiation (PCI) aiming at prevention of clinically overt brain metastases. Several randomized trials showed that PCI in patients who achieved a complete remission with chemotherapy significantly decreases the incidence of brain metastasis. The metaanalysis of these studies also demonstrated a small but significant overall survival improvement with PCI (the relative risk of death in the PCI vs. non-PCI group was 0.84 [95% CI: 0.73–0.97, p=0.01]), corresponding to a 5.4% increase in the rate of survival at 3 years.[6 ]Based on these results, PCI is currently recommended as a routine part of management in LS-SCLC patients who achieve a response to initial therapy. The dose of PCI has long been a matter of debate. Results of the randomized study comparing a standard (25 Gy in 10 fractions) vs. higher dose (36 Gy in 18 fractions) of PCI in LS-SCLC showed no significant difference in the 2-year incidence of brain metastases between two groups, and a lower overall survival in the higher-dose group.[7] In consequence, 25 Gy in 10 fractions remains the standard of care in LS-SCLC. In summary, current management in patients with LD-SCLC and good performance status includes the combination of cisplatin and etoposide, along with early thoracic radiotherapy (45 Gy in 3 weeks, 2 fractions daily, or 60-70 Gy in 6-7 weeks, one fraction daily), followed by PCI (25 Gy in 10 fractions) in those who achieved response to initial chemotherapy. References 1. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-24. 2. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2004;22:4837-45. 3. Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, et al. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: A systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev 2007: 33: 461–473 4. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057-63. 5. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-71. 6. Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-84. 7. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;10:467-74. The author declares no relevant conflict of interest.

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Prognosis for mesothelioma is bleak; median survival for the cohort is generally less than 12 months. However individual patients have been known to survive for many years. From the CARET study 5 year survival rates of 9% have been reported. Our own data shows 5 year survival at less than 5%. The most frequent question of newly diagnosed mesothelioma patients relates to their prognosis. Clinical and laboratory prognostic variables proposed nearly two decades ago from consortium data from the European Organisation for Research and Treatment of Cancer (EORTC) (Curran et al, 1998) and the Cancer and Leukaemia Group B (CALGB) (Herndon et al, 1998) have been validated. Prognostic variables including performance status (PS), age, gender, tumour histology, white blood cell count (WCC), haemoglobin (Hb) level, and the presence or absence of chest pain and weight loss are taken into account when giving the patient their prognosis. Clearly, besides tumour histology and possibly the laboratory variables, most relate to the overall health and fitness of the individual. Non-subjectively determined biomarkers have been proposed as an independent means of providing prognostic information. And indeed several markers have been shown in a research setting to reflect prognosis however few of these studies have taken into account the known clinical prognostic factors. The prognostic value of serum concentrations of soluble mesothelin, the most well studied mesothelioma biomarker, have been inconsistent between studies. Data is compromised by study cohort characteristics, as tumours of sarcomatoid histology tend to have low mesothelin levels and poor survival. Our own data suggests that mesothelin levels in patients with epithelioid tumours are reflective of tumour burden as assessed by chest x-ray, CT or PET scans, which itself is an indicator of survival. Several other serological biomarkers have been reported to have prognostic value, including aquaporin 1 and osteopontin. In addition there has been extensive work on inflammation-based prognostic indices, including the neutrophil to lymphocyte ratio as well as serum albumin levels. Another useful source of prognostic biomarkers is tumour associated antigens. We have shown that serum immunoreactivity to the ATP synthase protein ATP5B is positively correlated with prognosis, and have unpublished data showing a similar significant positive association of immunoreactivity to RAB38, a previously described melanoma associated tumour antigen. In addition to blood based biomarkers, in mesothelioma it is also possible to examine soluble biomarkers in the pleural effusion. There is evidence that pleural effusion concentrations of hyaluronic acid and of fibulin-3 may provide independent prognostic data. In the case of hyaluronic acid, higher concentration of this biomarker is associated with a better prognosis. Fibulin-3 has the potential to be a useful prognostic marker because its interpretation is not confounded by lower concentrations associated with a sarcomatoid histopathology; rather sarcomatoid effusions have higher concentrations of this marker and it has been shown to be markedly superior to effusion mesothelin as a prognostic marker. Other prognostic effusion biomarkers that have been identified are syndecan-1 and osteopontin. Recently, several novel pleural effusion based biomarkers have been reported from discovery studies; these include galectin-1, aldo-keto reductase and apoliproptein C-1. Of these high effusion levels of galectin-1 and aldo-keto reductase were associated with a relatively poor prognosis whereas high effusion levels apoliproptein C-1 were associated with improved prognosis. It is important to realize that these findings remain un-validated in other patient cohorts. These biomarkers that have been identified as having prognostic value were generally not initially investigated as prognostic markers, rather they have been studied for this purpose after their identification as potential diagnostic markers. Typically their initial identification has not been thoroughly investigated in independent cohorts of patients, nor have they been systematically investigated together to determine the degree to which they are independent of each other as prognostic markers. It is possible that more suitable markers could be identified that were initially investigated as prognostic markers. An example of this would be the identification of proteins that were under or over expressed in pleural effusions from patients with longer survival compared to those with a shorter survival time using proteomics discovery methods. This underscores the importance of prospective collection of biological samples with scrupulous recording of clinical details for future evaluation of markers as they are discovered.

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Abstract:
Platinum-based doublet chemotherapy is the standard first-line treatment for non-selected patients with advanced non-small cell lung cancer (NSCLC) who have a good performance status . However, some tumors are highly dependent on the function of specific oncogenes for proliferation and survival. This “oncogenic addiction” has leaded the development of targeted anticancer therapies and their ad hoc biomarkers as predictors of their efficacy. This fact has changed the diagnostic and treatment approach in NSCLC . Moreover, this ‘‘personalized medicine’’ approach, in which tumors might potentially benefit from a biology-guided treatment, has an impact in patients’ outcome . Personalized medicine is also feasible in other malignancies such as metastatic breast cancer, even for patients with rare genomic alterations (SAFIR01 trial) , and in other refractory malignancies (SHIVA trial) , reinforcing that the establishment of a comprehensive tumour molecular profile is feasible and compatible with clinical practice. Unlike “basket trials”, where researchers test the effect of a single drug on a single mutation in a variety of cancer types, “umbrella” trials are designed to test the impact of personalized medicine with different drugs on different mutations in a single type of cancer on the basis of a centralized molecular portrait . The phase II BATTLE (Biomarker-integrated Approaches of Targeted Therapy for lung Cancer) trial was the first prospective, biopsy-mandated, biomarker-based study, that adaptively randomised 255 pre-treated NSCLC patients to erlotinib, sorafenib, erlotinib plus bexarotene, or vandetanib, based on molecular biomarker analysed in fresh core needle biopsy specimens. Overall results included a 46% 8-week disease control rate (primary endpoint). This trial established the feasibility of “real-time” biopsies and personalized treatment in lung cancer. BATTLE-2 (NCT01248247), a phase II, randomised, multi-arm study in advanced pre-treated EGFR wild type and ALK non-rearranged NSCLC patients is currently ongoing. The SPECTA-lung (NCT02214134), included within the SPECTA-platform, is a program aiming at Screening Patients with thoracic tumors (lung cancer, malignant pleural mesothelioma, thymoma or thymic carcinoma at any stage) to identify the molecular characteristics of their disease for Efficient Clinical Trial Access. Second-generation trials encompass within the trial design to access to targeted therapies and usually incorporate a randomization process. SAFIR02-Lung (NCT02117167) is an open-label, multicentric randomised, phase II trial. Advanced no EGFR-activating mutation or ALK translocation NSCLC patients are biopsied during the two initial platinum-based chemotherapy cycles. A comparative genomic hybridisation (CGH) array and a next-generation sequencing are performed and analysed during the two subsequent cycles as a therapeutic decision tool. Only patients with a molecular alteration are randomized to maintenance targeted drug arm (AZD8931, Vandetanib, Selemutinib, AZD5363, AZD4547, AZD2014); or standard maintenance treatment (pemetrexed or erlotinib) after completion of four cycles of chemotherapy to test an improvement in progression free survival (PFS). Lung-MAP (NCT02154490) trial is a phase II/III multidrug, multi-sub-study, and biomarker-driven clinical trial in advanced second-line squamous lung cancer patients. Patients are randomized to standard second-line treatment (docetaxel / erlotinib) or five experimental drugs (four targeted therapies according NGS results and an anti-PDL1 immunotherapy based on immunochemistry results). The primary end-point of the trial is PFS. Approximately 500 and 1000 patients will be screened per year for over 200 cancer-related genes for genomic alterations. ALChEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is designed to assess whether adjuvant therapy with erlotinib (ALCHEMIST-erlotinib, NCT02193282) or crizotinib (ALCHEMIST-crizotinib, NCT02201992) for 2 years will improve survival over placebo for patients with completely resected stage IB-IIIA EGFR-mutant or ALK-rearranged NSCLC tumors following standard post-operative therapy. ALCHEMIST-screening trial (NCT02194738) will screen about 6,000 to 8,000 participants over 5 to 6 years, with 400 patients enrolled per arm. The RTOG1306 is a phase II trial in EGFR-mutant or ALK-rearranged unresectable stage IIIA (pN2) or IIIB (pN3) NSCLC patients. The aim of the study is to asses whether induction therapy with erlotinib or crizotinib for 12 weeks prior to chemo-radiotherapy improves PFS compared to those treated with standard care therapy alone. Molecular screening is also tested across prospective trials in different malignancies. The MOSCATO trial (NCT01566019) includes metastatic solid tumors and the primary objective is to use high throughput molecular analysis (CGH Array and sequencing) to guide treatment of patients with targeted therapeutics in order to improve the PFS compared to the previous treatment line. IMPACT trial (Initiative for Molecular Profiling in Advanced Cancer Therapy Trial, NCT00851032), is an umbrella protocol in 5,000 patients with advanced malignancies. The goal is to correlate the molecular profile with response to phase I therapies. The NCI-MATCH trial (Molecular Analysis for Therapy CHoice) trial is an umbrella protocol for multiple single-arm, phase II trials. Biopsies from as many as 3,000 patients will be screened by next-generation DNA sequencing to identify 100 actionable mutations, with 1000 participants being enrolled (25% of whom will have rare cancers). Co-primary end-points are overall response rate and PFS rate at 6 months. Finally, for advanced and refractory cancer patients who do not have recognised genetic abnormalities WINTHER trial (NCT01856296) aims at selecting rational therapeutics based on the analysis of matched tumors and normal biopsies according to micro arrays and gene expression profiling results. The main objective is to compare the PFS of the current treatment versus the previously prescribed treatment. Models of personalized medicine implementation (no organized compared with organized framework) , optimal technology for molecular profile , and the optimal patients’ selection are some of challenges to be overcome in personalized medicine. Moreover, the actual model of personalized medicine does not take in account secondary events, which will be involved in cancer resistance. A major challenge in molecular medicine will be to target these secondary events early enough, in order to avoid treatment resistance . Intratumoral heterogeneity plays a critical role in tumor evolution. However, molecular characterization of the tumor is provided from a single biopsy and at single time point. Multiregional evaluations to determine geographical heterogeneity, and molecular characterization of different samples collected over space and time to ascertain clonal evolution are not routinely carried out . The prospective TRACERx trial (TRAcking non-small cell lung Cancer Evolution through therapy [Rx], NCT01888601) in NSCLC patients, aims to define the evolutionary trajectories of lung cancer in both space and time through multi-region and longitudinal tumor sampling and genetic analysis by following cancer from diagnosis to relapse. The study aims to recruit 842 patients . Incorporating an analysis of the tumor immune contexture is also a key challenge and need for the design of new precision medicine trials . In the near future most patients with metastatic tumors will receive targeted therapies or immune modualtors delineated by tumor genotyping and analysis of immune contexture and all of these trials will help to validate current biomarkers facilitating rapid access to innovative therapies.

Abstract:
Lung cancer and mesotheliomas belong to the most lethal human malignancies with poor prognosis. The majority of these tumors is associated with carcinogen exposure (smoking and asbestos). Small cell lung cancer (SCLC) and mesothelioma patients show very poor survival statistics due to their late detection, invasive and high metastatic potential, and chemo-resistance. Using the Rbf/f;p53f/f mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells, characterized by mesenchymal and neuroendocrine markers. These cells often share a common origin. Crosstalk between these cells can endow the neuroendocrine component with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating functional tumor properties. Also specific genetic lesions appear to be associated with metastatic potential. We have studied the nature of this crosstalk and identified the components responsible for paracrine signaling and the downstream effector pathway critical for promoting metastatic spread. We have also evaluated the relevance of additional lesions that were frequently acquired in the mouse SCLC, such as amplification of Myc and Nfib. Therefore, we have derived ES cells from Rbf/f;p53f/f, equipped these cells with an exchange cassette in the ColA1 locus, and shuttled a conditional L-Myc and Nfib under a strong promoter into this locus. This accelerated tumorigenesis and resulted also in a shift in the metastatic phenotype. To investigate the cell-of-origin of thoracic tumors, we have inactivated a number of tumor suppressor/oncogene combinations (Trp53, Rb1, Nf2, Cdkn2ab-p19Arf, mutant Kras) in distinct cell types by targeting Cre-recombinase expression specifically to Clara cells, to neuroendocrine cells, alveolar type II cells and cells of the mesothelial lining (origin of malignant mesothelioma) using adenoviral or lentiviral vectors with Cre recombinase driven from specific promoters. Dependent on the induced lesions and the cell-type specific targeting, SCLC, NSCLC, or mesothelioma could be induced. We show that multiple cell types can give rise to these tumors but that the cell-of-origin is an important factor in determining tumor phenotype. Our data indicate that both cell type specific features and the nature of the oncogenic lesion(s) are critical factors in determining the tumor initiating capacity of lung (progenitor) cells. Furthermore, the cell-of-origin appears to influence the malignant properties of the resulting tumors. Sutherland, K., Song, J-Y., Kwon, M-C, Prooost and Berns A. (2014). Multiple cells-of-origin in K-RasG12D induced mous lung adenocarcinoma. Proc. Natl. Acad. SCi. USA, 111, 4952-4957. Kwon, M-C, and Berns, A. (2013) mouse models of Lung Cancer. Mol. Oncol. 7, 65-177. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J-Y., and Berns, A. (2011). Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung. Cancer Cell 19, 754-64. Calbo, J., van Montfort, E., Proost, N., van Drunen, E., Beverloo, H., Meuwissen, R., and Berns, A. (2011) A functional role for tumor cell heterogeneity in a mouse model of Small Cell Lung Cancer. Cancer Cell, 19, 244-56.

Background:
Imprime PGG (PGG) in combination with carboplatin/paclitaxel chemotherapy (C/P) and bevacizumab (Bev) increased objective response rates (ORR) and overall survival (OS) of patients (pts) with previously untreated stage IV non-squamous NSCLC in comparison to C/P + Bev alone in a randomized, controlled, multicenter phase 2 trial (Engel-Riedel W et al, Ann Oncol 25 [Suppl 5], 2014, LBA32). Herein, we report landmark survival analyses at the 1- and 2-year time points. The trial was sponsored by Biothera, ClinicalTrials.gov NCT 00874107, EudraCT 2008-006780-37.

Methods:
92 pts with stage IV nonsquamous NSCLC were randomized 2:1 to receive PGG (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + C/P + Bev (PGG group) vs C/P + Bev alone (Ctrl group). C/P was administered for 4 to 6 cycles; Bev +/- PGG were administered until disease progression or intolerable toxicity. The primary endpoint was ORR based on modified RECIST v1.0 and was assessed centrally. Secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response (DoR) and safety. Imaging assessments (CT of chest and abdomen) were reviewed every 6 weeks. The primary analysis occurred after all pts had either progressed or had the opportunity to complete at least 18 treatment cycles (54 weeks).

Results:
An objective response was achieved by 29 out of 48 evaluable pts (60.4%; 1 CR, 28 PR) in the PGG group and 10 out of 23 (43.5%; 0 CR, 10 PR) in the Ctrl group (p=0.21). Median (m) OS was 16.1 mos with PGG compared to 11.6 mos (HR=0.66; p=0.13) with Ctrl. The mPFS was 11.9 mos vs 10.2 mos (HR=0.86; p=0.59), and mDoR was 10.3 mos vs 5.6 mos (HR=0.92; p=0.90) among subjects receiving PGG vs Ctrl, respectively. Survival rates of pts (95% CI) in the PGG vs Ctrl groups were 62.8% (48.8, 74.0) vs 42.7% (22.7, 61.4) at 12 mos, and 37.0% (22.5, 51.5) vs 24.4% (7.9, 45.7) at 24 mos. Overall, the incidence of adverse events (AEs) was similar across treatment groups. The most common AEs (occurring in ≥ 5 pts) deemed possibly or probably related to PGG by the investigator were chills (13.6%); dyspnea, fatigue (10.2% each); nausea, pyrexia, and infusion-related reactions (8.5% each). Overall, 37.3% of pts receiving PGG and 43.3% receiving Ctrl discontinued the study due to AEs.

Conclusion:
The addition of PGG to C/P + Bev therapy was well tolerated and resulted in clinically meaningful increases in ORR, DoR, and OS. Results did not reach statistical significance in this phase 2 study. Further investigation is warranted to confirm the efficacy and safety of this combination.

Background:
This study aims to explore status of PD-L1 expression and FGFR1 amplification in stage IIIB/IV SQC, further to analyze their correlation with clinicpothological characteristics, efficacy of gemcitabine based chemotherapy and prognosis of SQC patients.

Methods:
128 stage III/IV SQC patients were enrolled into this study from May 1[st] 2009 to May 31[st] 2014, all of which had complete clinical profile. 78 patients received gemcitabine-based chemotherapy. Immunohistochemistry (IHC) was used to detect PD-L1 expression, fluorescence in situ hybridization was applied to detect FGFR1 amplification. SPSS17.0 was used for statistical analysis.

Results:
80 (62.5%) SQC had IHC positive PD-L1 expression. PD-L1expression was significantly higher in male and smoker population than female and non-smoker, respectively. (gender: 65.5% VS. 22.2%, P=0.011; smoke histology 67.0% VS. 44.0%, P=0.039). PD-L1 expression had no significant relationship with objective response rate (ORR) and disease control rate(DCR) for gemcitabine-based chemotherapy(54.8% VS.59.7%, P =0.434 and P=0.840). However, the overall survival (OS) of PD-L1 negative SQC was significantly longer than PD-L1 positive group (29.8 vs. 20.1 months, P=0.001). 32 cases showed FGFR1 FISH positive (32/128, 25.0%), and stage III patients presented lower rate compared with stage IV SQC (17.1% vs. 36.5%, P=0.013). FGFR1 amplification had no relationship with ORR and DCR in patients treated with gemcitabine-base chemotherapy(32.3% VS.30.6%. P=0.663 and P=0.659). No correlation between PD-L1 expression and FGFR1 amplification was found (P=0.916).

Conclusion:
PD-L1 expression could act as a prognosis factor in Chinese stage III/IV SQC patients. PD-L1 expression and FGFR1 amplification might be irrelevant.

Background:
Programmed Cell Death 1 (PD-1) inhibitor therapy is now an established therapeutic modality in certain solid malignancies, including non-small cell lung cancer (NSCLC). The purpose of this study is to determine whether disease progression patterns are different between PD-1 inhibitor therapy or chemotherapy in patients with advanced NSCLC.

Methods:
We performed a retrospective analysis of patients who received PD-1 targeted therapies and systemic chemotherapy for advanced NSCLC treated at the Winship Cancer Institute at Emory University. We reviewed demographic data and treatment history of these patients. RECIST criteria were used to evaluate the patients’ baseline tumor burden and their subsequent disease progression from imaging studies (CT, PET/CT, MRI).

Results:
The total cohort included 37 patients with a mean age of 67 years. The PD-1 therapy group included 19 patients (14 males, 5 females), with 9 on MK-3475, 3 on MDPL3280A, and 7 on nivolumab. This group included 3 African Americans and 16 Caucasians. The median number of lines of prior chemotherapy was 3. A comparator group of 18 patients on standard chemotherapy was identified (14 males, 4 females). This group included 8 African Americans and 10 Caucasians. In the PD-1 therapy group, 5 patients had no progression and 14 had disease progression. Of these, 5 progressed at their sites of known cancer (36%), 4 progressed at new sites (28.5%), and 5 progressed at both old and new sites (36%). In the chemotherapy group, 4 patients had no disease progression and 14 had progression. Of those 14, 2 were at old sites only (14%), 4 were at new sites only (29%), and 8 were at both old and new sites (57%). The median time to progression was 3.5 months with PD-1 targeted therapy (range 2-13 months) and 6 months with chemotherapy (range 2-21 months).

Conclusion:
Our data suggests no difference between the progression patterns between PD-1 inhibitor therapy and standard chemotherapy patients. Patients on PD-1 therapy appear to have a shorter time to progression than those on traditional chemotherapy.

Background:
Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in NSCLC patients.

Methods:
In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer gefitinib resistance in EGFR-mutant lung cancer cells.

Results:
Mechanistically, PXN-mediated ERK activation is responsible for gefitinib resistance via decreased BIM and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at Serine 69 and Mcl-1 at Threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated gefitinib resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the gefitinib resistance overcome by AZD6244 is more effective than that of obatoclax.

Conclusion:
Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant NSCLC patients whose tumors exhibit high PXN expression.

Background:
Icotinib hydrochloride, an oral EGFR tyrosine kinase inhibitor, was proved to be non-inferior to gefitinib in patients with non-small-cell lung cancer (NSCLC). Brain metastasis is a serious factor associated with poor outcomes of NSCLC because systemic chemotherapy usually showed little effects due to the blood-brain barrier. Besides, other treatments such as whole brain or stereotatic radiotherapy may cause neurological complications. There have been some studies showing that gefitinib or erlotinib plus concurrent brain radiotherapy or not was effective in controlling brain metastasis in NSCLC. Herein, we observed the function of Icotinib on brain metastasis in Chinese NSCLC patients harboring an EGFR mutation.

Methods:
The clinical data of 28 NSCLC patients with brain metastasis referred to Qingdao Municipal Hospital from May 2012 to December 2014 were retrospectively analyzed. All the patients had pathological diagnosis of adenocarcinoma. EGFR mutation state was confirmed by ARMS PCR or Sanger sequencing. The patients received first line Icotinib of 125mg three times a day after giving informed consent and they would continue to take Icotinib unless disease progressed or other reasons. No concurrent brain radiotherapy was given during this process.

Results:
Out of the 28 patients treated, 12 achieve partial response, 11 experienced stable disease and 5 experienced progressive disease. The response rate and disease control rate of Icotinib for brain metastasis was 42.8% and 82.1% respectively. After a median follow-up of 15.1 months (range 5-27 months), the median progression-free time was 7.5 months. Rash and diarrhea were the most common adverse events.

Conclusion:
Icotinib might be an alterative treatment for brain metastasis in Chinese NSCLC patients harboring an activating EGFR mutation.

Background:
Previously, data of Lux-lung 3 and Lux-lung 6 showed overall survival was improved with the afatinib for patients with 19del EGFR mutations and the absence of an effect in patients with L858R EGFR mutations suggests that EGFR 19del-positive disease might be distinct from L858R-positive disease. We aimed to assess the effect of first-generation reverse EGFR TKI (Gefitinib and Elotinib) on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from real world practice.

Methods:
This is a retrospective study, 134 patients with EGFRm 19del or 21L858R with reverse EGFR TKI gefitinib or elotinib in clinical practice from Jun.2012 to April.2014 in Shanghai Chest Hospital , follow-up to April.1,2015. To control for selection bias, matched groups of patients were selected using a propensity score matching method. Overall survival and PFS were estimated using the Kaplan-Meier method with log-rank test. The Wilcoxon rank sum test was used for variables not normally distributed. Categorical data are displayed as frequencies and comparisons were made with Chi-square tests (Fisher exact tests if appropriate).

Results:
After1:1 the propensity score matching, matching was based on a one-to-two nearest neighbor matching method with a tolerance level on the maximum propensity score distance (calipers of width 0.2 standard deviation of the logit of the PS). 70 patients were enrolled, the baseline variables (eg, age, sex, smoking , PS, line of EGFR TKI treatment ) were comparable between the matched cohorts (P > 0.05 for all). Follow-up time: 19del (median 16.2 months, range 1.0-49.2) , 21L858R (median 16.4 months, range 0.4-41.1). m PFS in 19 del and 21L858R was 16.3months, 16.8months, respectively, m OS in 19 del and 21L858R was28.4 months, 32.2 months, respectively, There are no significant difference between EGFR mutation 19del and 21L858R patients with the reversible first-generation inhibitors.

Conclusion:
CONCLUSION: There are no significant difference between EGFR mutation 19del and 21L858R patients with the reversible first-generation inhibitors either PFS or OS. The results maybe related to the sample size, waiting for the results of meta-analysis.

Background:
Gefitinib is effective as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations. Exon 19 deletions and the L858R point mutation are the most commonly encountered sensitive EGFR mutations in NSCLC, and have been shown to predict greater efficacy of gefitinib therapy. The objective of this study was to evaluate whether body surface area (BSA), body weight (BW), and body mass index (BMI) affect the efficacy of gefitinib in patients with NSCLC harboring sensitive EGFR mutations.

Methods:
We reviewed the medical charts of consecutive patients with advanced NSCLC harboring sensitive EGFR mutations who received gefitinib. The median values were used as the cutoffs to evaluate the impact of BSA and BW on the efficacy of gefitinib. BMI was categorized as underweight (BMI < 18.5 kg/m[2]), normal weight (BMI 18.5 to < 25 kg/m[2]), and overweight (BMI ≥ 25 kg/m[2]).

Results:
The median BSA and BW of the 138 NSCLC patients harboring sensitive EGFR mutations were 1.48 m[2] and 53 kg, respectively. The overall response rate, progression-free survival (PFS), and overall survival (OS) were 65.2%, 12.2 months, and 24.2 months, respectively. There were no significant differences in clinical outcomes between the high-BSA (BSA ≥ 1.43 m[2]) and low-BSA groups (BSA < 1.43 m[2]), with response rates of 68.5% and 72.0% (p = 0.92), median PFS of 12.2 and 11.5 months (p = 0.73), and median OS of 25.0 and 21.9 months, respectively (p = 0.28). Moreover, there were no significant differences in clinical outcomes between the high-BW (BW ≥ 53 kg) and low-BW groups (BW < 53 kg), with response rates of 63.3% and 67.1% (p = 0.72), median PFS of 12.2 and 10.8 months (p = 0.46), and median OS of 28.9 and 21.9 months, respectively (p = 0.22). For BMI, the median PFS and OS estimated among underweight, normal weight, and overweight patients were 10.6 and 19.2 months, 12.0 and 23.3 months, and 13.1 and 33.1 months, respectively. There were no statistically significant differences in PFS and OS among underweight, normal weight, and overweight patients (p = 0.52 and p = 0.30, respectively). Finally, to substantiate possible differences in the efficacy in patients who are young (<75 years) vs. elderly (≥ 75 years) and who have exon 19 deletions vs. L858R, we also evaluated these subgroups separately regarding BSA, BW, and BMI. However, there were no significant differences in the PFS and OS between these groups.

Conclusion:
The efficacy of gefitinib in patients with NSCLC harboring sensitive EGFR mutations does not differ according to their BSA, BW, and BMI.

Background:
Gefitinib is a potent oral non-cytotoxic, active and selective epidermal growth factor receptor tyrosine kinase inhibitor. This study evaluates treatment outcomes in 161 NSCLC patients from Czech Republic according to activated mutations located in exons 19 and 21.

Methods:
Data treated patients with gefitinib are collected in the TULUNG registry, which is a common project of the Czech Pneumological Society, Czech Oncological Society, and Institute Biostatistics and Analyses Masaryk University Brno. NSCLC patients with EGFR activated mutations were treated in first line between 02/2010 and 12/2014 in 10 institutions. Retrospective analyses were carried out to assess the effectiveness and safety of gefitinib treatment according to activated mutations located in exons 19 and 21. The analysed outcomes include following: treatment response rate, median Overall Survival (mOS), median Progression Free Survival (mPFS) and occurrence of types adverse events.

Results:
Out of 161 treated patients, 105 (70 female, 35 male) had EGFR mutations in exon 19, and 56 (39 female, 17 male) had EGFR mutations in exon 21. Median age was 66 years in the group with mutations in exon 19 and 69 years in the group with mutations in exon 21. There was no statistically significant difference in sex (p=0.727) and in age (p=0.204). No statistically significant difference was observed in the representation in smoking (p=0.354). There was statistically borderline significant difference in adenocarcinoma proportion (p=0.045). In the group with mutations in exon 19 were 96% patients with adenocarcinoma and in the group with mutations in exon 21 were 85% patients with adenocarcinoma. Between these two groups, there was no statistically significant difference according to performance status (p=0.547); no statistically significant difference according to disease control (CR+PR+SD) (p=0.479); no statistically significant difference according the response to the treatment (CR + PR) (p=0.052). There was no statistically significant difference in mOS (p=0.390). In the group of patients with mutations located in exon 19, the overall survival was 22.7 months (CI 95%: 17.7; 27.8), in the group with mutations in exon 21, overall survival was 16.3 months (CI 95%: 10.8; 21.8). There was no statistically significant difference (p=0.202) in mPFS; in the group of patients with mutations in exon 19 it was 11,0 months (CI 95%:9.1; 12.8) and in the group with mutations in exon 21 it was 9.4 months (CI 95% 6.6; 12.2). SimiIar numbers of adverse effects were observed in either group (35.2% and 35.7%). Almost 70% of patients with mutations in exon 19 and almost 60% of patients with mutations in exon 21 are still alive or were lost to follow up. These patients are censored to the date of last update.

Conclusion:
In both groups of patients, the treatment was very safe. Median PFS and median OS were satisfactory without statistically significant differences between the two groups; however, a better trend was observed in the group of patients with mutations in exon 19. Consequently survival estimates shows great variability and longer potential follow up is needed to confirm these results.

Background:
Central nervous system (CNS) invasion is a common occurrence in patients with non-small-cell lung cancer (NSCLC) and is associated with poor outcome. For patients who develop CNS invasion, epidermal growth factor receptor (EGFR) mutation derives clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). The clinical manifestation of CNS invasion, EGFR mutation, and prognosis are unclear in patients with resected stage I to III lung adenocarcinoma.

Methods:
The records of 261 patients with completely resected stage I to III lung adenocarcinoma who were hospitalized between March 2002 and January 2013 were reviewed retrospectively. Their pathological records indicated that EGFR mutation testing had been performed. Data on basic patient demographics, EGFR mutation, disease-free survival (DFS), and postoperative recurrence were collected. Kaplan Meier curves were used for survival analysis.

Results:
Of the 261 patients (median age: 68, range: 31-90) identified, 49% were male and 53% were EGFR mutant. Tumor stages were I, II, and III in 153, 47, and 61 patients, respectively.DFS after surgery for stage I, II, and III EGFR-mutant patients were 62 mo, 40 mo, and 29 mo, respectively, and 71 mo, 30 mo, and 74 mo, respectively, for patients with wild-type EGFR, showing no significant difference (p=0.19). Recurrence after surgery occurred in 124 patients (36 with CNS, 23 with bone metastasis, and 87 with other organ metastasis).In patients with CNS relapse, the incidence of CNS relapse as first metastasis was significantly high at 13.3% for EGFR-mutant patients, compared with 4.3% for wild-type EGFR patients (HR 2.5, p=0.046). As for second CNS metastasis, there was no significant difference between EGFR-mutant patients (8.1%) and wild-type EGFR patients (4.2%) (p=0.44).In patients whose first relapse was CNS metastasis, DFS after surgery was significantly longer at 22 months for EGFR-mutant patients, compared with 8 months for wild-type EGFR patients (p=0.012). Patients with recurrence in other organs showed no significant differences in terms of DFS regardless of being EGFR mutant or not.

Conclusion:
The EGFR-mutant patients showed a higher incidence of brain metastasis as the first relapse, and significantly longer DFS than the wild-type EGFR patients. In the present study, the brain metastasis of postoperative lung adenocarcinoma as the first relapse was limited to early in the wild-type EGFR patients, but occurred in later in the EGFR-mutant patients.

Background:
Since Jan 2007, China Charity Federation launched IRESSA Charitable Aid Project for advanced non small cell lung cancer which oral IRESSA was effective for 6 months and have failed previous chemotherapy or received first line IRESSA for EGFR mutation positive. This study investigated the survival and correlation influencing factor of China Charitable Aid Project in shanghai by COX multivariate analysis .

Methods:
A retrospective investigation enrolled advanced non small cell lung cancer patient of IRESSA Charitable Aid Project from Jan 2007 to 30 Jun 2013 at 7 centre in Shanghai . The patients oral IRESSA was effective for 6 months who have failed previous chemotherapy or received first line IRESSA for EGFR mutation positive. IRESSA 250mg QD was taken and prescribed monthly. Tumor assessment was performed every 8 weeks, patients continued to receive IRESSA until disease progression (timely withdraw) or unacceptable toxicity or no benefit from this project which was considered as slower progression(late withdraw). The patient were Followed up until 30 Aug 2014. The primary end point was OS and correlation influencing factor. Using the Kaplan-Meier and COX proportional hazards model analyze the correlation between survival and age, gender, smoking status, pathology, indications and timely withdraw of IRESSA.

Results:
A total of 1066 patients were enrolled, the median age was 64, including 339 cases of greater than or equal to 70. Most patients were female (845,79.3%) and no-smokers (992,93.1%), and 94.1% was adenocarcinoma. Indication for second and multiple line patients were 96.1%(1024). The midian PFS was 33 months (95%CI:29.8-36.2），and the MST was 37 months (95%CI:32.5-41.5). COX multivariate analysis revealed timely withdraw group was significantly longer OS ( hazard ration 1.627; 95%CI:1.378-1.922, p=0.000) , more than 70 years old, smoking and indication for second line patient was significantly worse OS (hazard ration 0.692; 95%CI:0.587-0.816, p=0.000; 0.714; 95%CI: 0.531-0.960, p=0.026; 0.498 ;95%CI: 0.265-0.935,p=0.03 respectively.

Conclusion:
96.1% of the patient in Iressa charitable aid projects were second or multiple line treatment due to chemotherapy failure, PFS and OS still reached 33 and 37 months, significantly better than the historical reports. The possible reason was enrolled patients with IRESSA effective for 6 months , It could be EGFR mutation positive, of which no-smoking patients ratio were as high as 93.1%, they maybe have a better prognosis. Multivariate analysis showed OS was significantly prolonged in timely withdraw group after disease deteriorate.

Background:
c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).

Methods:
Asian adults with locally advanced/metastatic NSCLC, Met+ status (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]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.

Results:
14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).

	Best overall response (n)
n=12	Partial response	Stable disease	Progression
IHC
2+	0	5	2
3+	4	0	1
FISH
c-Met:CEP7 ratio >2	1	0	0
≥5 copies in >50% of cells	3	1	1
Negative	0	3	2
Not valid	0	1	0

Conclusion:
The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.

Background:
Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations.

Methods:
We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at 5 institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy.

Results:
Between January 2006 and December 2012, 42 patients (8 men, 34 women; median age, 63 years [range, 39–75 years]) were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2%, 61.9%, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0%, 95.2%, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was indpendently associated with improved PFS.

Conclusion:
Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.

Background:
The results of fastact2 show that chemotherapy plus erlotinib significantly prolonged PFS and OS of patients with NSCLC. However, outcome of the combination therapy are similar to those reported in several trials of single-agent EGFR TKIs. So which is the optimal first-line treatment for patients who harbored a sensitive EGFR mutation? We need a head-to-head study to reply.

Methods:
77 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations, and with ECOG PS 0-1, were randomly assigned to 3 groups. 25 patients were allocated to the combination therapy group (group A), received pemetrexed (500 mg/m(2) on day 1) plus carboplatin (AUC 5 on day 1) combined with gefitinib (250 mg/day on days 5-21) and repeated every 4 weeks for up to six cycles, then continued to receive pemetrexed combined with gefitinib every 4 weeks. 26 patients allocated to the chemotherapy group (group B), received the same chemotherapy regimen alone every 4 weeks for up to six cycles, then continued to receive pemetrexed alone every 4 weeks. 26 patients allocated to the gefitinib group (group C), and received gefitinib alone. All therapies of 3 groups were continued until progression or unacceptable toxicity or death. The primary endpoint was Median PFS. Analyses were done on an ITT basis.

Results:
Median PFS for patients in group A was 19.1months, 95% CI (17.1, 21.1), Median PFS for patients in group B was 5.5months, 95% CI (4.4, 6.8), Median PFS for patients in group C was 9.9months, 95% CI (7.0, 12.7). 6-month PFS was96.0% (24 of 25) in the group A, 38.5% (10 of 26) in the group B, and 73.1% (19 of 26) in the group C. ORR was 80.0% in the group A, 34.6% in the group B, and 61.5% in the group C. The most common grade 3-4 adverse events were neutropenia (3 [12.0%] of patients in the group A vs 4 [15.4%] in the group B vs 0 [0.0%] in the group C ), fatigue (2 [8.0%] of patients in the group A vs 2 [7.7%] in the group B vs 0 [0.0%] in the group C ), and liver dysfunction (3 [12.0%] of patients in the group A vs 0 [0.0%] in the group B vs 1 [3.8%] in the group C ), skin allergy (0 [0.0%] of patients in the group A vs 1 [3.8%] in the group B vs 0 [0.0%] in the group C )

Conclusion:
Patients with lung adenocarcinoma who harbored a sensitive EGFR mutation have longer PFS if they are treated with pemetrexed plus carboplatin combined with gefitinib.

Background:
Although epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the key drug in patients with EGFR-mutant Non-small-cell Lung Cancer (NSCLC), some of them can not respond well to its therapy. An overexpression of Interleukin (IL)-6 in tumor cells is postulated as a potential mechanism for such resistance or low sensitivity to EGFR-TKI in the preclinical models (PNAS 2010). Here, we evaluated clinically if tumor IL-6 level can be predictive for the effect of EGFR-TKI therapy.

Methods:
A total of 52 patients with advanced EGFR-mutation NSCLC who had received gefitinib were retrospectively assessed. The protein expression of IL-6 in the tumor cells was immunostained. Each specimen was assessed independently by 2 physicians (YK and TT) and 2 pathologists (KI and TT), and judged as positive if ≥ 50% of 100 tumor cells were stained positively (BJC 1999). Serum IL-6 level was measured by CLEIA in 11 (21%) of 52 patients.

Results:
Patients demographics were as follows: 24 men; median age, 66 yrs; PS 0-1, 48; stage IV, 22; Ad, 49; exon19, 29). Of these, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse PFS (75% v 92% at 6m; p < 0.05), which was retained in the multivariate analysis (HR: 2.38; 95%CI: 1.00-5.68; p=0.05) (Fig1). In contrast, PFS in the platinum-based chemotherapy did not differ in groups P and N (p=0.47). The serum IL-6 level ranged from 0.75 to 23.80 pg/ml (median: 2.90 pg/ml), which correlated neither to that in the tumor cells (regression coefficient: 1.69, p = 0.29) nor PFS in gefitinib therapy (p = 0.44). Figure 1 Figure 2





Conclusion:
Patients in group P benefited less from gefitinib therapy. This might suggest the inhibition of IL-6 expression can improve the low sensitivity to EGFR-TKI especially in EGFR-mutation tumors with high IL-6 expression.

Background:
Afatinib is an irreversible ErbB family blocker that inhibits EGFR with activating mutations as well as the T790M resistance mutations. In Non-Small Cell lung cancer (NSCLC), afatinib has been evaluated in the LUX-Lung trials, with improvement in progression-free survival (PFS) in patients with acquired resistance to prior EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. This study investigated efficacy, safety and dosage of afatinib under a Named Patient Use (NPU) program in a single institution.

Methods:
We analyzed 60 patients with stage IV NSCLC that had been treated with ≥ 1 platinum based chemotherapy, and with activating EGFR mutation or disease control for ≥ 6 months with prior EGFR-TKIs (gefitinib or erlotinib). The daily dose of afatinib was started with 50mg, which was decreased to 40mg and 30mg according to adverse events and tolerability of patients. Of 60 analyzed patients, 2 received afatinib as 3rd line treatment, 27 as 4th line, 19 as 5th line and 12 as ≥ 6th line. Activating EGFR mutations were detected in 11 (exon 19 deletion) and 7 (L858R) cases. No activating mutation was found in 19 cases, and EGFR status was not studied in 23 cases.

Results:
Thirteen patients achieved partial remission, 33 stable disease, and 12 progression, and 2 not-evaluable resulting in a response rate of 21.7% and a disease control rate of 76.7%. Median PFS was 5.2 months (95% CI, 4.1 to 6.4 months) and median OS was 13.4m (95% CI, 12.6 to 14.2) since the commencement of afatinib. Toxicities leading to drug discontinuation were experienced by 4 patients (6.7%). Grade 3 diarrhea occurred in 10 patients (16.7%), and dosage reductions of afatinib were required in 35 patients, to 40mg in 25 and to 30mg in 10 cases. Patients were grouped by final dosage of afatinib (50mg in 25 cases, 40/30mg in 35 cases). The PFS and OS were significantly longer for patients whose dosage of afatinib were reduced to 40 or 30 mg, compared to patients without dosage reduction (7.5 vs 3.1m and 18.0 vs 9.1m, respectively, p<0.05). Figure 1



Conclusion:
Afatinib showed PFS of 5.2 months and OS of 13.4 months in selected patients after failure of prior EGFR-TKIs. Aggressive dosage reduction should be considered in the course of treatment with afatinib.

Background:
The incidence of brain metastasis in EGFR mutant advanced non-small cell lung cancer (NSCLC) is higher than EGFR wild type at the time of diagnosis. Although cranial radiotherapy is considered standard treatment for brain metastasis, EGFR tyrosine kinase inhibitors (TKIs) alone have shown promising activity with up to 80% of response in EGFR mutant NSCLC patients with brain metastasis. However, the role of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs remains to be determined.

Methods:
Advanced NSCLC patients harboring EGFR mutation (exon 19 deletion or L858R) with brain metastasis who were treated with EGFR TKIs were retrospectively reviewed. To investigate the role of cranial radiotherapy, we analyzed the clinical outcomes between patients treated with EGFR TKIs alone and those treated with cranial radiotherapy (WBRT or SRS) followed by EGFR TKIs (combination therapy). The primary end point was overall survival (OS) and secondary end points included intracranial and extracranial progression free survival (PFS).

Results:
A total of 573 patients who identified EGFR mutation and received EGFR TKIs treatment for NSCLC with brain metastasis from Jan 2007 to Dec 2013 at Samsung Medical Center were enrolled for analysis. Of all 573 patients, 121 patients had brain metastasis in initial work up. There were 38 males and 83 female, a median age was 59.5 years (range 30 – 80). All 121 patients were received gefitinib (n=103) or erlotinib (n=18) as EGFR TKI treatment for 1[st] line chemotherapy. 74 patients were treated with combination therapy (34 patients were taken SRS, 28 patients WBRT, 12 patients both), and 47 patients were treated with EGFR TKI alone. In combination therapy group, 32 patients had brain metastasis related symptoms.The median OS was 38.7 months [95% Confidence Interval 35.0 to 42.5] in combination therapy group and 28.6 months [95% CI 24.3 to 32.8] in EGFR TKI alone group (p=0.295). There were no significant differences in intracrainal PFS (18.6 vs 19.7 months, p=0.343) and extracranial PFS (15.7 vs 15.3 months, p=0.574) between two groups.

Conclusion:
In this retrospective analysis, the combination therapy with cranial radiotherapy followed EGFR TKI did not improve OS and intracranial PFS compared with EGFR TKI alone therapy in EGFR mutant NSCLC patients with brain metastases. Further prospective studies are needed to refine the role of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs.

Background:
Elderly patients with lung cancer have been increasing. Of all cases of lung cancer 47% were 70 years or older and 14% were 80 years or older. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a key drug for patients with EGFR mutation positive advanced non-small cell lung cancer (NSCLC). Although treatment of gefitinib is known to have fewer myelosuppression and gastrointestinal adverse events than cytotoxic chemotherapy, treatment of gefitinib frequently has skin rash and liver dysfunction. Until now, there have been few reports of the efficacy and safety of gefitinib in elderly patients with advanced NSCLC. Therefore, the efficacy and safety of treatment of gefitinib in elderly patients with EGFR mutation positive advanced NSCLC have yet to be confirmed.

Methods:
We retrospectively assessed the efficacy and safety of gefitinib in 52 patients with EGFR mutation positive advanced NSCLC who were 70 years older and were treated with gefitinib. In addition, we compared the frequency and severity of adverse effects between patients 70 to 79 years and patients 80 years or older.

Results:
Of 52 patients, 35 (67%) were female and 13 (25%) were performance status of 2 or more, and the median age was 75 (range, 70-89 years). Fifteen patients (29%) were 80 years or older. All patients were adenocarcinoma. The type of EGFR mutation was as follows: 28 patients (54%) had exon 19 deletion, 23 (44%) had exon 21 L858R, and 1 (2%) had exon 18 G719A. The response rate was 73.1% (95% CI, 59.0% to 84.4%) and the disease control rate was 90.4% (95% CI, 79.0 to 96.8%). The median time to progression was 10.7 months (range, 0 to 36.2 months). The median survival time was 23.8 months (range, 0.2 to 65.6 months). The common adverse events were skin rash (52%), liver dysfunction (29%), diarrhea (25%), and interstitial lung disease (4%). Doses of gefitinib were reduced in 12 patients (23%) and discontinued in 11 patients (21%) due to toxicity, mainly skin rash and liver dysfunction. There were no differences in response rates, disease control rates, survivals, adverse events, and dose reduction rates between patients 70 to 79 years and patients 80 years or older.

Conclusion:
Treatment of gefitinib is highly effective for elderly patients with EGFR mutation positive advanced NSCLC, although dose reduction rates were more frequent in elderly patients than those in recently published trials in younger patients.

Background:
The incidence rate of leptomeningeal carcinomatosis (LC) has been increased in advanced non-small cell lung cancer (NSCLC) patients, especially with EGFR mutations. The purpose of this study was to evaluate the efficacy of icotinib for the control of LC in NSCLC with sensitive EGFR mutations.

Methods:
Twenty-one NSCLC patients with sensitive EGFR mutations and cytologically proven LC diagnoses between 2011 and 2014 at Zhejiang Cancer Hospital were retrospectively reviewed.

Results:
Ten patients had exon 21 point mutations and eleven patients had exon 19 deletional mutations. Sixteen of 21 patients received standard dose of icotinib (125 mg/day, three times a day) after LC diagnoses. The other five patients had already used icotinib and switched to double dose of icotinib (250 mg/day, three times a day) after LC occurrence. Eight patients received intrathecal chemotherapy, and nine of them were treated with combined whole-brain radiotherapy. Eighteen of 20 patients (90.0%) showed improvement of dizziness and headache. Seventeen of 21 patients (80.9%) had an improved Eastern Cooperative Oncology Group performance status (ECOG PS) score after icotinib treatment. The median overall survival was 10.1 months (95% CI: 8.4–12.0). Univariate analysis showed that the poor ECOG PS score (PS > 2), coexisting parenchymal brain metastasis, and the taken of icotinib were unfavorable prognostic factors for patient survival.The ECOG PS scare was an only independently predictor for survival in the multivariable analysis.

Conclusion:
This study suggested that icotinib had efficacy for the control of LC in NSCLC with sensitive EGFR mutations and was well tolerated. The Further prospective study is warranted.

Background:
Lung cancer is among the most common malignancies in Brazil. The use of tyrosine-kinase inhibitors (TKI) is nowadays a solidIy stablished treatment strategy for EGFR mutaion bearing NSCLC metastatic tumors. In this study we describe the clinical evolution of a cohort of 115 EGFR-mutant NSCLC patients from a single brazilian institution.

Methods:
We describe a retrospective cohort of 115 consecutive patients bearing metastatic EGFR mutated NSCLC, treated at A.C.. Camargo Cancer Center, Sao Paulo, from August/2010 to December/2014. Patients were older than 18y and had to have a histologically confirmed NSCLC dianosis. Clinical and pathological data was extracted from their eletronical medical charts. Chi-square statistics, or Fisher’s exact test when appropriate, was used to compare proportions among groups, Kaplan-Meier method was used for survival analysis and log-rank’s test was performed to compare survival curves.

Results:
Median age was 64y, 62% of patients were female, 94% had adenocarcinoma and 22% were smokers/former smokers. Data about treatment and survival was available for 85/115 patients. Eighty eight percent (75/85) of them were metastatic at diagnosis, of whom 52% (39/75) received a TKI in first line, 24% (18/75) in second line, 5% (4/75) in third/later lines and 16% were never treated with a TKI. Median progression free survival (PFS) was 13.9 months (m) for first line TKI and 11.4m for TKI treatment in second line (p=0.028). Median PFS for first line platin-based chemotherapy was 9.6m as compared to 3.1m for platin-based chemotherapy in second line (p=0.001). PFS with TKI treatment was numerically superior but not statistically significant for patients bearing tumors with exon 19 deletions as compared to L858R mutantions (22.9m vs 13.4m, respectively; p=0.42). There was no difference in overal survival (OS) between patients treated with TKI in first or second line. Median OS for patients receiving first line TKI was 36.3m and was not reached for patients that received TKI in second line (p=0.61).

Conclusion:
OS survival was not different for patients bearing EGFR mutated NSCLC tumors treated in first or second line, despite a longer PFS for TKI given as first line therapy.

Background:
Alectinib, a next generation ALK inhibitor, was granted approval in Japan 2014, since it showed good efficacy and tolerability in ALK+ NSCLC patients without previous ALK inhibitor treatment in Phase I/II study (AF-001JP). We also reported its promising response and good tolerability for crizotinib pre-treated patients in JP28927 study (ESMO 2014). This report describes the update of efficacy and safety result in JP28927 study.

Methods:
Patients (with/without prior ALK inhibitor treatment) who had ALK+ NSCLC were enrolled in JP28927. Patients received alectinib (300mg) twice daily; treatment was continued until the investigator determined lack of clinical benefit.

Results:
Thirty-five patients were enrolled into JP28927 study. Median follow-up duration was 400 days (35-457 days). The median progression free survival (PFS) of 35 patients was 13.9 months (95%CI: 11.1- NR). Among 30 patients with the target lesions at base line, the overall response rate (ORR) was 70% (95%CI: 50.6-85.3) with rapid response (the median time to response was 1.2 months [95%CI: 1.1-2.1]). Twenty-three out of 35 patients had been confirmed the progressive disease with crizotinib treatment. Their median PFS was 12.9 months (95%CI: 3.9-NR). Twenty out of 23 patients had the target lesions at base line. ORR was 65% (95%CI: 40.8-84.6) and the median time to response was 1.2 months (95%CI: 1.1-1.3). The treatment-related adverse events (AEs) observed in more than 10% of the patients were constipation (31.4%), dysgeusia (25.7%), WBC count decreased (22.9%), neutrophil count decreased (22.9%), vomiting (14.3%), rash (14.3%), blood bilirubin increased (14.3%) and AST increase (14.3%). Treatment-related Grade 3 AEs, i.e. pulmonary thrombosis, lymphocyte count decrease, hypophosphatemia, were observed in 3 patients. No treatment-related Grade 4 or 5 AEs were observed.

Conclusion:
The updated results in JP28927 study once again endorsed our previous reports which had indicated alectinib’s promising response even for ALK+NSCLC patients who failed to crizotinib treatment.

Background:
Patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC) should have significant benefit of ALK inhibitor targeted therapy by crizotinib. Even if high frequency of response rate to this therapy is documented, wast majority of those tumors become resistent due to overgrow of secondary resistent mutations bearing tumour cells. Such resistence should be overcome with the help of an alternative second generation ALK inhibitors.

Methods:
We present our diagnostic and therapeutic single institution experience in patients having ALK-rearranged NSCLC, as examined by FISH. We also present two case reports of patients treated by a second generation ALK inhibitor (ceritinib) after failure of the initial crizotinib therapy.

Results:
Between January 2011 and January 2015, a total of 595 tumour tissue samples were prospectively analysed for a presence of ALK rearrangements. A conclusive FISH result was obtained from a subset of 483. ALK rearranement was found in 15 patients (3.1%). The group consisted of 9 males and 6 females, with a median age of 65. 13 of the tumours were adenocarcinomas, 2 adenosquamous carcinomas. 8 patients were nonsmokers, seven were smokers. Consequently, 6 patients were treated by crizotinib while the rest did show a rapidly progressing tumours. 3 of the 6 crisotinib patients had a documented benefit from the therapy lasting for 22, 15 and 6 months.Finally, after failure of crizotinib, 2 patients reached a second partial remission on ceritinib,lasting 9 and 6 months.

Conclusion:
Targeted therapy of ALK-positive tumours is capable to prolong survival of patients quite significantly. In crizotinib - resistent tumours, second generation ALK inhibitors (such as ceritinib in this case), maybring further benefits to patients.

Background:
Pulmonary adenocarcinomas may harbor driver mutations, that sensitize tumors to drugs that specifically target the genetic alteration. Metastasized NSCLC with an EML4-ALK translocation are sensitive to a range of tyrosine kinase inhibitors, of which crizotinib is most extensively studied. ALK-positive NSCLC was determined in a phase III trial with fluorescence in situ hybridisation (ALK FISH+). ALK immunohistochemistry (IHC) seems to run parallel with ALK FISH positivity. However discrepant cases occur, which include ALK IHC+ FISH-. The aim of this study is to collect cases with ALK IHC+ and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.

Methods:
A prospective multicenter investigator initiated research study was started in Europe. This study is supported by Pfizer. Cases diagnosed with ALK IHC+ lung cancer (5A4 or D5F3) treated with crizotinib are collected centrally. Slides are submitted centrally for validation of ALK IHC (with ETOP and Ventana protocol), ALK FISH (with Vysis probes) and DNA analysis.

Results:
The study started on April 1 2014 and is still open. Currently 10 centers are actively participating. 1443 cases have been examined with ALK IHC of which 39 (2.7%) recorded positive. 24 cases have been submitted to the database. The validation process is still ongoing. The fraction of ALK IHC+ FISH- cases is low. Two cases with ALK IHC+ FISH- metastastatic NSCLC responded to crizotinib treatment. In two cases ALK positivity could not be confirmed (ALK IHC- and ALK FISH-). These patients had progressive disease following crizotinib treatment.

Conclusion:
A clinically relevant question what the effect of ALK inhibitor treatment is on metastatic NSCLC ALK IHC+ FISH- compared to ALK IHC+ FISH+ is examined. Other centers with interested collaborating physicians are invited to participate.

Background:
Anaplastic lymphoma kinase (ALK) fusions are key oncogenic drivers in non-small cell lung cancer (NSCLC) that confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Despite this activity, ALK-positive patients ultimately develop resistance to ALK TKIs. In preclinical models, ALK fusion proteins are HSP90 clients and remain sensitive to HSP90 inhibition despite acquired resistance to ALK TKIs. We therefore designed a phase II trial of the HSP90 inhibitor AUY922 in patients with previously treated, ALK-positive NSCLC.

Methods:
In this single-arm, multicenter, open-label study, we enrolled patients with advanced, ALK-positive NSCLC who had failed at least one prior ALK inhibitor. Key eligibility criteria included ECOG PS 0-2, measurable disease based upon RECIST version 1.1, and presence of an ALK rearrangement by FISH. Participants were treated with AUY922 at a dose of 70 mg/m[2 ]IV once weekly until disease progression, unacceptable toxicity, or death. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Key secondary endpoints included safety, progression-free survival (PFS), and disease control rate (DCR). The planned sample size was 20 patients.

Results:
Between December 2012 and December 2014, 6 patients were enrolled. Median age was 52.5 years (range 42-54 years). A majority of patients (83%) were female. The median number of prior lines of therapy was 3 (range 2-4). All patients had previously received at least 1 ALK TKI (crizotinib n=5, alectinib n=1), and 2 patients had received a second ALK inhibitor (ceritinib n=2). Most patients (n=4) had received an ALK inhibitor as the last line of therapy prior to enrollment. Among the 6 patients enrolled, no objective responses were observed (ORR 0%). Three patients (50%) had a best response of stable disease (SD), but none remained on therapy beyond 3 months from the time of enrollment (Table). The median PFS was 1.43 months (95% CI 1.3-2.8 months). Common adverse events (AEs) included grade 1-2 diarrhea (83%), vision disorders (50%), fatigue (50%), and constipation (33%). The only treatment-related grade 3 AE was alkaline phosphatase elevation in 1 patient. The study was closed due to poor accrual in December 2012. Table 1

Patient	Best Response RECIST v1.1.	Progression-Free Survival (months)
1	-4.9%	2.80
2	36.5	0.73
3	5.1	1.03*
4	121.9	1.43
5	11	2.60
6	69.5	1.30
* Censored (Discontinued due to toxicity)

Conclusion:
Although limited by a small sample size and premature closure, this study suggests that AUY922 is associated with minimal anti-tumor activity in ALK-positive patients previously treated with ALK inhibitors. Combinations of ALK TKIs and HSP90 inhibitors may represent an alternative strategy, and several such studies are now ongoing.

Background:
The efficacy of pemetrexed-based first-line chemotherapy in ALK-positive NSCLC has been documented in several studies. More data for Chinese population are still needed.

Methods:
We retrospectively reviewed the chart of 34 patients with ALK-positive advanced NSCLC. All of them had received pemetrexed as the first-line chemotherapy in our hospital from May 2011 to October 2014. We analyzed the clinical characteristics and treatment outcomes of these patients.The primary end points were response rate and progression-free survival.

Results:
The median age was 52 years (range from 34 to 76) and 58.8% (20/34) of the patients were never smokers. All tumors were adenocarcinoma. There were two cases harboring ALK translocation and EGFR mutation. Pemetrexed combined with platinum was administered in the first-line setting and the median treatment cycle was 4.5. The median progression-free survival (PFS) of ALK-positive patients was 8.8 months (95%CI 7.397-10.213). At the time of analysis, 7 with PR (20.6%)，23 with SD (67.6%)，4 with PD (11.8%) and no CR achieved. The objective response rate was 20.6% (7/34)，and the disease control rate was 88.2% (30/34). Common adverse events with pemetrexed were neutropenia (52.9%)，nausea (58.8%)，transaminase elevation (29.4%) and fatigue (9.3%)，mainly in grade 1 or 2.

Conclusion:
Pemetrexed is efficient and well tolerated as first-line treatment for ALK-positive NSCLC in Chinese population. Thus, pemetrexed might provide an alternative option for the treatment of ALK-positive lung adenocarcinoma.

Background:
ALK translocations, occuring in 3-5% of patients with NSCLC (non-small cell lung cancer), has improved the treatment for these patients. We examined the clinical characteristics, diagnosis modalities and treatment outcomes of these ALK + NSCLC patients.

Methods:
Data from patients with adenocarcinoma and NSCLC/NOS (Not Otherwise Specified) whose tumors were routinely analyzed for EML4-ALK were reviewed. Patient characteristics including age, sex, race, smoking history, localization of biopsy, response to ALK inhibitors and presence/absence of brain metastasis were collected. All data were obtained from 4 hospitals in Austria with high expertise in the management of lung cancer from August 2011 till October 2014. EML4-ALK was identified by a two-step procedure. First an immunhistochemical staining was done with the Ventana anti ALK (D5F3), Opti View DAB IHC DetectionKit and Opti View Amplifikation Kit®. Further, all positive cases (weak to strong) were tested by ALK FISH (dual colour breakapart FISH/Abbott Vysis[®]).

Results:
1754 consecutive patients were tested for EML4-ALK mutation. EML4-ALK positive immunohistochemical staining was found in 226 patients (12.9 %). 37 of these patients (2.1 %) showed positive ALK FISH analysis. However 2 patients with strong immunohistochemical staining showed no rearrangement in FISH analysis. These 2 patients were also treated with an ALK Inhibitor and showed tumour shrinkage. From these EML4-ALK translocation positive 39 patients, 23 patients were women and 16 men. 24 patients (61%) were Never-Smoker, 9 were former smokers (23 %) and 6 smokers (15 %). Biopsies were taken in 24 patients from the primary tumor and in 8 patients from the lymph nodes; in 6 patients the analysis was performed by drainage of pleura effusions and in 1 patient by drainage of a pericardial effusion. 24 patients received an ALK inhibitor. 5 patients had a complete response, 18 patients a partial response, 0 patients a stable disease and 1 patient showed a progressive disease. 15 patients did not receive an ALK Inhibitor, because they were in an operable stage. Before therapy with an ALK inhibitor, 5 patients had initial brain metastasis and additional 8 patients developed brain metastasis during treatment.

Conclusion:
ALK rearrangements are observed in 2.2 % of Adenocarcinoma and NSCLC/NOS. It can be detected in all patients independent of any clinical characterization and/or smoking behavior. Therefore, reflex testing is recommended, since patients treated with an ALK inhibitor had a clear benefit from treatment.

Background:
To explore the dosimetry advantages, adverse reactions and efficacy of helical tomotherapy in the treatment of intracranial multiple brain metastases of lung cancer.

Methods:
Seven patients with intracranial multiple brain metastases from Feb., 2012 to May 2014 were treated with helical tomotherapy. Whole-brain radiotherapy: the clinical target volume (CTV) was 45 Gy/25 times and gross tumor volume (GTV) was 50～58 Gy/25 times, 5 times in a week.

Results:
Both the homogeneity and shape-adaptability of radiation in 7 patients were better. The response rate came up to 78%, and the adverse reactions could be tolerated.

Conclusion:
Helical tomotherapy in the treatment of intracranial multiple brain metastases of lung cancer has better dose distribution and short-term efficacy. It provides a new therapeutic platform for the treatment of multiple brain metastases of lung cancer.

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 a histology report. This happens in patients that consulted with a clinical presentation compatible with a pulmonary origin neoplasia and radiology reports concluding in thorax tumors, which had a lung dependency. But such patients had a very low performance status, because they did not assist to the second consult, they never started treatment, and finally because they died. Among these 178 patients 3 had other diagnoses, which initially were unclear: one had Gastric Cancer, the second had prostate carcinoma and the last one had breast cancer. Also, 12 Patients came with the diagnosis of Adenocarcinoma or Squamous cellular lung cancer, they only went to radiation treatment with us and the rest of the clinical treatment was taken in another clinic, or they died before treatment initiates, this group was called without following. There were 38 patients with adenocarcinoma. The proportion between Squamous Cellular and Adenocarcinoma was 1.7 patients with squamous cellular carcinoma for every patient with Adenocarcinoma. 28 patients were tested for the EGFR mutation analysis, from these, 5 had the EGFR mutation. The average age of the patients with adenocarcinoma was 64.2 years old. The median survival time found was 167.6 days and the calculation for confidence interval of 95% (CI~95%~ 67.3 to 267.9)

Conclusion:
Of the population evaluated, proportion of lung adenocarcinoma (ratio of tumors), is different than other reports of the world. Outcome is like patients with another tumors, because they consult to late, in advance stage of disease, then mortality is higher and shorter survival. Implementation in diagnosis of detection of epidermic growth factor receptor mutation (EGFR) in the institution has been of great value to reorient pharmacological treatment.​

Background:
Erlotinib is a low-molecular weight tyrosine kinase inhibitor (TKI) directed at epidermal growth factor receptor (EGFR), widely used in the treatment of locally-advanced or metastatic stage NSCLC. Although introduction of EGFR-TKIs have significantly extended survival of advanced-stage NSCLC patients, their efficacy in the entire patient population is relatively low, especially in Caucasians. Aside from activating EGFR gene mutations, no reliable biochemical or molecular predictors of response to erlotinib have been established. The aim of our retrospective study was to evaluate the association of baseline serum levels of C-reactive protein (CRP) with outcomes in patients with advanced-stage NSCLC treated with erlotinib.

Methods:
We retrospectively analysed clinical data of 595 patients with advanced-stage NSCLC (IIIB or IV) treated with erlotinib. Serum CRP was measured using immunoturbidimetric method.

Results:
Before the treatment initiation, high baseline levels of CRP (≥ 10 mg/l) were measured in 387 (65%) patients and normal levels (< 10 mg/l) were measured in 208 (35%) patients. The median PFS and OS for patients with high CRP was 1.8 and 7.7 compared to 2.8 and 14.4 months for patients with low CRP (p<0.001 and p<0.001). The multivariate Cox proportional hazards model revealed that CRP (HR=1.57, p<0.001), EGFR status (HR=2.22, p<0.001), stage (HR=1.31, p=0.013) and ECOG PS (HR=1.22, p=0.024) were significantly associated with PFS and also with OS (HR=1.63, p<0.001; HR= 1.97, p=0.011; HR=1.44; p=0.007 and HR=1.72, p<0.001, respectively).

Conclusion:
The results of the conducted retrospective study suggest that the baseline level of CRP was independently associated with PFS and also with OS. CRP is commonly used biomarker which is simple and easy to detect and thus it is feasible for the use in the routine clinical practice. 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:
Delay in patient management timelines in lung cancer may exceed recommended timeframes, potentially adversely impacting quality of life, curative resection rates, disease progression and survival. The aim of this study was to evaluate the contribution of health service variables to delay between referral (T0), diagnosis (T1) and treatment (T2) for lung cancer patients.

Methods:
Demographic, clinical and health service data from the Victorian Lung Cancer Registry (VLCR) was analysed to identify variables predictive of extended critical time intervals. Explanatory variables were included in multivariate models. Sub-group analysis of the magnitude of delay of each interval was also performed.

Results:
Among 1417 subjects, median T0-T1 interval was 15 days (IQR 5-38), T1-T2 was 12 days (IQR 0-34) and diagnosis to palliative care 19 days (IQR 5-48). Significant T0-T1 delay was associated with country of birth, whether English is the first language, treatment first received and health status at diagnosis (ECOG score). Significant T1-T2 delay was associated with country of birth, the type of hospital where treatment was provided, presence of major comorbidities and initial treatment type. Factors associated with T2-T3 delay included age at diagnosis, the type of hospital where treatment was provided, health status at diagnosis and initial treatment type. Multivariate analysis demonstrated that type of hospital, stage of disease at diagnosis, ethnicity and type of initial treatment were all associated with significant delay at various stages of the patient journey to initial treatment (T0, T1 and T2).

Conclusion:
Understanding factors associated with delay in patients with lung cancer receiving effective management is crucial to developing interventions to address gaps. This research has identified priority areas for action in Victoria

Background:
Patients with non-small cell lung cancer (NSCLC) with ipsilateral pleural dissemination previously treated without surgery. There are few reports about sucsessful surgical treatment of these patients. Using intrapleural hyperthermochemotherapy cans improve survival patients NSCLC with pleural dissemination. The aim of our research is increasing the efficiency of the treatment of these patients.

Methods:
From january 2006 to decemder 2012 in N.N. Alexandrov National Cancer Centre of Belarus twenty one patients with non-small cell lung cancer with ipsilateral pleural dissemination was included of the study under histological examination. All patients was shared in two groups: 1) control group – 10 patients was done chemotherapy (2-6 courses: cisplatin 75-90 mg/m[2] in 1 day, vinorelbine 30 mg/m[2] in 1 and 8 days); 2) study group – 11 patients was treated by multimodality care: pleuropneumonectomy, intrapleural hyperthermochemotherapy (IHTC) and adjuvant chemotherapy. The regimen of IHTC (ThermoChem HT-1000) was 42[0]C in 1 hour with cisplatin 120 mg/m[2] and vinorelbine 30 mg/m[2]. Adjuvant chemotherapy was done 4 courses: cisplatin 90 mg/m[2] in 1 day, and vinorelbine 30 mg/m[2] in 1 and 8 days.

Results:
4 patients was done intrapleural hyperthermochemotherapy before surgery, because of pleural dissemination was diagnosed by thoracoscopy. Radical surgery was done through 2-4 weeks after IHTC. The rest of patients intrapleural hyperthermochemotherapy was spent with surgery jointly, because pleural dissemination was seen and verified by thoracotomy. All patients of the control group was died during 24 months, while overall 3-years survival patients of the study group was 61.4±15.3% (p=0.05).

Conclusion:
Multimodality treatment is including: surgery, intrapleural hyperthermochemotherapy and adjuvant chemotherapy for non-small cell lung cancer with ipsilateral pleural dissemination, allowing to increase level of 3-years overall survival for patients from 0.0% till 61.4±15.3% (p<0.05) as compared with chemotherapy.

Background:
With the change of lung cancer epidemiology, the frequency of lung adenocarcinoma is steadily increasing. This histological subtype is often associated with brain metastasis, which negatively impact survival. Standard treatment for single-brain metastasis includes surgery, radiotherapy and platinum-based chemotherapy. However, this approach is often associated with acute and chronic toxicity and may negatively impact quality of life in these patients. We need simple prognosis factors to better determine which patients will benefit from this combined therapy.

Methods:
We performed a retrospective analysis of all lung cancer patients treated in the Oncology department of the Regional Oncology Institute, Iaşi, Romania between January 2012 and January 2014. Inclusion criteria: ECOG 1-2, stage IV lung adenocarcinoma with single-brain metastasis that underwent surgery and radiotherapy for the brain metastasis, followed by systemic treatment with a platinum-based regimen. Data were collected for each patient: age, sex, metastasis size and localization, neurological symptoms, the presence of other secondary lesions at diagnosis, concurrent illnesses, hemoglobin levels, white blood cells, platelets and lactate dehydrogenase (at the time of diagnosis). Data were analyzed by means of SPSS v.20 software - Cox regression. Continuous variables are expressed as mean±SE. Statistical significance was set at .05.

Results:
31 patients met the inclusion criteria. Mean age was 58.6±1.55 years. Overall survival (OS) was 266±28.32 days. Cox regression analysis indicated that a high white blood cell count, extra-cerebral metastatic sites, age and pre-existing illnesses negatively impact OS (p<0.05). In contrast, symptoms, localization and size of the brain metastasis, as well as hemoglobin, lactate dehydrogenase and platelets had no impact on OS in this analysis. Patients with a high white blood cell count (n=13) had an average OS of 168.3±35.3 days as compared with 336±33.2 days in patients with normal white blood cell count at diagnosis (n=18).

Conclusion:
As more and more aggressive therapeutic strategies emerge, we need simple and effective parameters that can predict survival in order to select the best approach for each individual patient. High white blood cell count, extra-cerebral metastatic sites, age and pre-existing illnesses were associated with decreased OS. A future prospective study is warranted to confirm our results.

Background:
Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet they are difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a new cancer treatment that utilizes the specificity of intravenously injected antibodies to target photosensitizers to specific cancers (Figure). Since one interesting property of the lung is that it transmits light better than any other organ, light therapy is a viable alternative therapy. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of disseminated pleural metastases in a non-small cell lung cancer (NSCLC) model.

Methods:
In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted within the intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. Body weight was measured as an index of systemic toxicity.

Results:
In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led to significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to a significant reduction in the volume of pleural metastases 1 day after PIT (p = 0.0180)(Figure). Fluorescence thoracoscopy confirmed this result (Figure). Body weight ratio showed no significant reduction in NIR-PIT treated mice. Figure 1



Conclusion:
NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC. We foresee NIR-PIT as an adjuvant to surgery with an initial conventional debulking procedure followed by NIR-PIT to “mop up” residual disease. Moreover, it would be feasible to deliver light via thoracoscopy, bronchoscopy or even during open-surgery. Thus, although this particular animal model is not typical of NSCLC, the feasibility of treating thoracic malignancies with light therapy is demonstrated. NIR-PIT is a promising therapy for disseminated pleural tumors.

Background:
Computed tomographic (CT) measurements of primary tumor and/or metastatic sites are commonly used for assessment of objective responses to chemotherapy by RECIST and/or WHO criteria. Decisions regarding continuation/stopping chemotherapy are often also based upon changes in clinical symptoms. There is paucity of published literature on symptom plus bronchoscopy based decision making in routine clinical practice. This study aimed to compare reliability of response evaluation of lung cancer patients undergoing chemotherapy by symptoms, chest radiograph (CXR) and fibreoptic bronchoscopy (FOB) based assessment with conventional CT based assessment.

Methods:
Prospective, non-interventional, comparative analysis study. Treatment naïve patients with lung cancer having atleast one evaluable lesion on FOB and planned for chemotherapy were enrolled over a 1-year period. All assessments were done at baseline and after 3[rd] cycle of chemotherapy. Six symptoms (dyspnea, cough, chest pain, hemoptysis, anorexia and weight loss) on visual analogue scale [VAS] were noted. Respiratory symptom burden (RSB) and Total symptom burden (TSB) were calculated from first four and all six symptoms respectively. CXR responses were assessed as per WHO criteria. Bronchoscopic findings were recorded in a proforma adapted and modified from European Respiratory Society (ERS) classification for tracheobronchial stenosis. Video-recording of all bronchoscopies was preserved for objective review. CT response as per RECIST 1.1 was taken as reference standard and agreements tested using Cohen’s kappa (k) statistic.

Results:
Of 87 patients enrolled, 53 completed ≥3 cycles and were included for final analysis. Mean age was 55 years, majority (81.1%) were males, had advanced/metastatic disease [stage IV 56.6%; IIIB 37.7%] and ECOG performance status of 0-1 (52.8%) or 2 (32.1%). Squamous cell carcinoma (50.9%) and small cell (35.8%) were the commonest histological types. Mean scores of all six individual symptoms, RSB and TSB showed statistically significant improvement after chemotherapy. Mean number as well as distribution of FOB lesions decreased significantly after chemotherapy. CXR response had poor agreement with both FOB based and CT based responses. Changes in RSB and TSB categories had no/minimal agreement with CT based responses. RECIST and WHO criteria had strong agreement (k=0.872) with each other for overall response assessment. Bronchoscopic assessment had minimal agreement with both RECIST (k=0.324) and WHO (k=0.349) criteria based assessment. For differentiating responders (CR+PR) from non-responders (SD+PD), FOB based assessment had weak agreement with both RECIST (k=0.462) and WHO (k=0.501) criteria based assessment. For differentiating disease control (CR+PR+SD) from disease progression (PD), WHO criteria based CT response had perfect agreement (k=1.000) while FOB based assessment had moderate agreement (k=0.629) in comparison to RECIST. Variable combinations of FOB based assessment with symptom based assessment and/or CXR response continued to show only moderate agreement (k=0.600-0.799) with CT based assessment for detecting PD.

Conclusion:
Majority of patients have symptomatic improvement after chemotherapy. However, changes in symptom scores and CXR responses correlate poorly with CT responses. CT scan based assessment by RECIST/WHO criteria remains the reference standard for objective evaluation of response to chemotherapy in lung cancer. Bronchoscopic progression may be used as a surrogate for disease progression if CT assessment is not feasible.

Background:
While most patients with non-small cell lung cancer (NSCLC) stage IV, presents an unfavorable prognosis, a small proportion presents median overall survival beyond 2 years. The aim of this study is to identify clinical factors associated with long-term survival (LTS) in patients metastatic NSCLC.

Methods:
Single-center, retrospective study performed from the selection of patients in electronic medical records with a diagnosis of NSCLC, metastatic at diagnosis, and treated at AC Camargo Cancer Center in Brazil, from January / 2007 to June / 2014. We compared the group of patients who survived more than two years, the long-term survivors (LTS), to that survived less than two years, the short-term survival (STS), regarding the clinical characteristics and treatments performed. Using the chi-square test (categorical variable), and T test (continuous variables), for univariate analysis and by binary logistic regression model for multivariate analyzes, adopting the significance level P < 0.05

Results:
From 292 patients with stage IV NSCLC, there were 46 (15.7%) patients who survived beyond 2 years, and the remaining 246 patients who survived less than two years, we selected a control group of 46 patients. In the LTS group, the median overall survival (OS) was 39.7 months, and five-year-survival was 10.8%, while in the control group median OS was 9.2 months. In the univariate analysis related to clinical factors, the LTS was associated with female gender (P: 0.03); not smoking (P: 0.013); ≤ 2 metastatic sites (P: 0.02); ECOG of 0-1 (P: 0.01); absence of extra-thoracic metastasis (P: 0.001); absence of liver metastasis (P: 0.004) absence of bone metastasis (P: 0.001); absence of weight loss (P: 0.03); absence of decreased appetite (P: 0.001); and the presence of activating mutation in the EGFR gene (0.024). In univariate analysis regarding factors related to treatment, the LTS was associated with: two or more systemic treatment lines (P: 0.001); partial or complete response in first-line chemotherapy (p = 0.0001); use of tyrosine-kinase inhibitor (p = 0.0001); and maintenance chemotherapy (P: 0.012). In multivariate analysis of clinical factors, were considered long predictors of survival: two or fewer metastatic sites (OR: 7.1; P: 0.008) and ECOG 0-1 (OR: 12.2 P: 0.024). There was a trend for female gender (OR: 3.1 P: 0.057).

Conclusion:
We conclude that, in our sample, patients with stage IV NSCLC who have ECOG 0-1 and oligometastatic disease (≤ 2 sites) are more likely to long-term survival.

Background:
The complexity of current treatment and management for patients with metastatic non-small cell lung cancer (NSCLC) continues to rise. The volume and pace of scientific advances make it challenging for the community practitioner to stay abreast of optimal patient care. Education is vital in disseminating critical information to practitioners and allows professional reflection of appropriate therapeutic decision making and peer discussion. Understanding the base knowledge, competence, and current practice patterns of practitioners is essential to identifying community needs and implementation of education that impacts patient care.

Methods:
From May through December 2014, educational outcomes assessments were gathered from 42 live independent continuing medical education (CME) activities held within community practices across the United States. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns. Assessments were repeated following the 1-hour CME certified activity. Long-term assessment was conducted electronically 6-weeks following the educational initiative.

Results:
The overall program educated 847 practitioners, including 477 physicians. Three patient scenarios were profiled during the activity: 1) non-squamous NSCLC, non-smoker, no targetable mutation, 2) non-squamous NSCLC, EGFR del19 mutation, and 3) non-squamous NSCLC, ALK rearranged. Participant responses at baseline indicated a need for further education about molecular testing, maintenance therapies, and front-line therapies. All three cases also addressed treatment options at disease progression following initial treatment. For all cases, education resulted in responses better aligned to current practice guidelines and clinical data. With respect to molecular testing there was a 28% increase in the number of participants who would recommend testing and a 17% increase in participants who would recommend sufficient biopsy specimen for testing prior to treatment. There was a large gap in knowledge about the need for a repeat biopsy after progression on EGFR TKI therapy to confirm the nature of the lesion and select the optimal targeted therapy. Education closed this gap with a 53% increase in respondents understanding this need. With respect to maintenance therapies in the different scenarios, there was 22% change in the use of pemetrexed for non-targeted NSCLC and 21% for radiotherapy after progression on crizotinib. Self-reported levels of competence to integrate biomarkers, clinical characteristics and tumor histology to provide an individualized treatment for patients increased after education. At 6-week follow-up the majority of participants reported that they were more likely to order molecular testing (80%), and were better able to select first-line (93%) and second-line therapies (93%). Participants also report increased familiarity with therapeutic options after education. Barriers to implementation included the newness of treatment data and lack of reimbursement.

Conclusion:
The results highlight baseline gaps in clinical practice. Several gaps are closed both in the short-term and the long-term through continuing education. Educational benefits appear to endure to the 6-week time point. Longer term follow-up would benefit CME educational providers and in turn drive more relevant activities that would benefit clinicians and ultimately, their patients.

Background:
Intrathoracic malignancies including lung, esophageal, and pulmonary metastases frequently recur locally or regionally after initial therapy. The existing literature on the safety and efficacy of multiple courses of thoracic irradiation is limited. The purpose of this study was to evaluate local regional control and toxicity in patients who received up to three courses of thoracic radiation.

Methods:
We conducted a retrospective review of 51 patients who had undergone at least two courses of thoracic radiation. Two patients were found to have only a previous course of whole breast irradiation and were thus excluded for a total of 49 patients. Patient age, diagnosis, courses and doses of radiation therapy, chemotherapy and surgery were extracted from the record. Time to recurrence was determined by time from last radiation treatment to pathological confirmation or radiographic progression. Six potential treatment related grade 4 or 5 toxicities were identified (5 deaths).

Results:
The median age at diagnosis was 64. Median follow up was 3 years (range 0.76-12). 43 of the patients were with primary lung malignancy, 2 with esophageal, 3 with metastases and 1 unknown. 49 patients received at least two courses of intrathoracic radiation, 5 received 3 courses. 38 patients had died at time of last follow up, 10 were alive and one lost to follow up. 46% had local-regional recurrence at time of last follow up while 24% were disease free. The median cumulative dose was 111Gy for all patients, 113 Gy in those with Grade 4 or higher toxicity (NS). Median survival after completion of the first radiation treatment was 3.2 years. Median survival after completion of the last course of radiation was 1.25 years versus 0.58 years for those without and with Grade 4-5 toxicity respectively. The median time between the first and last course of radiation was 1.7 years. Five of the six patients with severe toxicity were disease free at time of death or last follow up. Grade 5 toxicities included massive hemoptysis, tracheal erosion, cardiac arrest, and respiratory failure. Dosimetric evaluation of these patients is underway. 50% of patients with severe toxicity had previous or subsequent thoracic surgery versus 23% in those without. Median time from end of first treatment to end of last treatment was 634 days (range: 0.39 -7.5 years) versus 465 days (range: 0.6-2.3 years) for patients without and with Grade 4-5 toxicity, respectively. None of the 5 patients who received 3 courses of radiation exhibited severe toxicity.

Conclusion:
Repeat courses of thoracic irradiation appear to be generally safe and effective with a median survival of 1.26 years following the last radiation treatment with 10% Gr4-5 toxicity in this population with cancer specific mortality of 78%. Future studies will identify clinical and dosimetric parameters that predict for severe toxicity.

Background:
Approximately 30% of lung cancer patients develop central airway obstruction (CAO) increasing the risk of post-obstructive pneumonia and respiratory failure. Therapeutic interventional bronchoscopy including airway stenting (AS) can provide immediate and effective palliation to improve patient quality of life (QoL). Unfortunately, there is little data about the impact on OS or the risk of hospitalization in patients with CAO mandating stent placement versus patients with CAO lesions that did not require stent placement.

Methods:
Between 2011-2014, twenty five patients with advanced lung cancer were evaluated by the Interventional Pulmonary (IP) Service at the University of Cincinnati for endobronchial stent placement for CAO. We retrospectively reviewed the OS and the risk of hospitalization in patients with lung cancer with CAO mandating stent placements versus patients who did not have lesions requiring stent placement. Death was considered as the endpoint. Kaplan-Meier method was used to calculate median overall survival and 95% CI. Cox model was used to test the overall survival difference between the patients who need stent and patients who do not need stent adjusted for age and sex. Logistic regression was used to test the hospitalization rate difference between the patients who need stent and patients who do not need stent adjusted for age and sex. Data were analyzed using the SAS ® Version 9.4.

Results:
Between 2011-2014, twenty five patients with advanced lung cancer were evaluated by the Interventional Pulmonary (IP) Service at the University of Cincinnati for endobronchial stent placement for CAO. Eight patients did not require placement of a stent and 17 patients had obstructive lesions that required stenting. Age and gender did not have any impact on the risk of hospitalization or OS of both of these groups of patients. The eight patients whose lesions did not mandate stent placement had a significantly lower risk of hospitalization compared to the 17 patients with CAO requiring a stent (OR 15.9, 95%CI 1.2, 209.1; p =0.035). Patients with advanced NSCLC and CAO that required IP stent placement had a median OS of 424 days (95%CI, 119-606 days) compared to a median OS of 729 days (95%CI, 426-. days) for patients with CAO not requiring a stent. Even with a lower survival in patients with stent placement, their OS of 424 days was slightly longer than the reported one-year survival for patients with stage IV NSCLC suggestive of improved outcome of patients with advanced stage NSCLC supported by IP.

Conclusion:
Lung cancer patients with less severe CAO have a lower risk of hospitalization and have better OS compared to patients with CAO mandating stent placement; however, CAO patients with IP evaluation and management in addition, may have improved OS suggesting that IP consultation may offer both improvements in QoL and OS to patients with advanced NSCLC and CAO.

Background:
Next-generation sequencing (NGS) from tumor tissue is used to acquire comprehensive genomic information to aid clinical decision-making for cancer patients. In order to obtain sufficient tissue for tumor-based NGS, patients must often undergo repeat biopsies after diagnosis which are invasive, associated with risk and expense, and sometimes unsuccessful because of tumor size or location. Genomic information may also be obtained by analyzing cell-free DNA (cfDNA) from plasma samples, which affords the potential for NGS testing to a greater number of patients, and offers a wide variety of cancer diagnostic and surveillance applications. We sought to compare the results of tumor based-NGS with an analysis of circulating tumor cfDNA from matched plasma samples in patients with thoracic tumors (non-small cell lung cancer, small cell lung cancer and thymic malignancies) to determine concordance between the tests.

Methods:
We compared NGS results obtained from tumor tissue analyzed by Foundation One with plasma-based analysis of cfDNA using Guardant360, a 54-gene panel covering 80,000 base pairs with high sensitivity (75-85% in most solid tumors) and ultra-high specificity (>99.9999%). Guardant360 detects single nucleotide variants (SNVs), including synonymous alterations, variants of uncertain significance, and somatic point mutations, gene amplifications (CNVs), select insertions/deletions (indels) and genomic rearrangements. Because Foundation One is a 316-gene panel, concordance was defined based on the genes covered by both panels. Only patients with cancers originating in the chest were included.

Results:
Of 56 patients with Guardant360 testing performed between 6/2014 and 2/2015, 100% were successfully assayed. Eleven had matched NGS from tumor and concordance was noted in 5/11 (45%) of patients. TP53 and KRAS were commonly found in both tumor tissue and plasma cfDNA. A total of 34 patients (61%) with successful plasma-based cfDNA analysis were unable to undergo tissue-based NGS for various reasons; fourteen patients had tumor tissue sent for NGS analysis that was deemed “insufficient”, 16 had exhausted prior tumor biopsy specimen, and 4 patients were too ill to undergo a repeat biopsy. In 19 of these 34 cases where tissue NGS results were not available (56%), a genomic alternation was identified by plasma cfDNA analysis, which corresponded to targeted therapies available on clinical trials that otherwise would not have been known.

Conclusion:
Plasma-based NGS testing identified actionable genomic alternations in 23 of 56 (41%) patients tested. In most cases, this information was supplementary to that obtained from tumor-based NGS and partially concordant in matched cases. These findings support continued efforts to establish the value of cfDNA in those cases where repeat tissue biopsy is contraindicated or may pose undesirable risk of complications, or when tissue-biopsy based NGS is inadequate or uninformative.

Background:
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has an established role in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC). Icotinib is an EGFR-TKI with non-inferior efficacy but milder toxicities compared with gefitinib. Disease control for over 6 months suggests that the case is not primary resistant to the drug. The present study investigated the patient characteristics and treatment outcome of advanced non-squamous NSCLC with at least 6-month disease control from icotinib.

Methods:
Non-squamous NSCLC patients with disease control after 6-month icotinib treatment were enrolled and retrospectively analyzed. Clinical characteristics were collected from the medical records. Efficacy and outcome data were analyzed.

Results:
A total of 87 patients were enrolled onto this study in which 56 were female, 18 with brain metastasis, and 32 patients harbored known EGFR mutation. For the overall population, 42(48.3%) patients achieved partial response. Response rate were 65.6%（21/32）and 38.2%（21/55）in patients with EGFR mutation and those with unknown mutation status, respectively(P=0.014). Patients with brain metastasis appeared to have lower response rate (26.7% vs 56.9%, p=0.033).The median progression-free survival (PFS) after 6 months’ icotinib treatment was 9.7 months (95% CI 4.1-15.4 months) for the overall population, and 5.0 months (95% CI 0.6-3.9 months) and 12.9 months (95% CI 3.4-6.2 months) for those with and without brain metastasis, respectively. Median progression-free survival in patients with PR or SD showed no statistically significant difference (15.5 months vs 9.3 months, P=0.477).

Conclusion:
The present study provided evidence from a relatively large single institutional study of icotinib in clinical practice. Patients with disease control for over 6 months showed similar clinical features to those with EGFR mutation. Those patients will have prolonged clinical benefits with continuous icotinib therapy after 6 months, regardless of PR or SD. Brain metastasis is a potential unfavorable predictive factor for PFS for those patients

Background:
Cancer cachexia and sarcopenia are common in lung cancer, and are associated with poor outcomes. Several recent interventional trials in cancer cachexia in patients with lung cancer have endeavored to improve skeletal muscle mass (measured by skeletal muscle mass index – SMI - using DXA or CT) and to correlate changes with functional outcomes of benefit to the patient. While functional tests such as stair climb power and hand grip strength have been used, these measures are neither sufficiently sensitive in patients with cancer, nor do they evaluate outcomes demonstrated to be valuable to patients. Patient Reported Outcomes (PROs) such as EORTC, FACT and others, have been collected, but specific components useful to patients have not been identified as ones correlating highly with SMI. Recent large studies at baseline using the 3-Item Global Index (3IGI) of the Lung Cancer Symptoms Scale (LCSS) quality of life and functional measure found strong correlations predicting survival in non-small cell lung cancer (N = 602) and in mesothelioma (N = 444); thus the 3IGI appears to be a good factor for associating PROs with SMI changes (Symanowski ASCO 2014; Gralla ASCO 2014). Additionally, over 90% of patients with NSCLC have expressed that parameters such as activity level and quality of life (included in the 3IGI) are of great importance to them.

Methods:
The LCSS was measured every 3 weeks in patients with a minimum KPS = 60 who were receiving chemotherapy. Correlations of SMI changes with 3IGI scores were made at baseline (at the time of initiation of chemotherapy) and at a median of 14 weeks in patients with Stage IIIB or IV NSCLC. SMI was measured by CT (Slice-O-Matic software) at the L1 vertebral level. A change in SMI by ± 4% was considered a threshold change of importance.

Results:
We have analyzed 24 patients to date (50% female; medians: age 57, KPS 80%; baseline: BMI 24.3, SMI 59.9, with 38% of males < 55.4 SMI). 19 patients are evaluable at this time. 42% of patients had a change in SMI by ± 4%; of these 75% had either improvement or worsening of the 3IGI in the direction expected from the change in SMI (improved 3IGI with increased SMI; worsened 3IGI with decreased SMI). No clear relationship in SMI was observed with response to chemotherapy thus far in the analysis.

Conclusion:
These results suggest: 1) the 3IGI may be useful in identifying both positive and negative changes in SMI, when using a 4% threshold change; 2) while we continue to enlist patients in this study, a confirmatory larger evaluation should be conducted; and 3) no measure should be used in practice or clinical trials of cancer cachexia or sarcopenia unless it has demonstrated validity in patients with cancer.

Background:
Guidelines generally recommend entry into a clinical trial or best supportive care for patients with NSCLC who progress after second line chemotherapy. We sought to explore whether this strategy remains valid with newer drugs and regimens and to evaluate the benefit of additional treatment beyond second line in advanced NSCLC.

Methods:
A retrospective analysis of stage IV NSCLC patients treated at a tertiary teaching hospital from 2002-2012 was undertaken. Demographics, details of treatment and overall survival was recorded for each patient. Patients who originally received adjuvant therapy and no further treatment upon recurrence and those receiving first line treatment on a clinical trial with no further therapy were excluded from analysis. Statistical analyses was performed using SPSS software and calculated using log-rank testing.

Results:
409 cases of NSCLC were included in this analysis. 239 (58.4%) patients received second line chemotherapy, 102 (24.9%) received third line treatment, 36 (8.8%) received fourth line treatment and 11 patients (2.7%) received fifth line therapy. The addition of second line treatment was associated with a statistically significant improvement in overall survival, with median survival for patients received second line treatment of 18.7 vs 9.1 months (p<0.001) for patients not receiving second line treatment. The most commonly used second line regimens were single agent docetaxel, single agent pemetrexed, tyrosine kinase inhibitors or combined chemotherapy doublets and there was no significant difference in overall survival based on what regimen was used as second line therapy.. The addition of third line treatment also was associated with a statistically significant improvement in overall survival, with a median survival for patients receiving third line therapy of 26.1 vs 11.3 months (p<0.001) for patients not receiving third line treatment. The most common therapeutics regimens for third line treatment were single agent docetaxel, single agent pemetrexed, single agent gemcitabine, single agent vinorelbine, tyrosine kinase inhibitors or combined chemotherapy doublet, and there is no significant difference between these regimens regarding overall survival. The addition of fourth and fifth line treatment also resulted in statistically significant improvements in overall survival with median survival compared to patients not receiving this treatment of 32.7 vs 13 months (p<0.001) and 40.3 vs 13.4 months (p=0.003) respectively.

Conclusion:
Although the present analysis is limited by its retrospective nature, our data suggest that continuing treatment after progression in patients who previously responded to chemotherapy is appropriate and is likely to prolong survival, provided their performance status and functional reserve are adequate to tolerate further treatment. In addition, the sequence of chemotherapy regimens did not appear to have a major impact on survival. Analysis is ongoing.

Background:
Neutrophil count is associated with prognosis in some cancers. Direct cell-cell interactions between neutrophils and tumor cells enhance tumor growth in Non-small cell lung cancer (NSCLC). We planned to identify clinical and laboratory factors including neutrophil and lymphocyte counts that can be used to estimate the overall survival.

Methods:
We retrospectively reviewed 60 patients with advanced or recurrent NSCLC with adenocarcinoma histology diagnosed between 2009 and 2013. We performed univariate and multivariate stepwise Cox regression analyses to identify survival prognostic factors.

Results:
Median survival time was 18.0 months (95% CI; 13.8 – 22.2 months). Median age was 64.5 years old. Sixteen patients (26.7%) were current smoker, sixteen patients (26.6%) were past smokers and 28 patients (46.7%) were non-smokers. Forty three patients’ ECOG PS was 0 or 1 and remaining seventeen patients’ ECOG PS was 2. Number of metastatic sites was less than four in the forty four patients and remaining sixteen patients have more than four metastatic sites. In univariate analysis, seven factors were identified: Loss of appetite (HR, 0.344), brain metastasis (HR, 0.444), metastasis in other organs (HR, 2.886), WBC count (HR, 3), neutrophil count (HR, 2.322), lymphocyte count (HR, 0.431), neutrophil lymphocyte ratio (HR, 2.322). In multivariate analysis, two independent prognostic factors were identified: neutrophil count (HR, 2.418), lymphocyte count (HR, 0.414).

Conclusion:
Increase of neutrophil count and decrease of lymphocyte count can be used to predict survival in advanced or recurrent non-small cell lung cancer patients with adenocarcinoma histology.

Background:
Aging increases the incidence of lung cancer in octogenarians. In this population, only limited data about treatment strategies and results are available, as those patients are usually not eligible for clinical trials; meanwhile, previously reported cohorts mostly focused on early-stage tumors. Our objective was then to provide a global picture of the treatment strategies for lung cancer in octogenerians, and to parallel those with available standards.

Methods:
Retrospective observational study of all consecutive patients aged 80 or more, with pathologically-confirmed lung cancer, and diagnosed at the Hospices Civils de Lyon between January 2005 and April 2014.

Results:
337 patients were included, 298 (88%) with non-small cell lung cancer (NSCLC), and 39 (12%) with small-cell lung cancer. For NSCLC, tumor was stage I, II, III, and IV in 10%, 9%, 25% et 57% of cases, respectively. Overall survival was 8.4 months. Geriatric assessment had been done only for 11% of patients. Overall, a standard treatment strategy - i.e. based on available recommendations and guidelines - was conducted for 42% of patients, while 24% received non-standard treatment, and 34% best supportive care only. At multivariate analysis, favorable prognostic factors on overall survival were performance status 0-1 (p<0.001), stage I/II (p<0.001), adenocarcinoma histology (p=0.026), and a standard treatment strategy (p<0.001). In the setting of metastatic NSCLC, 35% of patients received chemotherapy, the most frequent regimen being carboplatine and paclitaxel.

Conclusion:
Octogenarians with lung cancer are eligible for antitumor treatment in nearly 70% of cases, consisting of standard, recommended therapy in about half of the cases. Our data provide a unique overview of the management of octogenarians with lung cancer, to foster future prospective studies dedicated to this subset of patients.

Background:
A prospective study in stage IV non-small cell lung cancer (NSCLC) patients was performed to assess the predictive value of early response of the primary tumor evaluated by [18F]FDG-PET/CT to bevacizumab containing combination therapy with or without nitroglycerin (NTG) patches as first line treatment. NTG is a vasodilator which is hypothesized to increase tumor blood flow thereby decrease hypoxia, and 1) leading to a decrease in [18F]FDG uptake, and 2) facilitating early response assessment using [18F]FDG to predict treatment outcome.

Methods:
In total, 223 patients were randomized between carboplatin-paclitaxel-bevacizumab (PCB) with or without NTG (day -2 to +3; NVALT12 trial, NCT01171170). 78 patients were available for image analysis having undergone an [18F]FDG-PET/CT scan prior to the first cycle of chemotherapy and a second (optional) [18F]FDG-PET/CT scan at day 1-2 after start of the second cycle. The primary gross tumor volume (GTV) was delineated on both PET/CT scans. On the [18F]FDG-PET scan, the maximum standardized uptake value (SUV), mean SUV, peak SUV and total lesion glycolysis (TLG defined as SUVmean*CTvolume) were calculated and correlated with progression-free survival (PFS) and overall survival (OS). Early response assessment was quantified using relative changes in [18F]FDG-PET uptake parameters of the GTV expressed as delta. The median of the parameter of interest was used as cut-off value for both study arms for analysis using cox regression. Furthermore response was assessed according to PERCIST and RECIST.

Results:

Hazard ratio os SUV parameters > versus < the median for PFS and OS

SUV parameter		median	PFS		OS
			HR (p-value)	95% CI	HR (p-value)	95% CI
Delta PCB+NTG (%)	SUVmax	40.4	1.026 (0.408)	0.966-1.090	1.006 (0.844)	0.945-1.071
	SUVmean	39.9	1.048 (0.127)	0.987-1.113	1.034 (0.279)	0.973-1.099
	SUVpeak	42.3	1.035 (0.258)	0.975-1.100	1.016 (0.615)	0.955-1.082
	TLG	64.5	1.064 (0.043)	1.002-1.131	1.039 (0.221)	0.977-1.106
Delta PCB (%)	SUVmax	53.2	1.027 (0.454)	0.957-1.103	1.009 (0.810)	0.939-1.084
	SUVmean	51.6	1.027 (0.465)	0.957-1.102	1.011 (0.766)	0.941-1.086
	SUVpeak	53.9	1.040 (0.281)	0.969-1.116	1.018 (0.623)	0.947-1.094
	TLG	75.9	0.994 (0.873)	0.927-1.066	0.998 (0.951)	0.928-1.072

1) On average no decrease in [18F]FDG-PET uptake was observed for the experimental NTG group. However, patients in the experimental group showed a significantly larger variation in most SUV parameters of the second PET/CT scan compared to control group without NTG. 2) In table 1 the hazard ratios are shown for the relative delta SUVmax, SUVmean, SUVpeak and TLG for both study arms. In the experimental group, patients with a small delta TLG (<64%) had a shorter PFS than patients with a larger change in TLG (HR:1.064; 95% CI 1.002-1.131; p=0.043). Response assessed by PERCIST and RECIST did not predict for a longer PFS or OS.

Conclusion:
Adding NTG did not result in a decrease in [18F]FDG-PET uptake compared to patients without NTG although NTG increased variability of the measured SUV parameters. Patients in the experimental NTG arm without an early response on [18F]FDG-PET/CT imaging had a worse PFS than patients with a response. For the group without NTG no difference was observed. Also, RECIST and PERCIST were not predictive.

Background:
Patients who had non-small cell lung cancer with brain metastasis at the initial diagnosis had poor prognosis and quality of life. We reviewed patients who had undergone lung resection and brain surgery. We also analyzed the characteristics of the patients and the factors affecting survival and recurrence.

Methods:
Between 2007 and 2012, 25 consecutive patients who had undergone lung resection and brain surgery because of non-small cell lung cancer with brain metastasis were retrospectively evaluated in a single-center. The non-small cell lung cancer subtype was adenocarcinoma in 23 patients, squamous cell carcinoma in 1 patient, and adenosquamous cell carcinoma in 1 patient. Twenty patients underwent Gamma Knife radiosurgery. Nodal stage was stage 0 in 9 patients, stage 1 in 9 patients, and stage 2 in 7 patients.

Results:
The median survival time after lung resection was 36.8 months. The 1-, 2-, and 3-year survival rates after lung resection were 95.8%, 79.2%, and 54.2%, respectively, and the 1-, 2-, and 3-year disease-free survival rates were 95.8%, 82.9%, and 64.2%, respectively. There were no local recurrences. Brain surgery methods did not affect disease-free survival (p=0.201) or overall survival (p=0.567). Nodal stage also did not affect disease-free survival (p=0.519) or overall survival (p=0.645).

Conclusion:
Even in cases of stage IV non-small cell lung cancer with brain metastasis, assertive lung resection and brain surgery bring improvements of survival and recurrence to patients. Brain surgery methods do not affect survival or recurrence. Therefore, Gamma Knife radiosurgery is a good choice for quality of life for patients.

Background:
Pleural metastasis is difficult to treat in malignancies, especially in lung cancer. Currently, the options of management of pleural metastasis include chemotherapy, operation with pleurectomy, or/and photodynamic therapy. Photodynamic therapy is a method utilizing photosensitizer to locate the site of tumor, and the tumor is exposed to the light after performing pleurectomy. Literature had reported successfully treatment of malignant mesothelioma by photodynamic therapy, a new approach for pleural malignancy dissemination. However, little was known about the result when in lung cancer.

Methods:
Between 2005 and 2015, we retrospectively reviewed the clinical characteristics, operative methods, and treatment outcomes of 25 patients with lung cancer with pleural seeding.

Results:
The mean patient age was 51.6 ± 10.7 years. There is no procedure-related mortality. Using Kaplan-Meier survival analysis, 3-year survival rate and 5-year survival rate was reached 71.8% and 59.3%, respectively. We compared the PDT lung cancer patients with those receiving chemotherapy or target therapy (n=51) and found that the PDT group had better survival than non-PDT patients (mean survival time: 42.8 versus 17.6 months; P=.041).

Conclusion:
With proper patient selection, photodynamic therapy of pleural dissemination in patients with lung cancer is feasible and associated with a good survival rate

Background:
Combination of weekly paclitaxel and bevacizumab showed synergistic effect, anti-tumor efficacy and a good toxicity profile in patients with non small cell lung cancer (NSCLC). We retrospectively reviewed safety and efficacy of this regimen in metastatic non-squamous NSCLC as fourth-line therapy or beyond.

Methods:
Thirty nine patients were included between November 2011 and December 2014; those were bevacizumab eligible and received weekly paclitaxel (80 mg/m[2], days 1, 8 and 15 every 21 days) plus bevacizumab (7.5 mg/kg at day 1) after three prior lines of chemotherapy. Efficacy was evaluated by CT-scan every 10 to 12 weeks and treatment was continued until progression or unacceptable toxicity. Main outcomes were overall response rate (ORR), progression free survival (PFS) and overall survival (OS).

Results:
Median age 61 (44-78), female 51.3%, never smokers 53.8%, ECOG >2 25.6% and more than four previous lines 53.8%. All patients were treated with a first-line platinum-based doublet with (38.5%) or without bevacizumab (61.5%) and all of them received docetaxel as second-line (ORR 33.4/SLP 4.6 months, CI95% 2-6.7). With weekly paclitaxel/bevacizumab the ORR was 36% and 28.2% achieved stable disease for at least 3 months. Median PFS was 5.8 months (CI95% 4.6-7.1) and OS was 18.0 months (CI95% 15.2-34.2). Grade 3-4 adverse events included neutropenia (10%), onycholysis (7.6%) and infection (5%). One patient died from a massive hemoptysis and prolonged responses were observed in two patients who had received bevacizumab as part of first-line chemotherapy and in another one who harbored an ALK rearrangement.

Conclusion:
In this retrospective series, our results suggest that weekly paclitaxel/bevacizumab had a good safety and efficacy profile in heavily pre-treated metastatic NSCLC.

Background:
In recent years, the number of NSCLC treatment options has increased. The majority of patients receiving first-line therapy (1L) for locally advanced or metastatic NSCLC progress; however, fewer than half receive subsequent treatment. This analysis investigated which factors might be predictive of patients receiving subsequent LOTs within a US community network.

Methods:
A retrospective data analysis was conducted using electronic health records in the US Oncology Network for adult patients with advanced NSCLC receiving second-line therapy from 3/1/10 to 12/31/12, with follow-up through 10/31/14. Patients receiving 1L tyrosine kinase inhibitors (EGFR/ALK+), with concurrent cancer diagnoses, or in a clinical trial were excluded. Data on monotherapy/combination treatments, LOT, staging, histology, ECOG performance status (PS), metastases, comorbidities, age, gender, geography and practice size were collected. Chi-square tests examined patient and disease factors related to the receipt of subsequent treatments (2L–3L and 3L–4L). Logistic regression was used to predict the likelihood of receiving a subsequent LOT in multivariate models. Overall survival (OS) was estimated from diagnosis and from the initiation of each LOT.

Results:
Of 2,122 patients receiving 2L treatment, 963 (45%) advanced to receive 3L and 319 (15%) advanced to receive ≥4L treatment. Median age at 2L was 67 years (range, 34–94); 58% were male. PS at 2L was available for 80% of patients; 8%, 68%, and 24% were PS 0, 1, or 2+, respectively. The histology breakdown was 54% non-squamous, 25% squamous, and 21% not-specified. In univariate analysis, significance (P<0.05) for receiving a 3L/4L+ therapy was found for age, PS, histology, and treatment type. Multivariate analysis results are presented (Table). Figure 1 Of patients receiving 2+ LOTs, median OS from advanced NSCLC diagnosis was 22 months (95% CI: 20, 23). Median OS from the start of 2L, 3L, and 4L was 8.9, 7.0, and 7.2 months, respectively. In 2L, median OS for patients who received a 3L compared to those who did not was 13.4 vs 5.0 months (P<0.0001); median OS in 3L for patients who received a 4L compared to those who did not was 12.9 vs 4.9 months (P<0.0001).



Conclusion:
Receiving subsequent LOTs is associated with improved OS in advanced NSCLC. Whether this represents the efficacy of therapeutic agents or an enrichment for patients capable of receiving additional therapy is unclear. Nonetheless, these data on patient and treatment predictive factors may assist in understanding how future treatments might allow more patients to advance to later LOTs.

Background:
There is currently no consensus regarding which chemotherapy regimen is best to administer with radiotherapy in patients with locally advanced non–small-cell lung cancer. Here, our aim was to compare the outcome of patients treated with either etoposide-cisplatin (EP) or docetaxel-cisplatin (DP) in this curative setting.

Methods:
The patients treated with concurrent radiotherapy with either EP or DP with from 2004 to 2012 were identified. Patients whose medical records and follow up information obtained in details were included to this retrospective study. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods.

Results:
A total of 105 patients were treated with concurrent chemoradiotherapy for locally advanced (IIB-IIIA-IIIB) non-small cell lung cancer in Istanbul University, Institute of Oncology between 2004 and 2012. Totally 50 patients (median age 54 yr; 32-70 yr) given concurrent EP and 55 patients (median age 55 yr; 37-73) given concurrent DP were enrolled to analyses. There was no statistically significant difference in baseline clinicopathological features including age, gender, performance status, and weight loss, histological subtype, primary lung side, clinical T, N and TNM stages between 2 groups. In univariate analysis, median overall survival of patients treated with EP was found to be higher than that of patients treated with DP (41 months versus 20 months, p= 0.003). Multivariate analysis further revealed survival advantage with EP as compared to DP (hazard ratio [HR], 0.46; 95% CI, 0.25 to 0.83) (p=0.009). Toxicity profile of 2 treatment groups were found to be similar except that pulmonary toxicity was higher in DP group compared to EP (grade 3-4: 0 versus 6%, p= 0.024).

Conclusion:
Concurrent chemoradiotherapy with EP may provide more favorable outcome than that of DP with acceptable safety profile.

Background:
Cisplatin combined with docetaxel is one of the stand treatment in advanced squamous cell carcinoma(ASQC) of the lung. Nedaplatin combined with docetaxel has demonstrated potent activity in ASQC in phase II study. But until now there is no randomized phase III study comparing these 2 chemotherapy regimens. The aim of this study was to evaluate and compare the efficacy and safety between the combination chemotherapy of nedaplatin or cisplatin plus docetaxel in patients with ASQC.

Methods:
This is a multicentre, open-label, randomized, phase III study in China (NCT02088515). Chemo-naive stage IIIB/IV squamous NSCLC with Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of nedaplatin (80 mg/m[2]) plus docetaxel(75 mg/m[2]) or cisplatin(75 mg/m[2]) plus docetaxel (75 mg/m[2]) . The primary endpoint was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate (ORR), disease control rate (DCR) and quality of life.

Results:
From December 2013 to January 2015, 117 patients were accrued: nedaplatin plus docetaxel (n = 57) and cisplatin plus docetaxel (n = 60). The objective response rates were 27% and 31% and the disease control rate were 78.92 % and 82.67% in nedaplatin and cisplatin groups, respectively. There is no significance difference in nausea / vomiting(21% vs 30%) , diarrhea(3% vs 5%), liver dysfunction(12% vs 15%), neutropenia(60% vs 65%), thrombocytopenia(10% vs 12%), anemia(8% vs 7%) between the 2 arms. The renal dysfunction incidence is higher in the cisplatin group(3% vs 0%). Although there is no 3/4 grade toxicities difference between 2 arms including nausea / vomiting(0% vs 0%) , diarrhea(0% vs 1%), liver dysfunction(0% vs 0%), renal dysfunction(0% vs 0%) , neutropenia(4% vs 3%), thrombocytopenia(0% vs 0%), anemia(0% vs 0%) . This is an interim analysis and we haven't got the data of survival and quality of life.

Conclusion:
There is no ORR difference between the group of nedaplatin plus docetaxel and cisplatin plus docetaxel. But the toxicity of nedaplatin regiment is less toxicities, especially in renal toxicity,as first-line treatment for patients with advanced squamous NSCLC

Background:
The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase Ⅲ trial. However, our phase Ⅱ trial (NCT01236716; CTONG1002), which compared the efficacy and safety of first-line nab-PC with gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung, only showed a marginally improved ORR caused by first-line nab-PC. Meanwhile, the matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) and caveolin-1 are potential biomarkers for advanced NSCLC patients receiving nab-PC. Therefore, we retrospectively aimed to explore their predictive and prognostic value using immunohistochemistry (IHC).

Methods:
From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w ) or GC (G, 1,250 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w). There were 110 patients evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) respectively. However, there were 72 patients with sufficient tissue for IHC of both SPARC and caveolin-1 proteins. Different cut-off values of IHC scoring systems were used to explore predictive and prognostic role of both biomarkers.

Results:
The last follow-up was on January 16, 2015. Considering treatment, when the maximum rank method was used for cut-off values, median progression-free survival (PFS) was 7.5 (95%CI: 2.4~12.6) months in higher SPARC-expression arm and 4.3 (95%CI: 2.2~6.3) months in lower SPARC-expression arm for patients treated with GC, HR=0.43 (95%CI: 0.19~0.94), p = 0.030; Median overall survival (OS) was 20.0 (95%CI: 14.7~25.3) months in lower SPARC-expression arm and 10.1 (95%CI: 6.2~14.0) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.41 (95%CI: 1.08~5.40), p = 0.027. When average method was used for cut-off values, median OS was 18.2 (95%CI: 9.6~26.8) months in lower SPARC-expression arm and 8.4 (95%CI: 5.1~11.7) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.46 (95%CI: 1.07~5.65), p = 0.029. Regardless of treatment, when the maximum rank method was used for cut-off values, median OS was 14.5 (95%CI: 6.8~22.1) months in lower SPARC-expression arm and 8.4 (95%CI: 5.3~11.5) months in higher SPARC-expression arm, HR=0.47 (95%CI: 0.27~0.83), p = 0.007. When average method was used for cut-off values, median OS was 14.4 (95%CI: 9.2~19.5) months in lower SPARC-expression arm and 8.4 (95%CI: 5.4~11.4) months in higher SPARC-expression arm, HR=0.48 (95%CI: 0.27~0.87), p = 0.013. ORR was not correlated with expression of SPARC, p＞0.05. However, there were no significant differences in ORR, PFS and OS between higher and lower caveolin-1 expression arms, p＞0.05.

Conclusion:
SPARC expression could be a negative prognostic factor for OS of patients with advanced squamous cell carcinoma of the lung, but was not a predictive factor for ORR and PFS, except for patients treated with GC. However, caveolin-1 expression had neither predictive nor prognostic value.

Background:
We assessed whether BRCA1 and RRM1 message RNA(mRNA) levels could help to select chemotherapy regimen to improve objective response rate in patients with advanced NSCLC.

Methods:
Eligible patients were randomly assigned 2:1 according to stratification factors of smoking, gender and histological type. In experimental arm, gemcitabine/cisplatin(GP) were selected if both RRM1 and ERCC1 mRNA levels were low, irinotecan/cisplatin(IP) if RRM1 high and BRCA1 low, gemcitabine/vinorelbine(GN) if RRM1 low and BRCA1 high, and docetaxel(T) if both high. GP was chose in the control arm. The primary end point was objective response rate (ORR). (Registered No. NCT01424709).

Results:
121 patients were enrolled and 120 received at least one dose of therapy. The median number of cycles given was four in both arms. In experimental arm, 36 patients treated with GP, 14 with IP, 13 with GN and 17 with T. The ORR and DCR were 33.3% and 79.5% in the experimental arm, which were not significant different from 32.5% (p=0.12) and 87.5%(p=0.18) in the control arm. When patients with both low mRNA levels of RRM1 and ERCC1 were removed, the sub-analysis showed the ORR in the experimental arm was marginally significantly higher than in the control arm (42% vs. 36.3%, p=0.06)). Survival analysis showed similar PFS in the two arms (5.1 vs. 5.3m, p=0.11), while sub-analysis revealed that PFS was marginally significantly longer in the experimental arm (5.7 vs. 5.3m p=0.09). No unexpected side effect happened in both arms.

Conclusion:
BRCA1 and RRM1 mRNA levels were potentially used for therapeutic decision making in newly diagnosed patients with advanced NSCLC.

Background:
It is known that the addition of endostar (recombinant human endostatin, a novel broad-spectrum inhibitor of tumor angiogenesis) to chemotherapy resulted in a significant effective benefit in the treatment of patients with advanced non–small cell lung cancer (NSCLC). Previous research showed that multicycle application of angiogenetic drug combined with chemotherapy might prolong overall survival of NSCLC. However, the optimal treatment duration of endostar and chemotherapy remains uncertain.

Methods:
A retrospective analysis of ≥ 4 cycles versus < 4 cycles of endostar combined with platinum-based doublet chemotherapy(PBDC) was performed in patients with advanced NSCLC. For efficacy assessments, patients received ≥ 4 cycles of therapy (extended group) were compared with those who received less than 4 cycles but not because of tumor progression (control group). Toxicity analyses were performed for all patients.

Results:
A total of 232 patients were enrolled, of whom 128 patients completed at least four cycles of the therapy (extended group), 64 patients ceased their therapy before 4 cycles not because of progression(control group). The median progress free survival(PFS) was 8.2 months versus 5.4 months in extended group and control group (p=0.027), and the median overall survival(OS) was 22.5 months versus 13.6 months (p=0.000), respectively. Subgroup analysis showed that, among the EGFR mutation-positive patients, the control group seemed to result in a trend toward survival benefit according to the Kaplan-Meier curves, although the differences are not statistically significant. Hematological toxicity and fatigue occurred more frequently in patients received 4 or more cycles (p﹤0.05), but no statistically significant difference was detected in all grade ≥3 adverse events. Figure 1Figure 2





Conclusion:
Extended treatment of endostar combined with chemotherapy exhibited increased survival and acceptable toxicity in previously untreated patients with NSCLC, supporting further evaluation in larger prospective studies.

Background:
3rd line treatment options are limited for patient (pts) with metastatic NSCLC. NKTR-102 is a long-acting topoisomerase-I inhibitor designed to concentrate in tumors and provide continuous exposure throughout the chemotherapy cycle. Based on clinical activity of irinotecan in NSCLC, we conducted a Phase II single arm trial to evaluate efficacy of NKTR-102.

Methods:
Pts >18 yrs with histologically proven NSCLC who received 2 prior systemic therapy regimens were eligible. Measurable disease, ECOG PS ≤1 and adequate end organ function were required. NKTR-102, 145mg/m2 was administered IV q3 weeks till progression. Response was assessed q6 weeks by RECIST 1.1. Primary endpoint was overall response rate. Secondary endpoints were progression free survival (PFS), overall survival (OS) and safety. Simon two-stage design was implemented; if 0/12 responses were observed in the 1st stage, the study would be terminated for futility. If there was at least 1 objective response in the 1st stage, the study would continue to stage 2, enrolling an additional 25 pts, for a total of 37.

Results:
Between 01/2013 and 01/2015, 37 pts have been enrolled. Median age 63 yrs (18-82), 45% female, ECOG PS 0=8 pts, 92% current/former smokers, 9 pts with squamous cell, 28 had adenocarcinoma. Median time from diagnosis to initiation of NKTR-102 was 18 mos (6-72). Pts received a median of 3 cycles (1-13). All pts were evaluable for response rate and toxicity. One pt in Stage I (adenocarcinoma) had a partial response. Fifteen pts had stable disease, 7 pts are still on treatment. 3 pts had Grade 3 GI toxicity attributable to NKTR-102. 6 pts required a dose reduction to 120 mg/m2 due to diarrhea. There was no hematological toxicity. Median PFS was 2.3 mos. For pts with >1 yr follow up (n=20), median OS was 5.5 mos. Complete PFS and OS data will be presented.

Conclusion:
NKTR-102 is well tolerated and leads to stabilization of disease in third line treatment of metastatic NSCLC. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent. Clinical trial information: NCT01773109.

Background:
The standard treatment for elderly patients in advanced NS-NSCLC is not defined. The aim of this study was to evaluate the efficacy and safety profile of the combination of carboplatin and pemetrexed in this population.

Methods:
Elegibility criteria included, histologically or citologically confirmed NS-NSCLC clinical stage IIIB vs IV, evaluable disease, no prior cytotoxic chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, an adequate organ function and ³ 70 years old. Patients received carboplatin at an area under the concentration time curve (AUC) of 5 and pemetrexed 500 mg/m2 for four cycles on day 1 every 3 weeks. In non-progressing patients, maintenance therapy with pemetrexed every 3 weeks was optional to continue at the discretion of the investigator, until either disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secundary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and the rates of adverse events.

Results:
A total of thirty-six patients were included in a phase II clinical trial from 6 different centers. The patients demographics were: median age 76 years (range 70-82), 8 female and 28 male; 33 patients adenocarcinoma and 3 large-cell lung carcinoma; tumor EGFR status wild type in all patients. 51% went to manteinance. Among 32 patients evaluated, the RR was 31,3%, disease stabilization 31,3%, disease progression 28,1% and non-evaluable 9,3%. The DCR was 62.5%. In non-manteinance group the PFS was 4.1 months and OS 8.6 months. In the manteinance group instead, the PFS was 9.5 months and OS 11.9 months. Most common attributable adverse events were fatigue and anemia. Each of the toxicities were controllable and there were no treatment-related deaths.

Conclusion:
These data provided that Carboplatin and pemetrexed combination is effective and well tolerated in elderly patients with advanced NS-NSCLC

Background:
Recent IFCT-0501 trial demonstrated that carboplatin (CBDCA) combined with weekly paclitaxel (PTX) would be advantageous compared with monotherapy. Subsequently, CA031 trial suggested that weekly nab-paclitaxel (nab-PTX) was superior in efficacy and safety compared with 3-weekly PTX when combined with CBDCA. Since the subgroup analysis for elderly patients (pts) in CA031 showed very promising data (34% of overall response rate (ORR) and 8.0 months of progression-free survival (PFS)), we conducted this multicenter, non-randomized, open label, phase II trial to evaluate the efficacy and tolerability of CBDCA plus weekly nab-PTX regimen for elderly patients with advanced non-small cell lung cancer (NSCLC) prospectively.

Methods:
Eligible pts were aged 75 years or older with newly diagnosed clinical stage IIIB, IV, and postoperative recurrence NSCLC; ECOG performance status (PS) of 0-1; adequate organ function; written informed consent. Pts received CBDCA (AUC 6) on day 1 and nab-PTX (75mg/m[2]) on day1, 8, and 15, every 4 weeks. The primary endpoint was ORR and secondary endpoints were PFS, overall survival (OS), and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 32 pts were required.

Results:
Between March 2013 and May 2014, 35 pts were enrolled and 32 pts were eligible. Median age was 78 years (range, 75-86), 84% (27/32) were male and 56% (18/32) were stage IV. 56% (18/32) had squamous cell carcinoma and 44% (14/32) had adenocarcinoma. Median treatment cycle was 4 (range, 1-6). ORR and DCR were 50% (95%CI: 33-67) and 94% (95%CI: 85-100), respectively. With a median follow-up of 9.1 months, median PFS was 6.4 months (95%CI: 4.8-8.0). Median OS had not been reached at the data cutoff point. Grade 3 or severer toxicities were as follows: neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). No febrile neutropenia and treatment-related deaths were observed.

Conclusion:
The combination of CBDCA and weekly nab-PTX demonstrated significant efficacy with acceptable toxicities in elderly patients with advanced NSCLC.

Background:
Plinabulin (N), a tubulin binding agent, which depolarizes microtubules, resulting in tumor vasculature obliteration, apoptosis via JNK pathway and maturation of dendritic cells. A multicenter randomized phase 2 study was performed to compare overall survival (OS) between plinabulin/docetaxel (DN) and docetaxel (D). Results of Intent-to-treat (ITT) analyses have been presented at ASCO 2014. The primary objective of OS prolongation was not met, however, exploratory mechanism based analysis revealed improvement in outcomes in patients with large tumors.

Methods:
From November 2008 to July 2011 172 patients with advanced NSCLC who progressed after at least one chemotherapy were enrolled. Patients were treated with D 75mg/m[2] on day 1 and N 30 mg/[2] on days 1 and 8. A second cohort of N 20 mg/m[2] was also enrolled. This exploratory analysis is based on 105 patients (50 DN arm and 55 D arm) receiving 30 mg/m[2] dose, which was selected for an ongoing Phase 3 study and explains the population chosen for future investigation.

Results:
Median OS was 8.7 months (m) (CI 6.6-12.6) in DN arm and 7.5 m (6.3-10.5) in D arm (p=0.899, HR=0.97). PFS was 2.8 m and 3.5 m and ORR was 14.0% vs 14.5% respectively. Among clinical parameters, lesion size (Table 1) and presence of pulmonary disease were identified to impact OS. The OS in patients with pulmonary disease was 11.3 m (6.7-15.1) in DN and 6.7 m (6-9.8) in D, respectively (p=0.29, HR=0.76) regardless of lesion size. Table 1: Exploratory Analysis of Overall Survival by Tumor Size

Patients	Tumor size	Median OS Months (95% CI)	Hazard Ratio	P-value
DN (30mg/m[2])	D
ITT 1 and 2 prior chemo-therapy	All	8.68 (6.33, 12.63) N=50	7.47 (6.17, 10.60) N=55	0.972	0.8993
≤ 3 cm	6.45 (3.73, NA) N=16	6.47 (5.6, 22.43) N=19	0.934	0.8687
> 3 cm	8.98 (6.60, 12.63) N=34	7.47 (4.77, 11.60) N=36	0.967	0.8990
> 5 cm	8.98 (4.57, 19.23) N= 20	6.70 (4.07, 12.93) N=21	0.750	0.4176
> 7 cm	7.32 (4.57, 19.23) N= 8	5.03 (2.93, 6.70) N= 10	0.507	0.1936

CI = confidence interval; D = docetaxel; DN, docetaxel + plinabulin; ITT = intent-to-treat; OS = overall survival (Months).

Conclusion:
Mechanism-based exploratory analyses of Phase 2 results have identified advanced NSCLC patients with lung lesion size >3 cm to have benefited from plinabulin. A Phase 3 to confirm this observation is on-going.

Background:
Chemotherapy dose modifications may impact clinical outcomes in patients with cancer. In a phase III trial, first-line treatment of patients with advanced NSCLC 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; 33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). This exploratory analysis examined the correlation between patients receiving protocol-specified dose modifications and clinical outcomes in the phase III trial.

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, both in combination with C AUC 6 on day 1, every 21 days (randomized 1:1). 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. Patients who discontinued treatment before cycle 3 or remained on treatment after 6 months were excluded from this analysis unless otherwise specified.

Results:
Dose modification and clinical outcomes for patients treated for ≥ 3 cycles but ≤ 6 months are shown in the Table. In the nab-P/C arm, 268 of 310 patients (86%) who were treated for ≥ 3 cycles and ≤ 6 months had a dose modification compared with 200 of 319 (63%) in the sb-P/C arm. In the nab-P/C cohort, ORR and PFS were significantly higher in patients who received a dose modification vs those who did not (Table), possibly due to better tolerability and longer treatment duration. In the sb-P/C arm, there were no differences in efficacy outcomes between either group. As predicted, patients with a lower numerical incidence of toxicity were those that did not require dose modifications.

Conclusion:
This exploratory analysis suggested that, in this patient subset, protocol-specified dose modifications did not negatively impact the primary endpoint of ORR and in fact resulted in a greater ORR for those receiving nab-P/C. Figure 1

Background:
In a phase III trial, weekly nab-paclitaxel (nab-P) plus carboplatin demonstrated a significantly higher response rate than paclitaxel (P) plus carboplatin every 3 weeks, with less grade ≥ 3 neuropathy, neutropenia, arthralgia, and myalgia but more thrombocytopenia and anemia in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062). We hypothesized that these differences might lead to differences in the cumulative dose received and regimen duration in clinical practice.

Methods:
Fully de-identified electronic medical records (EMRs) from October 1, 2012, to September 30, 2014, from a national EMR (OncoEMR; Altos Solutions, Inc) were analyzed. Patients receiving first-line therapy with P every week (P7), P every 3 weeks (P21), or nab-P every week for stage IV NSCLC were identified. The majority of patients also received carboplatin. The total cumulative dose (mg/m[2]), treatment duration, and database persistence (a surrogate for overall survival) for the taxane regimens were determined. Regression and Cox proportional hazards models were used to assess the 3 groups, with the inclusion of age, sex, race, platin use, bevacizumab use, histology, prior adjuvant taxane use, and comorbidities (a total of 11 degrees of freedom) to control for the potentially confounding effects of these variables.

Results:
A total of 475 patients had complete data. 208 patients with NSCLC received P7, 153 received P21, and 114 received nab-P. The total cumulative dose was significantly greater for nab-P (932 mg vs 487 mg for P7 and 695 mg for P21; P < 0.001 for both). The median treatment duration was 104.5 days for nab-P, 69.5 days for P7, and 84.0 days for P21 (P < 0.05 for both). The median database persistence after taxane initiation was significantly longer for nab-P (378 days vs 214 days for P7 and 196 days for P21; P < 0.001 for both).

Conclusion:
Patients with NSCLC treated with nab-P had a longer treatment duration, received a greater cumulative dose, and had longer database persistence than patients treated with P7 or P21.

Background:
Proteomic (VeriStrat®) serum test has prognostic and predictive value in response to erlotinib; but the relation between comorbidity index and test performance and usefulness of this test in different races has not been adequately studied yet.

Methods:
Patients and Methods: We have reviewed electronic records of lung cancer patients from 09/2009 till 07/2014who had proteomic test performed to help with therapy choice. Extracted data was analyzed for survival using SAS software 9.4.

Results:
Among 49 qualified patients, 31 had VeriStrat® test done before and 18 after the first line treatment for metastatic disease. Nineteen cases with good VeriStrat® (VSG) test received erlotinib, and 12 received chemotherapy; 4 cases with VeriStrat® poor (VSP) results received erlotinib and 12 received chemotherapy. When stratified for test results “VSG vs. VSP” overall survival did not differ between white race and other races (HR=1.005; 95%CI=0.43-2.35; p=0.99). There was a trend of better survival for combined effect of VeriStrat® good test (VSG) and African American (AA) race. Patients with VSG test had better survival than patients with VSP test in each Charlson comorbidity index (CCI) stratum.

Conclusion:
Our study shows that there is no significant impact of race on prognostic and predictive values of VeriStrat® test. Prognostic value of this test is independent of comorbidities and older age.

Background:
Poor prognosis of advanced non-small-cell lung cancer (NSCLC) patients and the promising therapeutic effect of platinum urge the oncologists to evaluate the role of platinum-doublet as second-line chemotherapy and establish the definition of platinum sensitivity in NSCLC.

Methods:
We retrospectively analyzed 364 advanced NSCLC patients who received platinum-doublet regimens as second-line chemotherapy after platinum-based first-line treatment. Patients were divided into four groups by their time-to-progression (TTP) after first-line chemotherapy: 0-3, 4-6, 7-12, and >12months group, respectively. Treatment efficacy of patients’ overall survival (OS), progression-free survival (PFS) and response rate (RR), as well as treatment-related toxicity, were compared among the four groups. A prognosis score system was established by Cox proportional hazard model.

Results:
All patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. As part of the platinum-doublet regimen,145(39.8%) patients received taxol, 81(22.3%) received gemcitabine, 99(27.2%) received pemetrexed, 32(8.8%) received vinorelbine, 4(1.1%) received etoposide, and 3(0.8%) received irinotecan. The most frequent grade 3/4 toxicity was neutropenia (20.1%) and nausea/vomiting (3.3%).The median follow-up time was 11.0 months. Patients with TTP> 12 months had significant longer survival than the rest of the group after second-line platinum-rechallenge (HR, 0.809; 95% CI: 0.703-0.931;P=0.003).Prognostic score (TAF score) was calculated by adding 1 point each for any of the following: TTP>12 months, age≤60 years, and female, all of which were independent prognostic factors for patient survival (P=0.015, P=0.002, P=0.012, respectively). Median OS were equal to 25.0, 16.0 and 11.0 months for best (2-3 points), intermediate (1 point) and worst (0 point) category, respectively (P<0.0001, Figure 1). Figure 1 Kaplan–Meier curves of overall survival according to patients’ TAF Score. After second-line platinum-based chemotherapy, patients with a TAF Score of 2-3 had significant better survival than those scored 0 or 1 (P<0.0001). Figure 1



Conclusion:
A TAF score of 2 or 3 points indicates a good prognosis if advanced NSCLC patients received platinum-rechallenge after disease progression.

Background:
Different prognostic variables have been proposed in non-small cell lung cancer (NSCLC). The present study aims to evaluate the prognostic value of patients’ gender in Saudi patients with advanced non-squamous NSCLC.

Methods:
In this retrospective study, patients with stage IIIB-IV non-squamous NSCLC, from 3 institutes in Saudi Arabia, were included. We examined the distribution of patients and treatment characteristics at diagnosis according to the gender.These categorical variables were compared using Chi-square test. Overall survival (OS) was assessed according to the gender in addition to age categories (≤ 60 vs. > 60 years), ECOG performance status (PS) (0-2 vs. 3-4), type of 1st line chemotherapy (pemetrexed containing vs. others) and EGFR status. Differences in survival distributions were evaluated via Log Rank test. Multivariate analysis by Cox proportional hazard model has been used to check for independent prognostic factors associated with OS.

Results:
One hundred and twenty patients were included (100 stage IV, 20 stage IIIB, 92 males, 28 females). Eighty patients had available results of EGFR testing and 26.2% of them were mutant. EGFR mutations were more common among female patients (45.4% vs.18.9%, p=0.023). Only half of EGFR-mutant patients received 1[st] line erlotinib, while the other half received erlotinib as a maintenance or 2[nd] line therapy due to delayed EGFR testing results. No difference in the distribution of other parameters according to the gender including age, PS, site (bone vs. others) and number of metastasis (single vs. multiple), type of 1[st] line therapy and number of cycles of chemotherapy. After a median follow up of 22 months (range 15-31 months), greater proportion of females were alive compared to males (60.7% vs. 23.9% respectively, p<0.0001). In univariate analysis, OS was improved in female patients (female; 23.0 months, 95% CI= 17.03-28.97 vs. male; 8.7 months, 95% CI= 5.16-12.24, p < 0.0001), PS 0-2 (PS 0-2;14.4 months, 95% CI= 10.66-18.14 vs. PS 3-4; 2.0 months, 95% CI= 0.50-4.99, p < 0.0001), those with pemetrexed-containing chemotherapy (pemetrexed-containing; 17.0 months, 95% CI=12.87-21.13 vs. others; 11.0 months, 95% CI=5.90-16.10, p= 0.019) and EGFR- mutant patients (mutant; 23.0 months, 95% CI=16.41-27.39 vs. wild;11.7 months, 95% CI=8.24-15.16, p=0.006). In multivariate analysis, mutant EGFR status (HR=2.49, 95% CI=1.19-5.19, p=0.015) and female gender (HR=2.78, 95% CI= 1.30-5.95, p=0.008) were independent predictors of improved OS.

Conclusion:
Female Saudi patients with advanced non-squamous NSCLC have better survival outcome irrespective of their EGFR status. Low frequency of smoking habit among Saudi females may explain this outcome.

Background:
Early stage lung cancer is largely asymptomatic; however, as the disease progresses, patients experience significant distress from their lung cancer symptoms. The assessment and monitoring of changes in NSCLC symptoms is increasingly important in clinical trials when making treatment comparisons between new therapies. The objective of this study was to capture the patient perspective on core symptoms of NSCLC in order to develop a new symptom measure for use in clinical trials.

Methods:
This was a non-interventional, cross-sectional qualitative study that consisted of conducting individual interviews with patients with a diagnosis of NSCLC who were either treatment-naïve or had already received surgery, chemotherapy, radiation, or targeted therapy. Patients aged ≥18 years with stage IIB-IV NSCLC took part in concept elicitation interviews to provide descriptions of NSCLC symptoms, including severity, frequency and development over time. Data were used to develop the items constituting the Symptoms in Lung Cancer (SILC) Questionnaire.

Results:
A total of 28 patients were recruited (17 treatment-naïve, 11 post-treatment) for concept elicitation interviews. In the treatment-naïve population, the most common spontaneously reported symptoms of NSCLC were cough (58.8%), shortness of breath (47.1%), chest pain (47.1%) and fatigue (29.4%). These symptoms were included in the initial 12-item version of the SILC. An additional 10 patients participated in cognitive interviews to ensure that the items were correctly interpreted, relevant, and disease-related (i.e., not treatment-related). Following cognitive interviews and analysis of data from treatment-naïve and post-treatment patients, the fatigue items were dropped after patients indicated that attributing a specific symptom to the underlying condition or treatment was challenging. The final draft of the 9-item SILC uses a 5-point verbal response scale (higher scores indicating greater severity/frequency), a 7-day recall period, and assesses 3 core symptom concepts: chest pain (severity and frequency), cough (severity and frequency), dyspnea (while lying down/sitting, standing, walking, carrying a light load and when walking up an incline).

Conclusion:
SILC is an easy-to-use and concise tool to assess the core symptoms of disease in NSCLC patients, and is in compliance with the FDA PRO Guidance (2009) document.

Background:
First-line Erlotinib (E) delays progression in 10-14 months in patients (p) harboring EGFR mutations (EGFRm+). Understanding the resistance mechanisms in order to personalize treatment justify the need for rebiopsy. However, undergoing this procedure could be not feasible on a daily basis. Due to different clinical courses and progression patterns, NCCN guidelines recommend strategies according to symptomatology, extent and site of metastasis in recurrent setting. Nowadays, identifying tumour recurrence patterns and evaluating the potential limitations of rebiopsy are relevant in clinical practice.

Methods:
ASPET is an ongoing, multicentre, observational study. Eligible p are chemonaïve with EGFRm+ advanced NSCLC treated with E (150mg/d, until unacceptable toxicity or progressive disease). Primary endpoint is to correlate PFS and tumour localization/characteristics at progression. The evaluation of potential feasibility of rebiopsy (questionnaires completed by physicians and p at diagnosis) is one of the secondary endpoints.

Results:
Baseline characteristics of 100 p included in this preliminary analysis: mean age 66 yrs; 65% female; 89% adenocarcinoma; 91% stage IV; 69% PS-ECOG 0-1; 60% never smokers; 31% central tumours; 57% Del19, 35% L858R, 8% other mutations. Different metastatic locations according to type of mutation have been reported (Figure 1). Objective Response Rate of 63.33% and Disease Control Rate of 90% (60 p evaluable). Main related grade≥3 toxicities were skin disorders (7%) and diarrhoea (2%). Questionnaires completed by 80 physicians: 81.2% considered technically feasible repeat biopsy, 66.25% believe that p would be willing to undergo rebiopsy and 72.5% would direct changes in therapy with rebiopsy results. Results from questionnaires completed by 69% of p are shown in Table 1. Table 1: Results from patient-reported questionnaires (N=69)

Before the biopsy procedure, you thought that it would be	N (%)
Not uncomfortable	13 (18.84)
Uncomfortable	31 (44.93)
Painful	22 (31.88)
Insufferable	3 (4.35)
The punctures of each lesion have been	N(%)
Not uncomfortable	23 (33.33)
Uncomfortable	34 (49.28)
Painful	9 (13.04)
Insufferable	3 (4.35)
Overall, you consider the procedure	N(%)
Not uncomfortable	20 (28.99)
Uncomfortable	37 (53.62)
Painful	9 (13.04)
Insufferable	3 (4.35)
If you would have to repeat another biopsy	N(%)
I will do it	52 (75.36)
I will not repeat it again	4 (5.80)
I would need anesthesia	13 (18.84)

Figure 1



Conclusion:
Rebiopsy is considered feasible for physicians in clinical practice and the majority of p would undergo a second biopsy. No new safety data have seen so far and efficacy results in terms of responses match with previously reported data.

Background:
Assessing response of locally advanced non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy by computed tomography (CT) can be complicated by treatment-related pneumonitis or fibrosis. Hypothesizing that measurements of tumor response by [18]F-fluorodeoxyglucose standardized uptake values (SUVs) on positron emission tomography (PET) are more reliably associated with treatment outcomes than those by CT, we compared outcomes and responses according to PET SUV vs. CT among patients in a phase II study of erlotinib+chemoradiation for stage III NSCLC.

Methods:
Trial 2005-1023 enrolled 46 patients in 2007–2010; patients received 63 Gy in 35 fractions over 7 weeks with daily erlotinib and weekly paclitaxel-carboplatin. Tumor response was assessed on diagnostic CT scans with contrast or CT from PET-CT and scored according to RECIST 1.1. Tumor response was also assessed by PERCIST 1.0 (based on SUV) as follows: complete response (CR), disappearance of all measurable tumors; partial response (PR), ≥30% reduction in the sum of SUVs of target lesions; progressive disease (PD), ≥30% increase in the sum of SUVs of target lesions; and stable disease (SD), insufficient change in SUV to qualify for PR or PD. The longest diameter of measurable primary lesions and the short axis of measurable lymph nodes were measured. All non-target lesions were also measured. Two-sided Pearson’s chi-square tests were used to assess frequency associations. Overall survival (OS) and local-regional control (LRC) rates were assessed from treatment start by Kaplan-Meier analysis and log-rank tests; P≤0.05 indicated significance.

Results:
One patient did not have CT and PET after treatment. For the 45 evaluable patients, best response by PET-CT at 6 months after treatment was CR for 15 patients (33%), PR for 19 (42%), SD for 0, PD for 4 (9%), and not available due to did not have baseline or post treatment PET for 7 (16%). Best response by CT at 6 months was CR for 11 (24%), PR for 27 (60), SD for 3 (7%), and PD for 4 (9%) (P<0.001). The 3 patients with SD by CT all died within 7 months after treatment; the 4 patients with PD had new distant metastases. Four-year OS was associated with best overall response on both PET and CT at 6 months (P<0.05) and at 1 year (P<0.05). LRC was associated with best overall response on PET (P<0.01) and best primary tumor response on PET (P<0.05) at 6 and 12 months. Lymph node response was not associated with OS or LRC by PET or CT.

Conclusion:
The CR rate was higher with PET than with CT. Tumor response at 6 months by PET or CT predicted treatment outcomes after chemoradiotherapy for stage III NSCLC. The best overall and primary tumor response by PET within 6 months after treatment was more reliably associated with LRC than was response on CT because of difficulty to assess response due to pneumonitis/lung fibrosis.

Background:
Majority of patients with non-small cell lung cancer (NSCLC) are elderly, and age is known to be an important factor for management and treatment. Elderly are underpresented in cancer research. Therefore, we conducted this phase II study aiming at assessing the efficacy and safety of adding bevacizumab to docetaxel as a second line treatment of elderly patients with advanced non squamous NSCLC

Methods:
Twenty five previously treated elderly patients with advanced non squamous NSCLC (stage III, IV) were enrolled into this study between May 2011 and May 2014. All patients received docetaxel 60 mg/m[2] followed by bevacizumab 15mg/kg, both agents were given via I.V infusion on day 1 and the cycle was repeated every 21 days until disease progression or unacceptable toxicity developed.

Results:
The median age was 70 years old (range 65-79 years); 19 (76%) patients were men; ECOC PS was 0 in 6 (24%) patients, 1 in 12 (48%) patients and 2 in 7 (28%) patients. The objective response rate was 60%, while disease control rate was 84%.The median progression-free survival time was 7 months, while the median overall survival time was 19.8 months. Grade 3/4 neutropenia had been recorded in 18(72%) patients, and grade 3/4 fatigue had occurred in 5(20%) patients. No cases of severe bleeding nor treatment-related deaths had been reported in this study.

Conclusion:
Bevacizumab added to docetaxel showed a real activity as a second line treatment in previously treated elderly patients with advanced NSCLC and has an acceptable toxicity.

Background:
The present study evaluated the efficacy and safety of pemetrexed, carboplatin and bevacizumab, followed by maintenance pemetrexed and bevacizumab, in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC).

Methods:
The patients were administered pemetrexed (500 mg/m[2]), carboplatin (AUC 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Patients who did not experience tumor progression remained on maintenance pemetrexed and bevacizumab until disease progression or unacceptable toxicity. Primary endpoints were overall response rate (ORR), progression free survival (PFS) and overall survival (OS).

Results:
Hundred forty-four Colombian patients were included and received treatment. The median age was 64 years (range, 32-86 years), 61% was female and 55% had some history of tobacco exposure. The median follow-up was 13.8 months, and the median number of manteinance cycles was 8 (range, 1- 32). Among patients assessable for response, the ORR was 66% (95%CI, 47% to 79%). Median progression-free and overall survival rates were 7.9 months (95%CI 5.9-10.0 months) and 21.4 months (95%CI 18.3 to 24.4 months), respectively. Grade 3/4 hematologic toxicity was anemia (14%), neutropenia (8%), and thrombocytopenia (16%). Grade 3/4 nonhematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). There was no grade 3 or greater hemorrhagic events or hypertension cases.

Conclusion:
Overall, pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab, was effective and tolerable in hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS.

Background:
The additional effects of bevacizumab (B) as first-line chemotherapy for non-squamous non-small cell lung cancer (Non-sq NSCLC) have been established. However, the efficacy of B in a second-line setting or further has not been clarified. It has recently become clear that S-1 (S), an oral fluoropyrimidine, is effective for advanced NSCLC, and S is now used with platinum as one of the standard forms of first-line chemotherapy. Furthermore, preclinical findings have suggested that the combination of S plus B is a promising treatment option.

Methods:
Non-sq NSCLC patients with an ECOG performance status of 0-2, and who had undergone prior platinum-based chemotherapy regardless of the use of B, were eligible for the study. S (80 mg/m[2]) was administered orally twice daily for 14 days, and B (15 mg/kg) on day 1 every 3 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS), and the planned sample size was 28 patients.

Results:
Between March 2012 and June 2014, 28 patients (14 males and 14 females; median age 62 years; PS 0/1/2: 21/7/0; Ad/Other: 26/2, EGFR mutation positive/wild type 12/16) were accrued from 4 centers in Japan. All 28 patients were included in analysis of efficacy and toxicity. With a median follow-up of 9.3 months, the median PFS was 3.2 months (95% CI: 2.2-4.0 months). Patients who had not received prior pemetrexed or who had shown a good response to prior chemotherapy tended to have a longer PFS (5.3 and 5.0 months, respectively), although this was not statistically significant. An objective response was observed in 4 patients (PR; 4, SD; 20, PD 4), the response rate and disease control rate being 14.3% and 85.7%, respectively. The treatment was well tolerated, the most common treatment-related side effects being anorexia (75%) and fatigue (68%).

Conclusion:
This is the first report to evaluate the efficacy and safety of SB. Although SB seems to have a higher tumor reduction effect than S alone for previously treated Non-sq NSCLC, this study failed to meet its primary endpoint. SB is well tolerated and no new toxicities were observed.

Background:
We prospectively evaluated the efficacy and toxicity of non-platinum triplet regimen, which consist of paclitaxel, irinotecan, and bevacizumab for patients with advanced non-small cell lung cancer (NSCLC) expected to be platinum resistant.

Methods:
All patients were diagnosed with NSCLC using endobronchial ultrasonography with a guide sheath (EBUS-GS) system. We defined the EBUS-GS as a core biopsy. RNA was immediately isolated from this unfixed biopsy specimens, and quantitative real-time reverse transcriptase PCR assays were performed to determine the excision repair cross-complementing 1 (ERCC1) mRNA expression. Patients with advanced, untreated NSCLC showing high ERCC1 levels (ΔCt≧6.5) were entered the phase II trial of the non-platinum triplet regimen. Paclitaxel of 180mg/m2 on day 1, irinotecan of 50mg/m2 on day 1 and 8, and bevacizumab of 15mg/kg on day 1 were administered every 4 weeks. Primary end point was the objective response rate (ORR), assuming 30% for a standard therapy and 60% for a target therapy (alpha=0.05 and beta=0.1), and the estimated required total number of patients was 28 by Simon’s Optimal Two-stage Design.

Results:
Total 141 untreated patients received EBUS-GS and were evaluated the expression of ERCC1, and 30 patients were entered in this trial. The ORR was 66.7%(95% confidence interval [CI]: 47.2-82.7). Median progression-free survival was 174 days. Grade 4 thrombosis occurred one patient, but other toxicities were mild and controllable. Fifty-three patients were treated with platinum-containing regimens and 22 patients were responded (ORR was 41.5% [95% CI: 28.1-55.9]). Twenty-three of these patients were high ERCC1 levels and 6 patients were responded, and 30 patients were low ERCC1 levels and 16 patients were responded (p=0.0053, by Fisher’s exact test).

Conclusion:
The triplet combination of paclitaxel, irinotecan and bevacizumab might be effective for patients with advanced, untreated NSCLC overexpressing ERCC1. ERCC1 mRNA levels extracted from unfixed lung biopsy specimens obtained by EBUS-GS also might be a predictive factor for platinum-containing regimens.

Background:
Nintedanib is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1-3, as well as FLT3 and Src. Currently, the molecule has proved benefit for second-line in non-small cell lung cancer patients. We report the results of a cohort of NSCLC patients receiving nintedanib within a compassionate-use program (CUP) in México.

Methods:
Patients with advanced NSCLC progressing after one line of chemotherapy were enrolled. Eligible patients received docetaxel 75 mg/m(2) (day 1) plus nintedanib 200 mg twice daily; days 2-21) in 21-day cycles. Data collection was monitored. Treatment continued until disease progression or unacceptable drug-related AEs. The intention of this CUP was to provide controlled access to nintedanib

Results:
From February 2014 to April 2015, 17 patients (63% male; median age: 61 years [range: 29-83 years]) were enrolled. Patients received nintedanib 200 mg BID (n=16). The primary analysis was done after a median follow-up of 7 months; the median overall survival was 42 months (33-52 weeks). Grade 3 or worse febrile neutropenia developed in eight patients (31 %) and neutropenia in four patients (15 %). The most frequent drug-related adverse events (all grades) were diarrhea (30%), asthenia (61.9%), nausea (23%), hand-foot syndrome (15%), and vomiting (7.6%). Drug-related adverse events all grades included neutropenia (12.5%), fatigue (18.7%), decreased appetite (18.7%), and elevations in alanine aminotransferase (37.5%) and aspartate aminotransferase (31.2%). Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred only in 2/16 patients (12.5%). All hepatic enzyme elevations were reversible and manageable with dose reduction. Among 16 evaluable patients, 13 (81.25%) had a partial response and 3 (18.75%) had stable disease by Response Evaluation Criteria In Solid Tumours criteria. Three of all patients died of events unrelated to disease progression; the most common of these events were sepsis and pneumonia.

Conclusion:
Based on cohort result, treatment with second-line nintedanib combined with docetaxel was well tolerated and showed efficacy in Mexican patients with advanced non-small-cell lung cancer.

Background:
Proteinuria caused by bevacizumab (BV) often becomes an obstacle to continuation of the treatment. Renin-angiotensin system inhibitor (RASI), angiotensin receptor blocker and angiotensin converting enzyme inhibitor, has demonstrated anti-proteinuria effect in diabetic nephropathy and nondiabetic kidney disease. This retrospective observational study was conducted to evaluate the anti-proteinuria effect of RASI for NSCLC patients (pts) who received BV chemotherapy.

Methods:
We reviewed the medical records of NSCLC pts between 2008 and 2014 at 11 hospitals. Eligible pts had a treatment of BV chemotherapy, no proteinuria, and no diabetes mellitus. Clinical characteristics, use of the antihypertensive drugs, change of the blood pressure, and proteinuria generation were investigated during first 6 courses of BV chemotherapy.

Results:
A total of 211 pts were enrolled. Pts characteristics were: male/female 121/90; median age 63 (range 35-88); ECOG performance status 0-1/2-3 199/12; stage Ⅳ/recurrent 189/22; dose of BV(/kg) 7.5mg/15mg 21/190; BV cycle 1-2/3-4/5-6 18/55/138; antihypertensive drugs RASI/non-RASI/none 59/44/108. Proteinuria was observed in 49 pts (23%) as grade 1/2/3 33/14/2. The rate of proteinuria generation was significantly lower in the RASI group than non-RASI group (17% vs. 41%, P=0.025). Multivariate analysis revealed that RASI significantly reduced proteinuria (HR=0.43, 95% CI=0.17-0.91, P=0.043).

Conclusion:
RASI demonstrated anti-proteinuria effect for NSCLC pts who received BV therapy.

Background:
As previously reported, the SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) chemotherapy significantly improved survival in patients with stage IV squamous NSCLC. Overall survival (OS), progression-free survival (PFS), and safety results are presented for Eastern Cooperative Oncology Group (ECOG) PS 0–1/2 subgroups.

Methods:
Patients with stage IV squamous NSCLC were randomized 1:1 to N (800 mg iv, days 1 and 8) plus GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) or GC alone every 21 days for up to six cycles in this multicenter, open-label study. N+GC patients without progression continued on N alone until progressive disease or intolerable toxicity. The study was powered for OS and PFS (previously reported). Preplanned subgroup analyses were performed for ECOG PS 0–1 and 2.

Results:
Subgroups PS 0–1/2 (n=996 [91%]/n=96 [9%]) were well balanced regarding baseline characteristics (males, 83% vs 86%; median age, 62 vs 65 yrs; smoking/ex-light smoker/nonsmoker, 91/4/5% vs 89/6/5%). GC median relative dose intensity was similar between PS 0–1/2 subgroups; N (overall) was higher for the PS 0–1 than for PS 2 subgroup (94.8% and 90.0%). Post-study therapy use was generally higher in the PS 0–1 than in the PS 2 subgroup, but was balanced between both arms. The OS hazard ratio (HR) for N+GC vs. GC was 0.85 (95% CI: 0.74, 0.98; p=0.026) for PS 0–1 and 0.78 (95% CI: 0.51, 1.21; p=0.275) for PS 2. The PFS HR (N+GC vs. GC) was 0.86 (95% CI: 0.75, 0.99; p=0.035) for PS 0–1 and 0.79 (95% CI: 0.50, 1.24; p=0.292) for PS 2. Select Grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the table. The percentage of patients with adverse events leading to discontinuation of any study drug was lower in the PS 0–1 subgroup (N+GC=30%; GC=23%) than the PS 2 subgroup (N+GC=42%; GC=41%). The percentage of patients hospitalized was higher in the PS 0–1 subgroup (N+GC=43%; GC=34%) than the PS2 subgroup (N+GC=25%; GC=30%). Table. Select TEAEs

Grade ≥3 Event*	PS 0-1 N+GC (%) N=490	PS 0-1 GC (%) N=495	PS 2 N+GC (%) N=48	PS 2 GC (%) N=46
Neutropenia	25.5	28.1	12.5	21.7
Febrile neutropenia	0.6	1.4	2.1	0
Anemia	11.2	10.3	4.2	17.4
Thrombocytopenia	10.4	10.5	8.3	13.0
Fatigue	7.1	7.1	8.3	6.5
Hypomagnesemia	9.8	1.0	4.2	2.2
Rash	7.8	0.4	0	0
Arterial thromboembolic events	3.7	1.8	6.3	4.3
Venous thromboembolic events	5.5	2.6	0	2.2

[*][Adverse events of possible relevance to treatment, according to either composite categories or preferred terms (febrile neutropenia only)]

Conclusion:
OS and PFS treatment results for N+GC were consistent and considered favorable across subgroups including ECOG PS 2 patients. Administration of N+GC was well tolerated in PS 2 patients, with no evidence of an increased safety risk in this subgroup.

Background:
Lung cancer is mainly a disease of modern era and probably one of the most important health problems today. Approximately 63,000 new lung cancer cases are reported each year (Ganesh et al., 2011) in India. In the series from west as well as from India, it is reported that 30% of lung cancers are of squamous cell histology (SQCLC) and 50-70% cases usually present in advanced stage (Becket, 1993; Govindan et al., 2006; Grivaux et al., 2011; Malik et al., 2013). The median overall survival observed with the current standard of care is 9-11 months and highlights the need for targeted agents that will add to the survival and quality of life of these patients. EGFR is the most evaluated target in lung cancer. EGFR overexpression is recorded in about 75-80% of the patients and associated with a worser clinical outcome. Nimotuzumab is humanized EGFR antagonist and is being actively evaluated in the management of advanced lung cancer. This study is done to observe the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV SQCLC with recorded EGFR overexpression.

Methods:
This single-center, open-label, study evaluating 20 patients to receive nimotuzumab plus chemotherapy (nimo group, n=10) or chemotherapy alone (control group, n=10), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m2 and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan–Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data.

Results:
The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (66% versus 34.5%; P=0.04). A complete response and partial response were achieved in 15% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. Median progression-free survival and median overall survival in nimo group and control groups were 5.9 vs 3.7 months and 12.2 vs 9.8 months respectively, both being significant for Nimotuzumab. Safety profiles were comparable between the two groups.

Conclusion:
Nimotuzumab plus chemotherapy significantly improved the tumor response, PFS and mOS as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV lung cancer.

Background:
Cancer stem cells may be responsible for initiation, maintenance, progression and metastatic spread of lung cancers and native or acquired drug resistance can allow cancers to escape from conventional therapy. Eradicating cancer stem cells may improve clinical outcomes. We (APF, VJ) showed that PKCi is an oncogene for NSCLC and is amplified in most squamous lung cancer cells (LSCC). PKCι is required for LSCC cell proliferation in vitro and tumorigenicity in vivo and for maintenance of the lung cancer tumor initiating cell (TIC) phenotype. LSCC oncospheres have cancer stem cell characteristics, express stem genes, and exhibit clonal expansion, enhanced transformed growth and the ability to maintain lung tumors and metastases in vivo. The PKCi-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs and PKCι knock down, impairs soft agar growth, clonal expansion and tumorigenicity. The gold salt auranofin (ANF) reproduces the effects of PKCι knock down on the PKCi-Rac1-Ect2-MMP10 signaling pathway and on clonal expansion and tumorigenicity. ANF potently and selectively inhibits oncogenic PKCι signaling and combined PKCι and mTOR inhibition synergistically reduces lung cancer cell proliferation and tumor growth in vivo and in vitro (Ross H, Justilien V, Hill K, Walsh M, Fields AP. Protein kinase C iota is required for maintenance of a tumor initiating cell phenotype in lung squamous cell carcinoma. Abstract 2644 WCLC 2013). A phase I/II clinical trial of oral ANF + the mTOR inhibitor sirolimus in patients with advanced or recurrent lung cancer is ongoing.

Methods:
A phase I/II clinical trial is accruing patients to test the hypothesis that combined inhibition of PKCι and mTOR is safe and effective in lung cancer patients. NCT01737502 NCI sponsored clinical trial R21 CA153000 Eligible participants are adults with confirmed diagnosis of lung cancer (squamous, RAS-mutated adenocarcinoma or small cell lung cancer), PS 0-2, adequate organ function, no significant comorbidities and who have completed at least one prior course of platinum doublet chemotherapy. Patients receive ANF + sirolimus orally daily in 28 day continuous cycles. Tumor biopsies are collected for biomarker assessment focused on the PKCi-Rac1-Ect2-MMP10 pathway. Study endpoints are safety, survival and biomarker development.

Results:
The trial has completed the phase I portion with six patients without dose limiting toxicity. The phase II portion of the trial is now accruing with doses of ANF 6 mg daily and sirolimus 5 mg daily continuously in 28 day cycles. Biomarker assessment is ongoing.

Conclusion:
The phase I portion of this trial demonstrated preliminary safety of the combination of auranofin and sirolimus at doses that were effective against NSCLC in preclinical models. Phase II accrual is ongoing.

Background:
KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a small molecule proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, open label, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers.

Methods:
Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the time of first bortezomib treatment. Simon two-stage minimax design was used (H0=10%, H1=30%, power=90%).

Results:
Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 44% women, 38% never smokers, 31% former smokers ≤15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12months). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and papulopustular rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2).

Conclusion:
In patients with G12D KRAS mutant lung cancers, bortezomib was well tolerated and associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted.

Background:
Malignant pleural effusion (MPE) is mainly caused by metastatic pleural cancer and defines malignant tumors with a poor prognosis. To achieve sufficient control of MPE and to minimize invasive interventions are the primary goals of the treating physicians. Recombinant human mutant tumor necrosis factor-alpha (rhu-TNF) has been used in the treatment of MPE. The aim of our research study, which included a total of 102 patients with MPE caused by lung cancer, was retrospectively to evaluate efficacy and safety of rhu-TNF application via ultrasound-guided chest tube for the treatment of MPE. Malignant pleural effusion (MPE) is mainly caused by metastatic pleural cancer and defines malignant tumors with a poor prognosis. To achieve sufficient control of MPE and to minimize invasive interventions are the primary goals of the treating physicians. Recombinant human mutant tumor necrosis factor-alpha (rhu-TNF) has been used in the treatment of MPE. The aim of our research study, which included a total of 102 patients with MPE caused by lung cancer, was retrospectively to evaluate efficacy and safety of rhu-TNF application via ultrasound-guided chest tube for the treatment of MPE.

Methods:
Rhu-TNF was administered as a single dose to 102 patients, and dexamethasone (Dmx, 5 mg) was administered 30 min before rhu-TNF in 35 patients in order to prevent side effects. The primary endpoint was the efficacy of the Rhu-TNF treatment (disease response rate) and side effects (pain, fever and flu-like symptoms) evaluated four weeks after instillation.

Results:
The disease response rate of Rhu-TNF treatment in 102 patients was 81.37%. Side effects included 13 (12.75%) patients complaining about flu-like symptoms, 15 (14.71%) with fever/chill, and 14 (13.73%) with chest pain. A significantly higher efficacy was observed for the treatment with three versus two million units rhu-TNF (= 0.036), while the adverse effects were similar. Although application of Dmx before the intra-pleural instillation of rhu-TNF reduced the incidence of adverse events, no significant differences were found.

Conclusion:
In conclusion, our study shows that intra-pleural instillation of rhu-TNF in MPE patients achieves sufficient control of MPE and minimizes invasive interventions.

Background:
Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody. We aim to evaluate the efficacy of dual inhibition of EGFR with nimotuzumab plus gefitinib in advanced non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Methods:
An open label, randomized, phase II trial was conducted in 6 centers; 160 patients were randomized (1:1) to either nimotuzumab (200mg, IV weekly) plus gefitinib (250mg p.o. daily) or gefitinib alone until disease progression or intolerable toxicities. The primary endpoint was progression free survival (PFS) rate at 3 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR) and safety.

Results:
A total of 155 patients (78 in nimotuzumab plus gefitinib, 77 in gefitinib) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (65.2%) and ECOG performance status 0 to 1 (83.5%). Among 102 patients with EGFR mutation results available, activating EGFR mutation was documented in 27 patients (12/50 in nimotuzumab plus gefitinib, 15/52 in gefitinib). With a median follow-up of 12.1 months, PFS rate at 3 months was 37.2% in nimotuzumab plus gefitinib and 48.1% in gefitinib [HR 1.03; 95% CI, 0.71–1.40; P=0.98]. Median PFS and OS were 2.0 months and 14.0 months in nimotuzumab plus gefitinib and 2.8 months and 13.2 months in gefitinib [HR 1.03, 95% CI 0.71-1.41, P=0.98 for PFS; HR 0.86, 95% CI 0.57–1.30, P=0.47 for OS]. The ORRs were 14.1% in nimotuzumab plus gefitinib and 22.1% in gefitinib, which was not statistically significant (P=0.76). As expected, patients with EGFR mutation showed significantly longer survival than those with wild-type EGFR or unknown EGFR mutation status (10.3 vs. 1.2 vs. 2.7 months, P < 0.001 for PFS; 23.5 vs. 13.5 vs. 10.5 months, P= 0.001 for OS). Combined treatment of nimotuzumab plus gefitinib did not show superior PFS compared to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=0.30) and patients with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=0.90). The median PFS was not significantly different between two treatment arms according to histology (2.8 vs. 2.9 months in gefitinib alone for adenocarcinoma, P=0.64; 1.2 vs. 2.8 months in gefitinib alone for non-adenocarcinoma, P=0.35). Adverse events (AEs) in both treatment arms were mostly grade 1 to 2 and easily manageable. Importantly, combined EGFR inhibition with nimotuzumab and gefitinib did not increase EGFR inhibition-related AEs, such as acneiform rash (32.4 vs. 30.3% in gefitinib alone, P=0.38), diarrhea (30.7 vs. 35.7% in gefitinib alone, P=0.32), and stomatitis (11.5 vs. 13.4% in gefitinib alone, P=0.19). There was no treatment-related death.

Conclusion:
The dual inhibition of EGFR with nimotuzumab plus gefitinib did not show superiority over gefitinib alone for second-line treatment of advanced NSCLC (NCT01498562).

Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase III study (NCT02395172) is an open-label, multicenter trial of avelumab compared with docetaxel in patients with non-small-cell lung cancer (NSCLC) that has progressed after treatment with a platinum-containing doublet.

Methods:
The primary objective of this head-to-head phase III study is to demonstrate superiority defined by overall survival (OS) of avelumab versus docetaxel in patients with locally advanced unresectable, metastatic, or recurrent NSCLC whose tumors express PD-L1 and whose disease has progressed following treatment with a platinum-containing doublet. Approximately 650 eligible patients (ECOG performance status 0-1 at trial entry, tumor archival material or fresh biopsy suitable for PD-L1 expression assessment, histologically confirmed NSCLC, and known-negative ALK mutation status, among other inclusion and exclusion criteria), including 522 patients with PD-L1—positive tumors, will be randomized 1:1 to receive either avelumab at a dose of 10 mg/kg as a 1h intravenous (IV) infusion Q2W or docetaxel at a starting dose of 75 mg/m2 (per label) by IV infusion Q3W. Patients will be stratified according to PD-L1 status. NSCLC histology and EGFR mutation status will be used to define 3 stratified levels for randomization: squamous cell, non-squamous cell/EGFR wildtype, and non-squamous cell/EGFR-activating mutations. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Responses will be evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. In addition to the primary endpoint of OS, secondary endpoints include progression-free survival, best overall response, quality of life assessments, and safety profile. Exploratory endpoints include duration of response, tumor shrinkage in target lesions per timepoint, immunogenicity, PK profile, and evaluation of molecular, cellular, and soluble markers in peripheral blood or tumor tissue that may be relevant to the mechanism of action of, or response/resistance to, avelumab. Safety profiling of trial drugs includes incidence of adverse events (AEs), serious AEs, and other assessments according to NCI-CTCAE v4.03. Patients receiving avelumab who have achieved a complete response (CR) will be treated for a minimum of 6 months and a maximum of 12 months after confirmation. In the case of relapse following a CR, treatment with avelumab may be re-initiated once at the discretion of the investigator and in the absence of treatment-related toxicity. For patients whose disease progresses with avelumab, treatment may continue past the initial determination of disease progression per RECIST 1.1 if the patient’s performance status has remained stable, other criteria are fulfilled, and the investigator’s opinion supports a possible benefit of continued treatment with avelumab. Patients treated with docetaxel may not crossover to the avelumab arm as long as the primary endpoint has not been met in the planned interim or final analyses. Enrollment in this trial began in April 2015. *Proposed INN.

Results:
not applicable

Conclusion:
not applicable

Background:
Outcomes remain poor in patients with non-small cell lung cancer (NSCLC) of squamous origin. There are few established therapeutic targets, and benefits of chemotherapy are frequently short-lived, with rapid development of treatment resistance. More effective therapies are urgently required. Substantial preclinical data demonstrate that heat shock protein 27 (Hsp27) affects numerous pathways implicated in cancer progression and treatment resistance. Approximately 70-98% of squamous-cell tumours express Hsp27. Apatorsen (OGX-427) is a second generation antisense oligonucleotide that effectively down-regulates Hsp27 in vitro and in vivo; clinical studies are evaluating apatorsen in lung, bladder, prostate, and pancreatic cancers.

Methods:
The phase 2, UK, investigator led, randomized, open-label trial Cedar trial was initiated in July 2014. Eligible patients have confirmed Stage IIIB/IV squamous cell lung cancer and no prior chemotherapy for advanced disease, with ECOG score of 0-2 and adequate bone marrow, renal, and liver function; patients with known EGFR mutation or ALK rearrangements are excluded. Planned enrollment is 140 patients; randomization (1:1) is stratified by stage and performance status. Patients receive 21-day cycles of gemcitabine (1250 mg/m[2]) and carboplatin (AUC5) or gemcitabine/carboplatin plus apatorsen (600 mg IV/wk, preceded by 3 doses during a 9-day loading period) for up to 6 cycles. Tumor evaluation occurs q6 wks. Patients randomized to apatorsen may continue weekly single agent maintenance until progressive disease (PD), unacceptable toxicity, or withdrawal of consent. The primary efficacy measure is progression-free survival. Secondary efficacy measures include objective response (OR), change in tumour size at 12 wks, clinical benefit rate, duration of OR/clinical benefit, overall survival, and proportion without PD at 12 and 24 wks. Efficacy analyses are intent-to-treat. Adverse events and laboratory results are assessed, and interim safety analyses are planned. Pre-specified subset analyses will characterize the relevance of Hsp27 expression in tumour and blood samples.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Necitumumab (N) is a human IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Squamous (SQ) histology accounts for 25-30% of non-small cell lung cancer (NSCLC) and gemcitabine combined with cisplatin (GC) is a standard of care for advanced or metastatic SQ-NSCLC. In the previous global randomized, open-label, Phase 3 trial (SQUIRE), compared with GC, the addition of N to GC (GC+N) significantly improved overall survival (OS) (HR=0.84, p=0.012; median 11.5 vs 9.9 months) and progression-free survival (PFS) (HR=0.85, p=0.020; median 5.7 vs 5.5 months). The objective response rate (ORR) was 31% vs 29% (p=0.400), and the disease control rate (DCR) was 82% vs 77% (p=0.043), respectively. The SQUIRE results were an important advance in the search for a new treatment for patients with metastatic SQ-NSCLC, where limited progress has been made over the last two decades. However, only 8% of patients in SQUIRE Trial were Asian and no Japanese institutions participated. We have therefore conducted this Phase 1b/2 trial to evaluate the efficacy and safety of GC+N in Japanese patients with advanced SQ-NSCLC.

Methods:
This trial consists of a Phase 1b and Phase 2 part. Patients with advanced (Stage IV) SQ-NSCLC are eligible for enrollment if they are aged³20 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; measurable or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0; adequate organ function. GC+N or GC may continue for a maximum of 4 cycles; patients with at least stable disease in GC+N may continue to receive N until disease progression or emerging non-acceptable toxicity. The purpose of Phase 1b part is to determine the recommended dose of the combination of GC (G=1000 or 1250 mg/m[2] iv, Days 1 and 8; C=75 mg/m[2] iv, Day 1; 3-week cycle) and N (800 mg iv, Days 1 and 8; 3-week cycle). Patients are enrolled in 2 cohorts using a conventional 3+3 study design, with dose-escalation of gemcitabine permitted according to the incidence of dose-limiting toxicity (DLT). The Phase 2 part is an open-label, randomized trial to evaluate the efficacy and safety of addition of N to GC. Patients are randomly assigned on a 1:1 basis (Stratification factors: ECOG PS and gender) to GC+N (Arm A) or GC (Arm B). The primary endpoint is OS for which the final analysis will be performed when at least 137 events are observed. The sample size of 180 patients (137 events) has 68% power for a log-rank test at 0.2 one-sided alpha. The secondary endpoints include PFS, ORR, time to treatment failure, Pharmacokinetics, safety and patient-reported outcomes. The relationship between EGFR protein expression level by immunohistochemistry (IHC) and each of several efficacy measures will also be assessed. Translational research analyses will be performed to analyze relevant biomarkers for clinical outcomes. ClinicalTrial.gov Identifier: NCT01763788.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Gemcitabine – cisplatin is one of the most frequent treatment used in patients with advanced S-NSCLC without any direct comparison with other active doublets and with superiority reported only versus pemetrexed-cisplatin (Scagliotti G., 2008). Oral vinorelbine-cisplatin is also one main standard doublet but no trial has been specifically conducted in S-NSCLC. The aim of the current study is to assess efficacy and safety of oral vinorelbine-cisplatin and gemcitabine-cisplatin in S-NSCLC patients (NAVoTRIAL 3).

Methods:
This is a phase II, international multicentre, randomised study (1:1). At baseline, patients must have stage IIIB or IV, squamous histologically or cytologically proven NSCLC, Karnofsky PS ≥70 and must not have received prior systemic CT or immunotherapy for NSCLC.Patients in arm A will receive oral vinorelbine at the dose of 60 mg/m² in combination with cisplatin at the dose of 80 mg/m² on day 1, followed by oral vinorelbine, 60 mg/m² on day 8 at the first cycle; the dose is increased at the second cycle to 80 mg/m² in absence of haematological tolerance. Both agents are repeated every 3 weeks, followed by maintenance after four cycles for patients with OR/SD: oral vinorelbine at the same dose as cycle 4, day 1, 8 every 3 weeks.Patients in arm B will receive gemcitabine at the dose of 1250 mg/m² in combination with cisplatin 75 mg/m² on day 1, followed by gemcitabine, 1250 mg/m² on day 8. Both agents are repeated every 3 weeks, followed by maintenance after four cycles for patients with OR/SD : Gemcitabine at the same dose as cycle 4, day 1, 8 every 3 weeks. The primary endpoint is the disease control rate (NC, CR, PR, RECIST 1.1). Enrolment began in March 2013 and 110 patients will be recruited.

Results:
Not applicable

Conclusion:
Not applicable

Background:
In clinical practice, approximately one third of patients with advanced non-small cell lung cancer (NSCLC) is candidate at third-line treatment. Currently, only erlotinib is licensed with this indication. Recent studies (TAILOR and DELTA trials) have questioned the role of erlotinib in second-line therapy of patients with advanced EGFR wild-type NSCLC, suggesting an inferiority in survival compared to chemotherapy with docetaxel. For this reason, the use of erlotinib is gradually shifting to the third-line. However, in this setting, chemotherapy drugs, such as gemcitabine or vinorelbine, could achieve similar survival results, with limited toxicity and lower costs than erlotinib. Therefore, the objective of this study is to evaluate the efficacy of chemotherapy (gemcitabine or vinorelbine) vs. erlotinib in the treatment of patients with advanced EGFR wild-type or unknown NSCLC progressing after two lines of chemotherapy in terms of overall survival (primary end-point). The treatments will be also compared in terms of activity, quality of life, toxicity and costs (secondary end-points).

Methods:
538 patients will be enrolled from 40 clinical Italian centers and assigned by randomization to one of 2 treatment arms (chemotherapy vs. erlotinib) with a ratio of 1:1. As stratification factors will be considered: the center, histology (squamous vs. non-squamous), EGFR (wild type vs. unknown) and PS (0-1 vs. 2). Patients will be randomized to receive treatment with erlotinib 150 mg/day (control arm) or chemotherapy with gemcitabine 1000 mg/m[2] or vinorelbine 25 mg/m[2] on days 1, 8 every 21 days (experimental arm), according to investigator choice and previous treatment received. Treatments will be administered until disease progression, patient refusal, unacceptable toxicity, patient clinical deterioration or investigator decision. It was estimated that with 440 deaths from any cause the study would have 85% power to detect a hazard ratio of 0.75 at a two-sided significance level of 5%. If the superiority comparison will fail to detect a significant difference between treatments, the non-inferiority of the chemotherapy arm will be tested with a power equal to 65% against a prospectively defined margin for non-inferiority of the HR equal to 1.25.

Results:
not applicable

Conclusion:
If this study should be positive, it will follow a change in clinical practice with an improvement in life expectancy of patients with advanced NSCLC and savings in terms of economic resources for the NHS. This study (CONFERMER trial) is supported by NHS, Regione Emila Romagna. As to 14 April 2015, 44 patients were randomized.

Background:
The recombinant, humanized, monoclonal antibody bevacizumab targets vascular endothelial growth factor (VEGF) and is approved globally, including in the United States (US) and European Union (EU), for the treatment of select solid tumors, including as a first-line therapy, in combination with platinum-based chemotherapy, for advanced non-squamous non-small cell lung cancer (NSCLC). PF‑06439535 is being developed as a potential biosimilar to bevacizumab and has the same primary amino acid sequence as EU- and US-sourced bevacizumab (bevacizumab‑EU and bevacizumab‑US, respectively), with sufficiently equivalent physiochemical properties and comparable inhibition of VEGF/VEGF-receptor binding in vitro. In a nonclinical model using sexually- and skeletally-immature male cynomolgus monkeys, PF‑06439535 showed similar toxicokinetic parameters to bevacizumab‑EU and no induction of anti-drug antibodies. In a phase I trial in healthy male volunteers, PF‑06439535 showed pharmacokinetic similarity to bevacizumab‑EU and bevacizumab‑US and had a comparable safety profile. These strong foundational data supported implementation of a phase III study. This phase III, multinational, double-blind, randomized, parallel-group clinical trial (NCT02364999) is evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of PF‑06439535 versus bevacizumab‑EU, in combination with paclitaxel and carboplatin, in previously untreated patients with advanced non-squamous NSCLC.

Methods:
A total of 798 patients (399 per treatment arm) will be enrolled. Eligible patients are aged ≥18 years (or ≥ age of consent in the region), and have newly diagnosed stage IIIB/IV NSCLC or recurrent NSCLC with no prior chemotherapy for metastatic disease; predominantly non-squamous disease; ≥1 measureable lesion per RECIST 1.1; Eastern Cooperative Oncology Group performance status 0/1; and adequate hematologic, renal, and hepatic organ function. Patients with known sensitizing mutations in epidermal growth factor receptor (EGFR) or translocation positive mutations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) are excluded. Patients will be stratified by region, gender, and smoking status, and randomized 1:1 to receive PF‑06439535 or bevacizumab‑EU (15 mg/kg intravenously [IV]) plus paclitaxel (200 mg/m[2] IV) and carboplatin (area under the curve 6 mg·min/mL IV) on Day 1 of 21-day cycles. Following 4–6 cycles of chemotherapy, patients will continue to receive PF‑06439535 or bevacizumab‑EU as blinded monotherapy every 3 weeks until disease progression or unacceptable toxicity. Tumors will be radiographically assessed every 6 weeks according to RECIST v1.1 until Week 25, after which tumor assessments will be performed every 9 weeks. The primary objective of the study is to compare objective response rate (ORR) achieved by Week 19 between treatment arms; objective responses will be subsequently confirmed by 6 weeks thereafter. Secondary objectives include evaluation of safety, additional measures of tumor control (eg, duration of response and 1-year progression-free survival and overall survival rates), population pharmacokinetics, and immunogenicity. The main hypothesis to be tested is that the 90% confidence interval of the relative risk of ORR of PF‑06439535 versus that of bevacizumab‑EU by Week 19 is within a pre-specified margin of 76%–132%. The study is open for enrollment.

Results:
Not applicable

Conclusion:
Not applicable

Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with non-small-cell lung cancer (NSCLC) who have not been previously treated for metastatic or recurrent disease. Prior to adding this first-line cohort, this study had enrolled a separate cohort of patients with NSCLC who had received a prior platinum-containing doublet regimen.

Methods:
This trial cohort is enrolling patients with histologically confirmed stage IV (according to IASLC) or recurrent NSCLC who have not previously received treatment for metastatic or recurrent disease. In addition, this cohort is restricted to patients without an activating EGFR mutation or ALK rearrangement. Patients with unknown EGFR or ALK status will be tested during screening and are required to have negative status for inclusion. Eligible patients also must have tumor archival material or fresh biopsy, an ECOG performance status of 0 or 1 at the time of trial entry, and disease with at least 1 measurable lesion according to RECIST 1.1. Exclusion criteria include prior therapy with immune checkpoint drugs or a known history of autoimmune disease. Up to 150 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab as a first-line therapy. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Immunomonitoring of cellular and soluble markers and intratumoral cellular surveillance will also be carried out. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Tumor evaluation will be performed every 6 weeks until progression. Enrollment in this cohort began in March 2015. *Proposed INN.

Results:
not applicable

Conclusion:
not applicable

Background:
A randomized study comparing carboplatin plus weekly paclitaxel versus single-agent chemotherapy in elderly patients with non-small cell lung cancer (NSCLC) demonstrated a survival advantage for combination therapy, however, increased toxicity and treatment-related deaths were also observed. Thus, single agent approaches remain the standard of care and the improvement of treatment remains a challenge in elderly patients. The combination of bevacizumab and other platinum-based chemotherapies is the standard of care in non-elderly patients with non-squamous NSCLC. Additionally, a randomized phase II study suggested the improvement of efficacy for the combination of B plus single-agent pemetrexed or docetaxel compared with single-agent alone. Even in elderly patients, two prospective studies which we conducted demonstrated the feasibility of the combination of bevacizumab and single agent pemetrexed or docetaxel. Thus we plan this randomized phase II study (TORG1323) to select the optimal regimen for experimental arm of the future phase III study in elderly patients.

Methods:
TORG1323 is an open label multicenter randomized phase II study to compare docetaxel plus bevacizumab (DB) with pemetrexed plus bevacizumab (PB). The primary endpoint is progression free survival (PFS, assessed by independent review committee). The secondary endpoints are safety, PFS (assessed by investigators), objective response rate, overall survival, time to treatment failure and quality of life. Eligible patients are 75 years or older, have histologically or cytologically documented stage IIIb, IV or recurrent non-squamous NSCLC for which they had no received chemotherapy, ECOG performance status 0 or 1, and adequate organ function. Patients are randomly assigned to PB and DB arm (1:1). Bevacizumab is administered 15 mg/kg, pemetrexed is 500 mg/m[2] and docetaxel is 50 mg/m[2] every 3 weeks until disease progression or unacceptable toxicity. Selection design is adopted for this study. The planned sample size is 120 patients to yield 80 % power to select an optimal regimen correctly. Enrollment time is 2 years 8 months and follow-up time is 1 year. The first patient on this clinical trial was enrolled in April 2014. Further details can be found on UMIN Clinical Trials Registry (UMIN000012786). Figure 1



Results:
not applicable

Conclusion:
not applicable

Background:
Approximately 1.6 million people are diagnosed with lung cancer annually, of which 85% of cases are NSCLC. Due to limited efficacy of current conventional chemotherapy, the majority of patients face poor prognosis; thus, combining chemotherapy with agents targeting the tumor microenvironment may be a novel approach to improving survival outcomes. Pirfenidone (5-methyl-1-phenyl-1H-pyridine-one), an agent demonstrating activity against fibroblasts and growth-promoting cytokines (TGF-β1, fibroblast growth factor [FGF], epidermal growth factor [EGF], and platelet-derived growth factor [PDGF]), has demonstrated clinical efficacy in IPF but has not yet been studied in lung cancer. We propose a proof-of-concept trial testing a novel combination of pirfenidone plus standard first-line chemotherapy in the treatment of advanced-stage NSCLC. Pirfenidone Pirfenidone has demonstrated activity against growth-promoting cytokines such as TGF-β1, FGF, EGF, and PDGF. A recent Phase III clinical trial of pirfenidone compared to placebo in patients with IPF demonstrated improved lung function, exercise tolerance, and progression-free survival (PFS) with an acceptable side-effect profile. To date, pirfenidone has not been studied in cancer, but its anti-fibroblast properties may play an important role in the tumor microenvironment. Our hypothesis is that pirfenidone (by targeting CAFs) in combination with standard chemotherapy will act synergistically and proffer a more potent strategy for NSCLC treatment. Data Generated in Dr Antonia’s Lab at Moffitt Cancer Center Using low doses of pirfenidone (0.5 mg/ml), we observed a small decrease in cell proliferation (20%), also noted with low doses of cisplatin (10%). When both drugs were used, we observed a synergistic decline in proliferation (60%). An in vivo model was performed to verify this data: nude mice were inoculated with a combination of A549 cells and CAF cells at a 1:1 ratio. Treatment with pirfenidone and cisplatin began as soon as tumors were palpable. Cisplatin- or pirfenidone-treated mice had a larger tumor size than mice treated with the combination, and on the final day (43 days after start of treatment), the combination showed statistically significant improvement compared to controls. This led to our hypothesis that similar tumor regression may occur in NSCLC patients.Figure 1



Methods:
Phase I, single-center, dose-escalation study. Phase I trial, followed by an expansion of 20 pts with non-squamous and 10 pts with squamous cell lung cancer. Primary Objectives: Determine safety, tolerability, and MTD of pirfenidone plus chemotherapy in pts with advanced NSCLC, and obtain the preliminary ORR. Secondary Objectives: Determine OS and PFS of pts treated with pirfenidone plus standard first-line chemotherapy.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Lung cancer is the most common cause of cancer-related deaths in the US, with adenocarcinoma being the most common histologic subtype. Aromatase, a critical rate-limiting enzyme in estrogen biosynthesis, is notably expressed in NSCLC cells. Retrospective studies show that high NSCLC aromatase levels are associated with worse clinical outcome, particularly in postmenopausal women (Weinberg et al., Cancer Res, 2005; Mah et al., Cancer Res, 2007; Garon et al., J Thoracic Oncol, 2013). Estrogens are known survival factors in lung and promote expression of nucleotide excision repair enzyme ERCC1 that is implicated in resistance to platinum-therapy. In NSCLC cells, ERCC1 transcript expression is blocked by exemestane, an aromatase inhibitor (AI), enhancing cisplatin-induced apoptosis. In preclinical NSCLC xenograft models, exemestane exerts synergistic antitumor activity combined with cisplatin and results in prolonged tumor suppression (Marquez-Garban et al., Ann NY Acad Sci, 2009). These data provide a rationale to assess an AI in the clinic.

Methods:
Based on our preclinical studies, we are conducting a phase IB, open-label, single-center study in postmenopausal, treatment-naïve (except prior single-agent tyrosine kinase inhibitor use) women with metastatic, non-squamous NSCLC (NCT 01664754). We plan to enroll 12-15 participants divided into two dose-escalation cohorts of exemestane. All participants receive standard chemotherapy with pemetrexed (500 mg/m[2]) and carboplatin (AUC 6), both given intravenously every 3 weeks. Cohort 1, which added exemestane 25 mg orally daily, has completed enrollment without any dose-limiting toxicities. Cohort 2, for which enrollment started in December of 2013, evaluates exemestane at 50 mg orally daily. Our primary aim is to evaluate safety and tolerability of the indicated regimen. Secondary objectives are tumor response rate, quality of life, pharmacokinetics/pharmacodynamics, and correlative studies of biomarkers (such as blood estrogens, tumor ERs, aromatase, and apoptosis) with tumor response.

Results:
Not applicable

Conclusion:
Not applicable

Background:
First-line afatinib, an oral, irreversible ErbB family blocker, improved progression-free survival (PFS), objective response rate and symptom control in patients with epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), when compared with standard platinum-doublet chemotherapy. Afatinib also significantly prolonged overall survival in patients with Del19 mutations. Some EGFR mutation-positive patients still receive first-line chemotherapy and there are limited data regarding the effect of afatinib in chemotherapy pre-treated EGFR mutation-positive patients. This study was designed to evaluate the efficacy and safety of 40 mg/day afatinib in the second-line setting.

Methods:
Across centers in Europe, Asia and North Africa, 60 patients with locally advanced or metastatic NSCLC (stage IIIB/IV) harboring common EGFR mutations (Del19 and/or L858R) who have failed first-line platinum-based chemotherapy will be recruited to this ongoing, single-arm, open-label, Phase IV trial. Patients will be treated with oral afatinib 40 mg/day until the development of progressive disease or study discontinuation due to intolerable adverse events (AEs). Inclusion criteria include age ≥18 years, ECOG PS 0 or 1, documented EGFR Del19 and/or L858R mutation with no other known EGFR mutation, and adequate organ function with a life expectancy of ≥3 months. Patients are excluded from enrolling if they have received >1 line of prior therapy for disease (radiotherapy and radiosensitizers and/or intrapleural administration of anti-cancer agents is not counted as a line of therapy), or received <3 cycles of platinum-based chemotherapy due to toxicity and/or intolerance of treatment, or received previous treatment with an EGFR-targeted tyrosine kinase inhibitor or antibody. The primary endpoint is objective tumor response (complete response [CR], partial response [PR]) according to RECIST v1.1. Secondary endpoints include PFS, disease control (CR, PR, stable disease) and assessment of safety. All patients who received at least one dose of afatinib will be included in the analysis of safety, with AEs graded according to CTCAE v3.0. Efficacy and safety will be evaluated in a descriptive manner; there are no formal statistical hypotheses. This trial was initiated in October 2014 and is open for accrual. Study locations include 22 trial sites in 7 countries. Trial sites are currently open to enrollment in Egypt, Romania, and Serbia. Enrollment will soon be open in Malaysia, the Philippines, Poland, and Thailand. The estimated completion date for the primary outcome is December 2016; further details are available at ClinicalTrials.gov (NCT02208843).

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Many patients with advanced non-small cell lung cancer (NSCLC) will experience disease progression during first-line chemotherapy. Effective and well-tolerated second-line treatment options for this patient population are limited. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the primary endpoint of overall response rate (ORR) compared with solvent-based paclitaxel plus C in patients with advanced NSCLC (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). nab-P combined with CC-486, an oral formulation of azacitidine, resulted in promising outcomes in a phase I trial of patients with relapsed/refractory solid tumors (LoRusso et al. Mol Cancer Ther. 2013;12(11 Suppl):Abstract A120). In the open-label, multicenter phase II ABOUND.2L trial, the safety and efficacy of nab-P with or without CC-486 will be evaluated in the second-line treatment of patients with advanced nonsquamous NSCLC.

Methods:
Approximately 160 patients who have received 1 platinum-containing chemotherapy regimen for treatment of advanced disease will be randomized 1:1 to CC-486 200 mg/day on days 1 to 14 every 21 days plus nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 8 and 15 every 21 days or nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days. Key eligibility criteria include histologically or cytologically confirmed advanced nonsquamous NSCLC, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, no prior taxane therapy, no known EGFR mutation or EML4-ALK translocation, and peripheral neuropathy grade < 2. Randomization will be stratified by ECOG performance status (0 vs 1), sex, and smoking status (yes vs no). ClinicalTrials.gov identifier NCT02250326.

Key Endpoints

Primary	-Progression-free Survival
Secondary	-Disease control rate -Overall Survival -ORR -Safety
Exploratory	-Changes in quality of life -Healthcare resource utilization throughout the study -Correlation between pretreatment tumor characteristics and response to treatment

Results:
Not applicable

Conclusion:
Not applicable

Background:
Non-small cell lung cancer (NSCLC) accounts for 85–90% of all lung cancer cases. Approximately 35% of patients with NSCLC have Stage III disease at the time of diagnosis. Platinum-based, concurrent chemoradiation therapy is the standard treatment for patients with locally advanced, unresectable NSCLC. However, most patients progress despite treatment, and 5-year overall survival (OS) is only ~15%. Therefore, there is a significant unmet need for novel, effective therapeutic approaches to prolong survival. Immunotherapies that block checkpoints used by tumor cells to dampen immune responses are a promising new treatment option. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs). MEDI4736 is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, preventing PD-L1-mediated inhibition of T-cell activation. It has been engineered to harbor a triple mutation in the fragment crystallizable domain, which removes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). Chemotherapy and radiotherapy upregulate the expression of tumor PD-L1, which could increase sensitivity to PD-L1-directed therapy. Based on this rationale, the PACIFIC study (NCT02125461) will evaluate the efficacy and safety of MEDI4736 in patients with locally advanced, unresectable NSCLC (Stage III) whose disease has not progressed following platinum-based, concurrent chemoradiation therapy.

Methods:
In this Phase 3, randomized, double-blind, multicenter, international study, ~700 patients will be randomized 2:1 to receive MEDI4736 (10 mg/kg IV) or placebo every 2 weeks for up to 12 months. Eligible patients must have previously received ≥2 cycles of platinum-based concurrent chemoradiation with no subsequent disease progression, have received a total dose of radiation of ≥60 Gy, and have archival tissue available. Patients treated with sequential chemoradiation therapy for locally advanced disease and those with metastatic disease are excluded. Randomization must occur within 42 days of radiation. Co-primary endpoints are OS and progression-free survival (PFS) (RECIST v1.1). Secondary endpoints include OS at 24 months, proportion of patients alive and progression-free at 12 and 18 months, time to second progression, objective response rate, duration of response, health-related quality of life, safety/tolerability, pharmacokinetics and immunogenicity of MEDI4736. Patients who achieve and maintain disease control up to 12 months will enter follow-up. Patients will be recruited at approximately 300 sites across Australia, Asia, Europe, North and South America and South Africa. Recruitment is ongoing.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Tumor Treating Fields (TTFields) are a novel, non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. TTFields predominantly affect two phases of mitosis: metaphase – by disrupting the formation of the mitotic spindle, and cytokinesis – by dielectrophoretic dislocation of intracellular constituents. Efficacy of TTFields in non-small cell lung cancer (NSCLC) of all histologies has been demonstrated in multiple in vitro and in vivo models, as well as in a phase I/II pilot study, in combination with pemetrexed. At the time of this study, squamous histology patients were still treated with pemetrexed, and those enrolled in the trial surprisingly demonstrated a high median overall survival of 13.8 months. The promising preclinical data, high safety profile and initial clinical data in squamous histology patients have led to the design of the current study.

Methods:
The LUNAR Clinical Trial 300 patients with advanced NSCLC of squamous histology will be randomized in a ratio of 1:1 to receive either standard doublet chemotherapy alone or chemotherapy combined with TTFields. Patients will be followed-up every 6 weeks clinically and radiographically until intra-thoracic progression, then continue a follow up for vital status. Objectives To test the efficacy and safety of TTFields in combination with chemotherapy in this patient population. Endpoints Overall survival (primary), radiological response, progression free survival, in field vs. out of field time to progression, quality of life and safety (secondary). Statistical Considerations This is prospective, randomized, multicenter study for 300 patients. The total sample size of 300 patients (272 + 10% loss to follow up), will achieve a 80% power with an alpha of 0.05 using a two-sided log rank test to detect a hazard ratio of 0.69 for OS. Patients will be stratified based on presence of extra-thoracic disease (intra-thoracic disease only versus extra-thoracic disease), gender (male vs. female) and region. Key Eligibility Criteria Age > 18 years; Intra-thoracic advanced (stage IV) NSCLC with squamous histology; No prior chemotherapy or biological therapy for advanced disease; No prior intra-thoracic radiotherapy for advanced disease; ECOG performance status of 0-1; No serious co-morbidities; No contraindication for chemotherapy or TTFields; Adequate bone marrow, liver and renal functions. Treatment Continuous, daily TTFields Therapy at 150 kHz, applied to the thorax using the NovoTTF-100L System. The System is a portable medical device allowing normal daily life activities. The device delivers alternating electric fields to the thorax using 4 Transducer Arrays. Chemotherapy options include a taxane or gemcitabine platinum-based doublet.

Results:
not applicable

Conclusion:
not applicable

Background:
For early stage non-small cell lung cancer (NSCLC) surgery is potentially the only curative treatment. However, a proportion of lung cancer patients develop recurrence, even after complete resection. The factors affecting recurrence in these patients are largely unknown. This study aimed to identify the predictive factors for recurrence in patients with stage I/II NSCLC.

Methods:
We retrospectively reviewed all patients diagnosed with stage I/II NSCLC at our institution from 2000 to 2013. Initial diagnosis at our institution and a minimum follow up of 36 months were required. Cox regression model was used for multivariate analysis.

Results:
A total of 673 patients with stage I/II were identified, of those 175 (26%) developed local or distant recurrence, with a median time to recurrence of 18 months. Median age was 74 (range: 44-96 years), 56% were current or former smokers. Patients were more likely to have upper lobe tumors than all other tumor locations combined (58% vs 42%), adenocarcinoma was the most prevalent histologic subtype (53%) and 47% had poorly differentiated or anaplastic tumors. 152 patients (87%) received surgery with lobectomy being the most common procedure followed by wedge resection. 24% received chemotherapy and 7% radiation. Median overall survival was 26 months (95%CI: 17.2-34.5). Patients with squamous cell carcinoma had a shorter median time to recurrence when compared with adenocarcinomas (13.2 months vs. 19.7 months) (p<0.02). Smoking history (HR: 1.98, 95%CI: 1.62-2.82, p<0.007), central tumor location (HR: 1.24, 95%CI: 1.09-1.56, p<0.01), squamous subtype (HR: 1.46, 95%CI: 1.22-1.84, p<0.002) , high histologic grade (HR: 2.76, 95%CI: 1.34-5.97, p<0.01) and lymphovascular invasion (HR: 4.3, 95%CI: 3.32-5.00, p<0.001) were independent predictors of recurrence by multivariate analysis. Poorly differentiated tumors were associated with a higher frequency of distant recurrence when compared with well differentiated tumors (OR: 2.7 vs. 1.2). In 43% of the patients with recurrence lung cancer was the primary cause of death.

Conclusion:
In our cohort, we observed that patients with lymphovascular invasion have the highest recurrence risk followed by high histologic grade tumors with the former having a direct correlation with distant metastasis. Patients with these risk factors may benefit from close surveillance after surgical resection, adjuvant therapy and aggressive management of local recurrence.

Background:
We analyze the long-term survival of patients that underwent video assisted thoracoscopic (VATS) anatomical lung resection for Stage I Non-small cell carcinoma (NSCLC) of the lung before at the Northshore University Health System

Methods:
This is a retrospective analysis of data from patients that underwent VATS lung anatomical resection before December 31st of 2010.We extracted the data through standard queries and by manual extraction from the Electronic Data Warehouse of the Northshore University Health System. The patients were selected based on surgical description of anatomical resection defined as lobectomy, bilobectomy or segmentectomy for proven NSCLC. Patients with more than one procedure performed, diagnosis of carcinoid tumor or incomplete data were excluded. The variables evaluated included demographics, preoperative workup and clinical evaluation, pathology reports, intra-operative data and post-operative outcomes and 3 and 5 years overall and disease free survival.

Results:
A total of 265 patients were included. The mean age at the time of diagnosis was 70.9 (±9.9) years, 68.5% were female, 84.3% were Caucasian with a 39.6 (±26.3) pack year smoking history. The most common comorbidities encountered were hypertension (66.3%), COPD (34.8%) and coronary artery disease (28.1%). VATS lobectomy was performed in 90% of the patients. FEV~1~ data was available in 91.1% of the patients whereas DLCO data was available in 84.3% of the patients that underwent VATS anatomical resection. The mean procedure time was 151 (±59) minutes; the median length of chest drainage with tube thoracostomy was 3 days. Eighteen (20.2%) patients required admission to the Intensive Care Unit (ICU) with a median length of stay in the ICU of 2.2 days. The median length of stay in the hospital was 3.6 days. There were no deaths within 90 days post-surgery. The overall rate of complications was 25.8% with prolonged air leak (>5 days) (11.2%) and atrial fibrillation (9.0%) being the most frequent complications. The rate of adverse events decreased over time from 27.8% in 2008 to 20% in 2010. Only one patient required a second intervention within 30 days of the first surgery for a persistent chylothorax. The median follow-up was 57 months. Recurrences occurred in 10.2% of the patients with a mean time of 1.7 (±1.0) years after surgery. Local recurrence occurred in 68.4% of the times 1.9(±1.09) years after surgery whereas distant recurrences occurred in 31.6% of the times 1.4(±0.89) years after surgery. Overall mortality was 16%. The 3- and 5-years overall survival was 86% and 76.2%. The 3 and 5-years disease-free survival was 86.8% and 82.2%

Conclusion:
VATS anatomical lung resection does not seem to affect the long-term survival in comparison with reported analysis for open thoracotomy for patients with stage I NSCLC. Our data demonstrated a decreasing rate of complications with a high rate of cure for this group of patients, which might be utilized to compare with nonsurgical therapy for NSCLC

Background:
The appropriate protocol of postoperative surveillance for patients with non-small cell lung cancer (NSCLC) is still controversial. The aim of this study is to evaluate the detectability of recurrence and the prognostic impact of the serum CYFRA 21-1 levels.

Methods:
We retrospectively reviewed 1076 patients who underwent surgical resection for NSCLC at Juntendo University Hospital, between January 2008 and May 2013. Patients with renal dysfunction were excluded.

Results:
Recurrence developed in 47 patients (30.5%) in high preoperative serum CYFRA 21-1 group, and 147 patients (16.0%) in normal preoperative serum CYFRA 21-1 group. High preoperative serum CYFRA 21-1 was related to the high recurrence rate (p<.0001) and the poor prognosis (p<.0001). In high preoperative serum CYFRA 21-1 group, 111 patients measured the serum CYFRA 21-1 level within the 1-3 months after surgery. Among them, 31 patients (27.9%) had an elevated serum CYFRA 21-1 level, and the poor prognosis (p<.0001) (Fig.). In 94 patients who measured the serum CYFRA 21-1 level during the follow-up period, 35 patients (37.2%) could detect recurrence by an elevated serum CYFRA 21-1 level before recurrence. Only for high preoperative serum CYFRA 21-1 group, 23 patients (67.6%) could detect recurrence.

Conclusion:
High preoperative serum CYFRA 21-1 was related to the high recurrence rate and the poor prognosis. In addition, high early-postoperative (1-3 months after surgery) serum CYFRA 21-1 was related to the poor prognosis. Measuring the serum CYFRA 21-1 level during the follow-up period is useful in the detection of recurrence, but that rate is low.

Background:
Programmed cell death protein 1, also known as PD1, is a 288 amino acids cell surface protein in the immunoglobulin superfamily. [[1]] PD-1 is expressed on T-cells and pro-B cells, plays a pivotal role in their differentiation. [[2]] PD-1 has two ligands, PD-L1 and PD-L2, which are the members of a peripheral membrane protein family called B7. [[3][4]] PD-L1 can suppress immune system in some special events such as pregnancy and auto immune disease. Binding of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. [[5]] PD-L2’s expression is more restricted compare to PD-L1 and mainly in antigen-presenting cells like Dendritic Cells and microphages. [[4]] Here we report a study of 139 NSCLC patients diagnosed and undergone primary surgery in Shanghai Chest Hospital. The expression of PD-L1 was exanimated by immunohistochemistry, and has a positive correlation with the stage of NSCLC. We also observed a significant correlation between PD-L1 over expression and EGFR mutation, which has the potential to be an favorable prognostic factor. High PD-L1 expression and EGFR mutation also correlated with a significant longer survival time of patients

Methods:
One pathologist examined the H&E- and IHC-stained slides and evaluated the results. The evaluation were done blinded as to the clinical pathologic characteristics and patient outcome. A series of 139 patients diagnosed with NSCLC and undergone primary surgery at Shanghai Chest Hospital (Shanghai, China) from January to December of 2008 were selected in this study. All the patients received lobectomy standard with systematic lymph node dissection. Immunohistochemistry staining for PD-L1 were performed both for tumor and tissue surrounding the tumor.PD-L1 positivity (PDL1+) was defined as 5% tumor cell membrane staining at any intensity.One pathologist examined the H&E- and IHC-stained slides and evaluated the results. The evaluation were done blinded as to the clinical pathologic characteristics and patient outcome. Overall survival data were obtained for each patient by following up visit performed on 2014.

Results:
A total of 139 tumors were examined after exclusion of uninformative slides. There were 72 patients (54.1 %) with stage II, and 61 (45.9 %) with stage III disease. For histological sub­types, there were 90 with adenocarcinoma, 43 with square carcinoma, and 6 with others. Of these, positive evaluation of PD-L1 staining was present in 81 (61.8 %) specimens, while 50 ( 38.2 %) specimens showed negtive/low PD-L1 staining, while the tumor adjacent tissue showed also negtive/low PD-L1 expression .We also did genotyping for the specimens and found about one third of them (50 in a total 133 specimens, 33.3%) carry EGFR mutation. Among the mutations,15 are happened on exome 19 and 33 are on exome 21. PD-L1 positively expression imply a longer survival time compared with PD-L1negatively expression.

Conclusion:
Our results suggest a prognostic value of PD-L1 expression evaluation, which can also be a potentiall immuno-target therapy for lung cancer

Background:
Continued surveillance of lung cancer patients after curative surgery allows for the diagnosis of new disease. However, there is a relative paucity of data in regards to the development of third primary lung cancers. The goals of this study were to examine the incidence of third primary cancers and the results of surgical therapy.

Methods:
Surgically resected Stage 1 second primary lung cancers with complete data were identified in The Survival Epidemiology and End Results (SEER) database between 2004 and 2010. Among these 238 cases, those which developed a third primary lung cancer 6 or more months after the diagnosis of the second primary were analyzed. Statistical methods were performed using Kaplan-Meier and multivariate analysis. A p value < 0.05 was considered statistically considered significant.

Results:
Twenty-four patients (10.1%) experienced a third primary lung cancer; sixteen cases (66.7%) were diagnosed in stage I. Twelve patients (50% of cases) underwent cancer surgery. Nine patients (37.5%) were treated with beam radiation – alone (8 cases, 89%) or in combination with surgery (1 case, 11%). Surgery was performed more frequently in early stages (75% of surgical cases were stage I versus 58% of non-surgical cases). There was no difference in age between patients who underwent any treatment and those who did not. Length of follow-up in third primary cancers was 18 months if surgically treated and 8 months if not surgically treated (p < 0.02). At multivariate analysis, the only independent predictor of improved survival was treatment (Hazard ratio (HR) 0.21, 95% CI: 0.07-0.66; p=0.007). Both surgery (HR=0.02; 95% CI: 0.002-0.29) and radiation (HR= 0.04; 95% CI: 0.002-0.54) significantly improved survival. Figure 1



Conclusion:
The overall incidence of third primary lung cancers after a second primary is 10.1%. Surveillance and intervention at early stage results in improved survival.

Background:
In Japan, the ratio of lung cancer patients of octogenarian was still increasing in 2012. Elderly patients used to have comorbidities. Thus it is more difficult to select the surgical treatment of the elderly person in the lung cancer. Therefore, we aimed to clarify the preferred surgical management in this patient group.

Methods:
A retrospective study was conducted between April 2008 and March 2015 that included patients with non-small cell lung cancer (NSCLC) aged ≥75 years. Patients were divided into those who underwent partial resection and those who underwent lobectomy.

Results:
This study included 44 patients: 28 men and 16 women. We divided into two groups; one is partial resection (P-group) and another is lobectomy group (L-group). In patient’s characteristics, there were mostly no significant differences between two groups, without preoperative diabetes mellitus (p = 0.0271), tumor size on CT (p = 0.0002), operation time (p < 0.0001), post-operative hospital days (p = 0.0003), or pathological tumor size (p < 0.0001). In survival analysis, there were significant differences in overall survival (OS) between P-group and L-group (p = 0.0335). However, there was no significant difference in disease-free survival (DFS) rate among the two categories (p = 0.41), and in OS among stage I patients (p = 0.16). Postoperative complication caused poor prognosis (p = 0.0004). However, operation procedure did not correlate with postoperative morbidity. Cox regression analysis revealed statistical significance for the Brinkman Index(BI) (p = 0.0318), the ratio of the pulmonary artery diameter to the ascending aorta diameter (PA:A) (p = 0.0182), and the alveolar–arterial oxygen gradient (A-aDO2) (p = 0.0300). Only the PA:A ratio remained significant after multivariate analysis, with a higher ratio associated with better survival. Only the PA:A ratio remained significant after multivariate analysis, with a higher ratio associated with better survival, by Wilcoxon’s test (p = 0.0376).

Conclusion:
In elder patients with NSCLC, surgical resection should not be denied by only age. However, operation procedure should select Partial resection, compare to Lobectomy, as much as possible, especially, with the higher patients of PA: A ratio.

Background:
The 5-year survival rates of N1 non-small-cell lung cancer (NSCLC) were reported to be between 27% and 67%. The aim of the study was to identify common prognostic factors in NSCLC with N1 nodal involvement.

Methods:
The medical records and the follow-up data of the patients operated for NSCLC(p-N1) between January 1991 and December 2013 in Yokohama Rosai Hospital were analyzed retrospectively. Fifty-four patients with NSCLC (p-N1) who underwent lung resections with negative surgical margins were included in this study.

Results:
The subjects were 45 men and 9 women with a mean age of 67 years (range, 45-81 years). Among them 24 had adenocarcinoma, 16 had squamous cell carcinoma, 6 had large cell carcinoma, and 8 had the other histologies. T-factor of the primary tumor was T1 in 12 patients, T2 in 34, T3 in 7, and T4 in 1. Among N1 disease, peripheral zone lymph node (#12,13,14) metastasis was 18 cases, while hilar zone node(#10,11) metastasis was 30 cases, and both zone in 6 cases. The overall 5-year survival rates were 54.7 % in N1 disease. In a univariate analysis, survival was worse in case of higher T factor (T3,4) (p<0.01), multiple-N1-node involvement(p<0.01), and multiple-N1-zone involvement(p<0.01). Among patients with single-N1-zone involvement, overall survival was lower in patients with hilar zone metastasis than in those with peripheral zone metastasis, although this difference was not statistically significant (p=0.272).Figure 1



Conclusion:
In pN1 NSCLC patients, higher T-factor, multiple-N1-node involvement, and multiple-N1-zone involvement were worse prognostic factors.

Background:
Along with the research progress of lung cancer-related driver genes, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinas(EML4-ALK) positive non-small cell lung cancer(NSCLC), which is a distinctive molecular subtype, has been concerned. In this study we evaluate the clinical features of EML4-ALK positive and postoperative NSCLC patients.

Methods:
Clinical data of 42 patients with EML4-ALK positive, postsurgical NSCLC were retrospectively analyized. The organs of distant metastasis were observed. Log-rank test were used to analyse the relationship between clinical characteristics and disease free survival(DFS), overall survival(OS).

Results:
EML4-ALK positive patients are raletive young, most of them are never-smokers, peripheral type. The tumors were either moderately or poorly differentiated. The most common organ of distant metastasis was brain. Much more brain metastasis occurred in center type patients than in peripheral type patients(70.0% vs 30.0%，P=0.004).The median time from operation to brain metastasis was 17.2 months. The median post brain metastasis OS was 9.4 months. The DFS of earlier stage, peripheral type, moderately differentiated, without lymph node metastasis and with adjuvant treatment patients were significant longer than those of later stage(30.3months vs 12.8 months, P=0.016), center type(27.4months vs 7.3months, P=0.000), poorly differentiated(27.0 months vs 11.9months, P=0.048), with lymph node metastasis(30.0months vs 12.8months, P=0.027) and without adjuvant treatment(19.1months vs 1.8months, P=0.000) patients. Earlier stage, peripheral type, with adjuvant treatment patients obtained longer OS than later stage, center type, without adjuvant treatment counterparts（respectively 55.5months vs 26.2months，P=0.025; 39.2months vs 20.9 months， P=0.003; 33.4months vs 15.7months，P=0.001）. Tab 1 Clinical characteristics of paients

Characteristics	No. of patients	Percent(%)
Gender
Male	23	54.8
Female	19	45.2
Age(yr)
≤55	26	61.9
＞55 Median(range)	16 52(23-71)	38.1
Smoking history
Yes	13	31.0
No	29	69.0
Stage
Ⅰ stage	10	23.8
Ⅱ stage	3	7.1
Ⅲ stage	24	57.1
Ⅳ stage	5	11.9
Tumor location
Center type	12	28.6
Peripheral type	30	71.4
Histology
Adenocarcinoma	39	92.9
Squamous cell carcinoma	0	0
Adenosquamous carcinoma	1	2.4
Others	2	4.8
Differentiation degree
Well differentiated	0	0
Moderately differentiated	26	61.9
Poorly differentiated	16	38.1

Tab 2 Relationship between clinical characteristics and DFS, OS

Group	DFS(month)	P	OS(month)	P
Gender
Male	14.7	0.117	26.2	0.630
Female	18.8		32.8
Age(yr)
≤55	19.1	0.257	32.0	0.652
＞55	17.4		30.0
Stage
Ⅰ+Ⅱ stage	30.3	0.016	55.5	0.025
Ⅲ+Ⅳ stage	12.8		26.2
Tumor location
Center type	7.3	0.000	20.9	0.003
Peripheral type	27.4		39.2
Smoking history
Yes	7.0	0.167	22.9	0.524
No	17.4		32.8
Differentiation degree
Moderately differentiated	27.0	0.048	39.2	0.055
Poorly differentiated	11.9		26.2
Tumor diameter
>3cm	12.8	0.200	32.0	0.502
≤3cm	27.0		33.4
Lymph node metastasis
Yes	12.8	0.027	27.8	0.071
No	30.0		45.0
adjuvant treatment
Yes	19.1	0.000	33.4	0.001
No	1.8		15.7

Conclusion:
EML4-ALK positive, postoperative NSCLC patients have distinctive clinical characteristics. The most common location of extrapulmonary metastasis was brain. DFS was associated with TNM stage, tumor location, differentiation degree, lymph node metastasis and adjuvant therapy. OS was related to TNM stage, tumor location and adjuvant therapy.

Background:
Prolonged air leak (PAL) is a common complication, which occurs in 3% to 25% of patients undergoing pulmonary resection. PAL may cause severe morbidity such as pneumonia and empyema, and prolong the need for chest tube drainage and hospitalization. Thus, a careful perioperative management to decrease the risk of PAL is needed. The purpose of this study is to analyze the significance of various risk factors for postoperative PAL (air leak longer lasting more than 7 days) in patients undergoing pulmonary lobectomy for lung cancer.

Methods:
This study includes 134 patients who underwent pulmonary lobectomy for lung cancer between September 2009 and December 2014 at Kyoto Prefectural University of Medicine. We usually approached through video assisted thoracoscopic surgery that used a mini-thoracotomy and two ports. The divided interlober fissures and the small pleural defects causing minor air leak were covered with bioabsorbable sheet and/or fibrin glue. The patients with pulmonary air leak lasting until postoperative day 7 underwent pleurodesis. We retrospectively analyzed the perioperative variables in the two groups of the patients with PAL or without PAL. All results were expressed as mean ± standard error (patients with PAL vs patients without PAL). P-value <0.05 was considered statistically significant.

Results:
PAL occurred in 17 patients (12.7%), lasting an average of 8.9 days. The patients were 16 men and 1 woman with a mean age of 70.3 years old (58-79 years old). All patients underwent pleurodesis with successful closure of air leak and no patients required re-thoracotomy. Univariate analysis demonstrated significant independent predictors of PAL; a male predominance (94 vs 57% ;p=0.004), a high Brinkman index (960±580 vs 490±590; p=0.003), a preoperative low serum albumin level (4.0±0.7 vs 4.3±0.3 g/dl; p=0.003), and a long operative time (230±84 vs 184±53 min; p=0.045). A tendency toward a longer stapler length used for the interlober fissure division was also shown in the patient with PAL (109±61 vs 77±68 mm; p=0.064). PAL was not influenced by age, BMI, preoperative serum total protein level, preoperative hemoglobin, preoperative total lymphocyte count, %VC, FEV1.0%, resected lobe, and pleural adhesions.

Conclusion:
We report that a male, a long smoking history, a preoperative low albumin level, and a long operative time increased the risk of air leak lasting more than 7 days following lobectomy for primary lung cancer. Pleural adhesion, which had been reported to be a risk factor of PAL, was not related with PAL. Our analysis suggests that, for the sake of preventing PAL, we should pay attention to the preoperative nutritional status as well as well as surgical techniques, such as interlober fissure division in the cases that need multiple stapling to complete fissures.

Background:
Increasingly, localization of small lung nodule (solid or ground glass) is needed for thoracoscopic resection of accurate diagnostic and/or curative intent. Hook wire implantation is one of important localization techniques. Meanwhile, tumor recurrence in the chest wall of the percutaneous FNA tract is well known in thoracic malignancy, particularly lung cancer.

Methods:
We report the case of a 64-year-old-man with tumor recurrence of the chest wall. Eight months earlier, he underwent hook wire-guided thoracoscopic resection of RUL nodule and further anterior segmentectomy because of intraoperative diagnosis of NSCLC (squamous cell carcinoma, pT1aN0M0 IA).

Results:
Location of the chest wall tumor was coincident with the hook wire tract. The tumor was resected en-bloc, and reported as a metastatic squamous cell carcinoma. Figure 1Figure 2





Conclusion:
To reduce the risk of the tumor recurrence related with localization techniques, thoracic surgeons had better know very well the topographical anatomy of lung and avoid an unnecessary localization technique, and the wire is recommended to be withdrawn through the VATS port rather than percutaneously. This is the first report of tumor recurrence related with hook wire localization in the PubMed search.

Background:
The use of digital drainage systems after thoracic surgery is becoming accepted as a safe method. The aim of this study was to assess the effectiveness of the digital drainage system versus traditional devices on chest tube removal and air leak duration after lung resection. We report the management of a digital drainage system in patients undergoing lung resection.

Methods:
This study is retrospective study of patients undergoing anatomical lung resection (segmentectomy, lobectomy, sleeve lobectomy, or bilobectomy).145 patients who underwent lung resections for lung cancer were evaluated. Chest tubes were removed when an air leak was not evident anymore and the drained fluid was less than 200 mL/day.

Results:
These series includes 140 lobectomies, 2 sleeve lobectomies, 1 bilobectomy and 2 anatomical segmentectomies. Patients who use digital drainage system had a significantly shorter air leak duration (0.9 versus 1.7 days; p=0.037), no significance of duration of chest tube placement (4.4 versus 5.5 days; p=0.112) and no significance of chest tube placement after the air leakage disappearance (3.5 versus 3.8 days; p=0.71).

Conclusion:
Patients managed with digital drainage system experienced a shorter duration of air leak compared with those managed with traditional devices. Digital devices appear to be safe and effective and may prove to be a useful tool in the management of lung resection.

Background:
Radiotherapy after initial surgery significantly improves outcomes in patients with pathological N2 non-small–cell lung cancer (NSCLC). Here, we aimed to identify best candidates for postoperative radiotherapy among patients with local recurrence.

Methods:
Among patients who underwent complete resections for NSCLC between August 2007 and December 2011 in our hospital, we enrolled all 21 patients with clinical N0–1 and pathological N2 NSCLC in this study. We assessed their age, sex, tumor size, histology, differentiation, lymphatic permeation, vessel invasion, pathological N2 location, pathological N2 number, and adjuvant chemotherapy, and classified them as the local recurrence group (recurrences limited to lymph nodes up to N3 or adjacent to the surgical margin), the distant recurrence group (in whom distant recurrence occurred within 6 months after local recurrence) and the no-recurrence group. Relationships between these clinical parameters and recurrence patterns (local or distant) were statistically assessed by Fisher’s exact test.

Results:
All 21 patients underwent lobectomies and systematic mediastinal nodal dissections that included upper mediastinal nodes and subcarinal nodes. Postoperatively, 17 patients underwent chemotherapy and none underwent radiotherapy. Recurrence was seen in 15 patients: 5 local and 10 distant recurrences. Histologically, squamous cell carcinomas (SCC) were significantly more common in the local recurrence group (P=0.0358) at 3 SCC and 2 adenocarcinomas (AD), compared with the distant recurrence group: 0 SCC and 10 AD; and the no-recurrence group: 2 SCC and 4 AD. No other clinical factors were significantly associated with recurrence. Notably, vessel invasion was seen in 80% of the local recurrence group, 90% of the distant recurrence group, and 17% of the no-recurrence group.

Conclusion:
Among patients with clinical N0 or N1 and pathological N2 NSCLC, postoperative radiotherapy was most suited to those whose pathology showed SCC.

Background:
Localization of ground glass nodule is a difficult challenge for thoracic surgeons, especially for those GGOs less than 10 mm in diameter. In this study we implant a new method for Preoperative localization of ground glass pulmonary opacity (GGO).

Methods:
From October 2013 to December 2014, CT-guided percutaneous Polylactic acid injection localizations were performed for 5 pulmonary nodules in 5 patients (2 men and 3 women; mean age, 59.8 years; range, 54-65 years). Figure 1



Results:
The injection was feasible in all patients and the localization effect was excellent, with total procedure duration 12.6 minutes (range; 10-15), Volume of Polylactic acid injected 0.38ml (Table 2). The wedge resections were easily and successfully performed in 5 cases, the cutting margin was no less than 2cm from lesion.

Conclusion:
This technique will be promising for GGO location in facilitating thoracoscopic surgery for wedge resection.

Background:
Chronic obstructive pulmonary disease (COPD) is a risk factor and important coexisting disease for lung cancer; at the same time, coexisting COPD owes unfavorable effect on management of lung cancer. However, the current status of management of COPD in lung cancer patients with operable sites is not fully described. This study addressed this issue in a general teaching hospital in China.

Methods:
All patients with lung cancer underwent surgery were collected retrospectively from Jan. 2002 to Dec. 2008. Medical records were reviewed about clinical information, pathological records, lung functions, etc., so as to analysis comorbidity rate about COPD and characters. The definition of COPD was according the spirometric criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document. The diagnostic rate (COPD recorded as a discharge diagnosis/spirometry-defined percentage) and conformity to GOLD treatment guidelines were investigated. The factors influencing diagnosis were analyzed.

Results:
Among all 437 undergone surgery patients aged older than 40 years old, 94 patients were diagnosed COPD, the prevalence of COPD was 21.36%(41 as GOLD 1, 52 as GOLD 2, and 1 as GOLD 3)。Among them, 89.36% was male, with average age being 63.3 years old. Only 9 patients were diagnosed as COPD, the rate of misdiagnosis was 90.4% and all of them did not receive pulmonary function test. 71.3% of those patients with COPD had smoke history; average smoke intensity was 26.7 pack-year. All surgery of pathological staging were classified as followed according to the standards of the Union International Contre le Cancer (UICC):Ⅰstage (A+B：38+119); Ⅱ(A+B：14+83); Ⅲ(A+B：100+32); IV: 31; No specific: 20 cases. And patients complicated with COPD presented stages as followed:Ⅰstages (A+B：6+23)、Ⅱ(B：21); Ⅲ(A+B：33+7); IV: 1; No specific: 3 cases. The rate of lung cancer complicated with COPD was 24.8%, 21.6%, 30.3% respectively.

Conclusion:
Patients of lung cancer undergone surgery have high risk morbidity of COPD. To improve the result of peri-operation period management, COPD should be pay attention to treat for these patients.

Background:
Multidisciplinary team meetings (MDM) have become the standard of practice across a variety of medical disciplines. In particular, MDMs have found utility in the management of complex diseases requiring multi-modal treatment such as cancer. Advancements in information sharing technology have extended the reach of MDMs to improve care in previously remote and underserved areas. Lung cancer management is now largely directed through MDMs. However, MDMs are, by their very nature, resource intensive. In a world of increasing accountability for the distribution of limited resources, a review of the evidence for benefit of MDMs, as well as the different strategies employed in running a successful MDM, is necessary to ensure efficient provision of this care.

Methods:
A review of the existing peer-reviewed literature on MDM was conducted on Pubmed, using the broad search term of “multidisciplinary team meeting.” Existing reviews and original research were included, while non-English studies and letters were excluded.

Results:
Introduction of MDMs have been attributed to a variety of positive outcomes in the management of multiple oncological diseases. While there are a handful of studies questioning the cost-benefit of MDM without adequate patient selection in colorectal cancers, the evidence for improving management in most cancers (including lung cancer) is strong. An additional benefit is the increased reach of clinical trials, with MDMs being demonstrated to improve subscription rates. However, while lung MDMs have been demonstrated to make significant improvements to the overall care of a lung cancer patient, the evidence for improved survival remains limited. The limited impact of lung MDM to overall survival may be at least partially attributable to the late-presenting nature of the disease. This may be exacerbated by geographical limitations of some healthcare networks. However, with improvements in health informatics and telemedicine, standardising early care across a vast region has been shown to be possible and improve outcomes in other cancers.

Conclusion:
While it is clear that disease management is improved with the introduction of lung MDM, further study is needed to optimise its efficacy and define its impact on survival.

Background:
The number of thoracoscopic pulmonary resection has been increasing due to the less invasiveness and development of endoscopic instruments and perioperative management of the patients. However, the intraoperative unexpected bleeding cases which required emergent conversion to thoracotomy were gradually reported. The aim of this retrospective study was to review our experience, management, and the outcome of unexpected bleeding during thoracoscopic surgery.

Methods:
All patients who underwent thoracoscopic anatomical pulmonary resection for primary lung cancer were analysed. Hemostatic procedures with angiorrhaphy and/or using the sealant were defined as intraoperative unexpected bleeding in this study. The location, cause, management of injured vessels, and perioperative outcome, including blood loss, hospital stay, the rate of morbidity and mortality were investigated to compare those without vessel injured.

Results:
From 2007 to 2014, a total of 241 thoracoscopic anatomical pulmonary resection was performed. 20 (8.3%) cases were required hemostatic procedures with angiorrhaphy and/or using the sealant. 15 (75%) cases of 20 were converted to thoracotomy. Injured vessels were pulmonary artery (n=13), vein (n=3), azygous vein (n=3), and superior vena cava (n=1), respectively. In pulmonary artery, the injury was seen in first branch (n=5) and small branches to right upper lobe (n=5). The main causes of injured vessels were related to the technical problems of energy devices and staplers. 16 (80%) cases were direct suture, ligation or division of injured vessels, and 3 cases were successfully controlled by TachoSil without converted to thoracotomy. Blood loss of 20 cases ranged from 150-2160 (median, 500) ml. 6 (30%) were administered with blood transfusion. Perioperative 5 comorbidities were identified in 4 patients, consisted of prolonged air leak in 2 patients and atrial fibrillation, transient recurrent laryngeal nerve palsy, and chylothorax in each patient. No mortality was identified in this study. The difference between vessel injured and non-injured patients in operation time (285 vs 235 minutes, average, p=0.003) and blood loss (804 vs 121 ml, average, p<0.001) were significant, but perioperative comorbidities including respiratory and cardiovascular complications and the duration of chest tube insertion (4.5 vs 3.5 days, average, p=0.20) and postoperative hospital stay (12.7 days vs 11.0 days, average, p=0.08) were not significant.

Conclusion:
The frequency of unexpected bleeding in this study was relatively high, but the management and the outcome of patients in this study were feasible in terms of safety. TachoSil is a useful sealant to be used next step for bleeding. For surgeons, it should be establish algorithms for this catastrophic intraoperative complication during thoracoscopic pulmonary resection.

Background:
There are no accurate data on the diagnostic value of preoperative flexible bronchoscopy (FB) for persistent ground-glass nodule (GGN) of the lung. We evaluated the value of preoperative FB in patients with suspected GGN-type lung cancer.

Methods:
We retrospectively searched a database for subjects who had ‘ground-glass opacity’, ‘non-solid nodule’, ‘part-solid nodule’, or ‘sub-solid nodule’ on chest computed tomography reports between February 2004 and March 2012. Patients who had infiltrative ground-glass opacity lesions, mediastinal lymphadenopathy, or pleural effusion, focal ground-glass opacity lesions >3 cm, and were lost to follow-up were excluded. We assessed the diagnostic value of preoperative FB in patients with persistent GGNs who underwent surgical resection.

Results:
In total, 296 GGNs were evaluated by FB in 264 patients with persistent GGNs who underwent preoperative FB and surgical resection. The median size of the GGNs was 18 mm; 135 (46%) were pure GGN and 161 (54%) were part-solid GGN. No visible tumor or unsuspected endobronchial metastasis was identified by preoperative FB. Only 3 (1%, 3/208) GGNs were identified preoperatively as malignant by bronchial washing cytology; all were part-solid GGNs. No other etiology was identified by FB. Of the GGNs, 271 (91%) were subsequently confirmed as malignant and 25 (9%) were confirmed as benign at surgical resection. Consequently, the overall diagnostic sensitivity and negative predictive value of preoperative FB on a per-nodule basis was 1% (3/271) and 8% (25/293), respectively. The preoperative FB did not change the surgical strategy.

Conclusion:
Preoperative FB did not add much to the evaluation of persistent GGNs of the lung. Routine preoperative FB may have limited value in surgical candidates, especially in patients with small persistent pure GGNs.

Background:
Some non-small cell lung cancer (NSCLC) patients showed preserved pulmonary function after surgery. Video-assisted thoracic surgery (VATS) is currently widely performed and well known to preserve pulmonary function compared to open thoracotomy. However, it is unknown which factors are associated with the preservation of pulmonary function after VATS in NSCLC patients.

Methods:
Three hundred and fifty one patients with NSCLC who underwent VATS were enrolled. Pulmonary function tests were performed preoperatively and at 12 months postoperatively. Patients who showed preserved forced expiratory volume in 1 second (FEV~1~) and diffusing capacity of carbon monoxide (DLCO) were compared with patients who did not.

Results:
FEV~1~ was preserved after VATS in 65 (18.5 %) patients. They were significantly related to undertake VATS sublobar resection (P<0.001) and resect at right upper lobe (RUL) or right middle lobe (RML) (P<0.05) in multivariable analysis. DLCO showed preservation in 95 (27.1%) patients. VATS sublobar resection (P=0.005), lower baseline DLCO (P<0.001) and RUL or RML resection (P<0.05) were significantly associated with DLCO preservation in multivariable analysis.

Conclusion:
For the preservation of pulmonary function after NSCLC surgery, VATS sublobar resection was superior to VATS lobectomy and the surgical location of RUL or RML was superior to other sites.

Background:
Surgery remains the cornerstone of therapy for medically operable patients with early stage NSCLC. Differences in the frequency of surgery for patients with respect to their age, sex and socioeconomic deprivation have been described. Older patients have been found to be less likely to undergo surgery compared with younger patients even when they have similar performance status. Several randomized trials and meta-analyses have shown that adjuvant chemotherapy after resection of stages II–IIIA NSCLC improves survival.

Methods:
The medical records of all 164 patients ≥70 years, who underwent surgery for NSCLC from 2003 to 2009 at our department, were reviewed retrospectively.

Results:
One-hundred twenty-six given no adjuvant therapy. Eigthy-seven (52.4%) were male. Median mean and range of age male patients was 75.0, 74.8 and 70-85 years, while in females, these figures were 74.0, 75.5 and 70-84 years. Eighty-one (94.2%) of the males and 65 (82.3%) of the females were smoker/former-smoker. In both sexes 99% had performance status 0-1. Eighty-one (93.1%) of male patients and 71 (89.9%) of the females were stage I-II. Adenocarcinoma was the common histology in both sexes (55% of the males and 67.1% of the females). Squamous cell carcinoma came in second place, 31% respectively 20%. Lobectomi performed in 61 (84.1%) of the male patients and 62 (86.2%) female patients, left pneumonectomy in 6 (7.3%) male patients and 5 (6.9%) in female patients, right pneumonectomy in 1(1.4%) female patient. One-hundred twenty-six (77%) did not receive adjuvant therapy, mainly because of age. Median overall survival among all was 7.2 years, in the non-adjuvant group was 6.7 years and 7.6 years in the adjuvant group (p=0.5712).

Conclusion:
This single-institution series demonstrates that surgical intervention for appropriately selected elderly patients with NSCLC results in improved overall survival. Surgery should, therefore, be strongly considered for select patients ≥ 70 years of age with stage I/II and select stage IIIA NSCLC who have adequate pulmonary reserve.

Background:
Prediction of postoperative forced expiratory volume in 1 second (FEV1.0) is known as the basis for surgical indications of lung resection. The 0.8L or less estimated postoperative FEV1.0 has been reported an increase in surgery related deaths. In fact, there are some cases that the postoperative FEV1.0 is less than prediction of postoperative FEV1.0. The postoperative respiratory function have been reported in segmentectomy and lobectomy, but little is known in sleeve lobectomy.

Methods:
Between January 2008 and October 2014, 37 patients underwent sleeve lobectomy and evaluated respiratory function tests of preoperative and passing more than six months after surgery at the Juntendo university, Tokyo, Japan. We defined postoperative FEV1.0 / prediction of postoperative FEV1.0 ratio as postoperative FEV1.0 ratio. The patients were divided by postoperative FEV1.0 ratio into the 16 patients who evaluated postoperative FEV1.0 ratio < 1 and the 21 patients who postoperative FEV1.0 ratio ≧ 1. We investigated clinic-pathological features, postoperative complications and predictive factors in postoperative reduction of FEV1.0.

Results:
In the group of postoperative FEV1.0 ratio < 1, the median age was 63 years old (range, 35-77 years), 14 cases (88%) were male, the median postoperative FEV1.0 was 2.05L (range, 0.99-2.54) and the median prediction of postoperative FEV1.0 was 1.82L (range, 0.97-2.23). The group of postoperative FEV1.0 ratio < 1 had marginally more phrenic nerve resection (19%) and blood transfusion (50%) than the group of postoperative FEV1.0 ratio ≧ 1 (p=0.077 and p=0.072). There was no difference in the incidence of morbidity between both groups. The phrenic nerve resection was marginally risk factors of postoperative reduction of FEV1.0 in univariate analysis (p =0.053). The phrenic nerve resection and right side were risk factors of postoperative reduction of FEV1.0 in multivariate analysis (p =0.026 and p =0.048).

Conclusion:
Right side and phrenic nerve resection were independent factors to predict the postoperative FEV1.0 falls below postoperative prediction FEV1.0.

Background:
The results of lung cancer surgical treatment depend on several factors inherent to the tumour, the patient and the socio-economic context in which the disease is managed. Few studies have described the results of surgery for lung cancer in emerging countries, particularly in Africa. The objective of this study was to report a large monocentric experience of a North African country.

Methods:
The results of lung cancer surgical treatment depend on several factors inherent to the tumour, the patient and the socio-economic context in which the disease is managed. Few studies have described the results of surgery for lung cancer in emerging countries, particularly in Africa. The objective of this study was to report a large monocentric experience of a North African country.

Results:
There were 1485 males and 196 females (sex ratio 7.57) with a mean age of 58 (range 10-91). Clinical findings were dominated by thoracic symptoms and 176 (10.4%) were asymptomatic. Imaging findings showed a peripheral mass in 883 cases (52.5%). The mean tumour size was 5.3 cm (range, 1 – 20 cm). 48 patients received induction therapy (this treatment was not prescribed before 2009). Lobectomy or bilobectomy was performed in 1036 patients (61.6%) and pneumonectomy in 448 patients (26.6%), thoracotomy was exploratory in 153 cases (9.1%), the rate of exploratory thoracotomy has fallen at 4.5% in the last 10 years (2003 to 2012). The histology diagnoses were: squamous cell carcinoma (n=693), adenocarcinoma (n=622), carcinoid tumour (n=135). Different stages were: IA (n=167), IB (n=523), IIA (n=56), IIB (n=393), IIIA (n=244), IIIB (n=188) and IV (n=109). There were 4 operative deaths. 69 died within 1 month of surgical complications. Post operative course was uneventful in 1203 patients (71.5%) and the most frequent post operative complication was persistent air leak. Post operative mortality was 4.3% (within 30 days PO), 3.47% for lobectomies and 6.25% for pneumonectomy. Adjuvant therapy was performed in 157 patients. The median survival time was 45 months with a maximum of 276 months. The overall 5-year survival rate was at 30% and it was at 67%, 41%, 44%, 24%, 17%, 3% and 13% respectively for stages IA, IB, IIA, IIB, IIIA, IIIB and IV. Survival was influenced by sex; age over 70 years, tumour size, nodal status, tumour stage and surgical procedure. By cons, post operative radiotherapy and neoadjuvant chemotherapy did not significantly improve the prognosis of our patients.

Conclusion:
Our 30 years experience initiated in 1985 of surgery for lung cancer demonstrated that major thoracic surgery is feasible with good early results and low mortality and morbidity rates. Survival rates are lower than those of the world literature; this may be related to the more advanced stages of our series and the lack to a complete assessment of the patients: number of patients did not have CTscan in the beginning of the series, and nowadays we don’t yet have PET scan in our country.

Background:
The presence of prolonged air leak (PAL) after pulmonary resection sometimes results in serious complications, such as empyema. Therefore, early prediction and intervention for PAL should be performed. Thopaz[TM] is a digital monitoring thoracic drainage system which enables the objective evaluation of air leak. This study aimed to establish the diagnostic criteria for the early prediction of PAL using the Thopaz[TM ]system.

Methods:
The postoperative data of 150 patients who underwent pulmonary resection and for whom the digital monitoring of thoracic drainage was performed using Thopaz[TM] between December 2013 and January 2015 were prospectively collected. When the air flow level was < 20 mL/min for > 12 hours, the chest tube was removed. We examined the postoperative data, including the chest X-ray findings, the presence of postoperative complications, the duration of air leak, the duration of chest tube placement, the patterns of air leak until 72 hours after operation and the level of peak air flow until 24 hours after operation as determined by Thopaz[TM]. The patterns of air leak were defined as Types A-E (A: No air leak was observed until the removal of the chest tube; B: Air leak flow gradually decreased; C: Although no air leak was observed immediately after operation, air leak occurred postoperatively; D: The repeated exacerbation and remission of air leak was observed; E: Air leak was observed without a trend toward improvement).

Results:
There were 100 men and 50 women; 99 smokers and 51 never-smokers; and 119 cases of lung cancer and 31 cases of other diseases. Their surgeries included 23 wedge resections, 24 segmentectomies and 103 lobectomies. Air leak at the time of the sealing test during the operation was observed in 82 (55%) patients. Air leak was observed in 31 (21%) patients, in whom the mean (± SD) duration of air leak was 3.9 (± 3.7) days. The mean (± SD) duration of chest tube placement was 3.2 (± 1.9) days in the whole study population (n = 150) and 5.2 (± 2.7) days in the 31patients with postoperative air leak. On chest X-ray films, 12 cases of subcutaneous emphysema and 4 cases of atelectasis were observed postoperatively. No complications associated with Thopaz[TM] developed. PAL > 4 days was observed in 10 (6.7%) patients. The frequencies of PAL according to the air leak patterns were 0% (0/119) in type A, 23% (3/13) in type B, 20% (2/10) in type C, 50% (2/4) in type D and 75% (3/4) in type E. The frequencies of PAL according to the peak air flow were 11% (2/18) in < 100 ml/min, 62% (8/13) in ≥ 100 ml/min, 60% (6/10) in ≥ 200 ml/min, 83% (5/6) in ≥ 400 ml/min and 80% (4/5) in ≥ 500ml/min.

Conclusion:
The risk of PAL was higher in patients showing type D and E air leak patterns, and a peak air flow of ≥ 400 ml/min. The results indicate that PAL after pulmonary resection may be predicted by air leak patterns and peak air flow using the Thopaz[TM] system.

Background:
Several studies have reported that acute exacervation (AE) of idiopathic interstitial pneumonia (IIP) can occur after lung resection for patients with non-small cell lung cancer (NSCLC), though the strategy of the perioperative management is controversial.

Methods:
We examined our institutional data about the lung cancer patients from June 1994 through October 2013 at Nagasaki University Hospital in a retrospective manner.

Results:
A total of patients who underwent lung resection for NSCLC(1701 cases) was investigated, 58 had IIP, for an incidence rate of 3.8%. The majority of patients were men (52 cases, 89.6%) and ex- or current smokers (53 cases, 91.3%), and the average of Packs per year was 54.1 (range 30-150). Squamous cell carcinoma was the most common type of lung cancer (23 cases, 39.6%), and the second common type was adenocarcinoma (22 cases, 37.9%). Surgical procedure was wedge resection in 12 cases, segmentectomy in 6 cases, lobectomy in 39 cases, pneumonectomy in 1 case, respectively. 6 cases(10.3%) had AE of IIP following lung resection, 3 cases(50%) of those patient died in the hospital. The univariate analysis and multivariate analysis were carried out to identify possible risk factors for AE. The univariate analysis identified LDH and bleeding amount. Multivariate analysis further identified only LDH. As a treatment for AE, we performed steroid pulse therapy and administration of Neutrophil elastase inhibitor. In some cases that no effect was given by such treatments, we performed direct hemoperfusion with a polymyxin B immobilized fiber column and administered immunosuppressant.

Conclusion:
Patients with lung cancer combined with IIP increases the risk of chest surgery, and the prognosis of them is poor. Because the prediction of AE is often difficult, surgery and perioperative management should be done very carefully.

Background:
Data from prospective randomized clinical trials are lacking in the comparison between lobectomy (L) and SABRT in operable patients and ongoing trials have troubles in recruiting. In inoperable patients a local control of 64-95% in retrospective and 92-98% in prospective trial is reported when BED is over 100 Gy.

Methods:
From 2003 to 2013, 182 I-IIA NSCLC patients were treated at our Institution. Clinical characteristics are summarized in table I; cyto-histological prove of NSCLC was available in all surgical patients and in 61/88 (69%) SABRT patients. Spirometry was available in 120/182 (66%). Response was evaluated according to RECIST criteria after primary treatment. Toxicity was graduated according to CTCAE version 4 criteria.

	RT	Surg	Total	p^
	n=88 (%)	n=94 (%)	n=182(%)
Gender
Male	70(79.5)	61(64.9)	131(72.0)	0.032
Female	18(20.5)	33(35.1)	51(28.0)
Age (median)
<72	26(29.5)	67(71.3)	93(51.1)	0.0001
>72	62(70.5)	27(28.7)	89(48.9)
Hystology
Adenocarcinoma	36(59.0)	69(73.4)	105(67.7)	0.14
SCC	23(37.7)	24(25.5)	47(30.4)
Large Cell Carcinoma	2(3.3)	1(1.1)	33(18.1)
Performance Status
0	13(14.8)	62(66.0)	75(41.2)	0.0001
1	45(51.1)	29(30.9)	74(40.7)
2	30(34.1)	3(3.1)	33(18.1)
FEV1
<1.5	35(43.8)	7(17.5)	42(35.0)	0.005
>1.5	45(56.2)	33(82.5)	78(65.0)

Results:
Median follow-up time was 25 months (range: 6-110). Three local relapses (LR) were observed in L and 18 in SABRT group (p=0,0001). No difference in distant metastases was observed (19 in L vs 18 in SABRT group) (p=1-data not shown). Results of univariate survival analysis are shown in table II. Multivariate analysis confirmed the protective effect of L on OS and of good FEV1 (>1,5L) on DFS. A subgroup comparison of SABRT patients treated with BED>100Gy vs surgical patients showed no difference in local control (LC) (p=0,60) while OS and tumor-specific survival (TSS) remain in favor of L (p=0,001 and 0,049 respectively). Moreover, comparing surgical patients with SABRT with known histology and BED>100 Gy no difference was seen in TSS (p=0.10) nor in LC (p=0,36). No grade 3-5 toxicity was observed in both group.

	Died	% OS	p^	LR	% DFS	p^
Age (median) <72	26	56.1	0.001	10	84.3	0.50
>72	50	10		11	79.9
Hystology Adenocarcinoma	34	37.9	0.66	9	87	0.81
SCC	22	35		3	91.2
Large Cell Carcinoma	1	66.7		0	100
Performance Status 0	17	59.8	0.001	7	87.3	0.52
1	29	19		9	79.5
2	3	18.3		5	81
FEV1 <1.5	27	20.4	0.14	11	86.2	0.005
>1.5	37	14		7	80.9
Treatment Radiotherapy	62	4.4	0.0001	18	67.4	0.0001
Surgery	14	72.9		3	95.1
Total	76	12.2		21	82.4

Conclusion:
SABRT with adequate doses vs L in operable patients shows promising results in terms of LC and TSS with few toxicitiy. OS is mainly influenced by the selection of patients addressed to L vs SABRT.

Background:
Of the major malignancies, carcinoma of the pancreas and the distal biliary duct are the most lethal, primarily because the diagnosis is usually made at an advanced stage and the cancer is relatively resistant to therapy. Occasionally, pancreatic cancer presents as a relatively indolent disease and localized blood-borne lung metastases may be solitary and potentially resectable for therapy. As well, some lung lesions that develop may represent another disease unrelated to the pancreatic cancer and may be treated with surgical resection. Therefore we reviewed our experience with therapeutic lung resections in pancreatic cancer patients.

Methods:
We performed a retrospective, case-control study of treated pancreatic cancer patients who underwent subsequent therapeutic lung resections from 1998-2015. All clinical and pathologic data were gathered for comparison in patients undergoing pancreatic pulmonary metastasectomy and those undergoing lung resection for other diseases. Kaplan-Meier (KM) analyses of survivals were calculated.

Results:
25 patients with treated biliopancreatic cancer underwent lung resections with curative intent. 13 patients (mean age 60.2 ± 10.7 years) had resection of isolated biliopancreatic cancer metastases. 11 patients had 12 resections of primary lung cancers (all Stage I) and 1 patient had resection of active Cryptococcus granulomas (mean age 70.8 ± 7.0 years). A smoking history was present in 77% of metastasecomy patients and 67% of lung cancer resection patients. All never-smokers with lung cancer were females. There were no surgical complications or operative mortalities. The median times from pancreatectomy to pulmonary metastasectomy was 29 months (range 0-64), and 12.5 months (range 0-108) for the lung cancer resection group. During the study period, 11/25 (44%) patients died, although only 64% of the deaths were related to pancreatic cancer recurrence. The KM median survivals after lung resection in the pulmonary metastasectomy group was 28 months (range 3-76) and 78 months (range 2-81) in the lung cancer resection group (see Figure). Figure 1



Conclusion:
Although biliopancreatic cancers have an overall dismal prognosis with just a 12.7 month median survival, 40% present with potentially resectable disease. The lung is the primary site of recurrence after resection of the primary biliopancreatic cancer. Based on our experience, we recommend considering pulmonary metastasectomy in highly selected patients who present with no evidence of disease elsewhere. Pulmonary resection can be done safely in this patient population. Additionally, not all new lung masses in pancreatic cancer patients are metastases, and resection should be considered, whenever feasible, for often we find a second primary lung cancer.

Background:
Limited resection for non-small cell lung cancer is gaining popularity because of early detection and the increase of elderly patients. To reveal the relevant indications for wedge resection, we retrospectively investigated patients who underwent wedge resection by dividing them into positive (PW) and negative (NW) indication groups.

Methods:
Clinical N0M0 cases with tumours <1 cm or predicted lepidic pattern adenocarcinoma were labelled PW, while other wedge resection cases were labelled NW. We investigated 35 PW and 32 NW cases surgically treated at our hospital between 2002 and 2009. The mean age was 66 years in the PW group　and 77 years in the NW group. All PW cases were c-stage IA, while the NW group included 21, 7, 2, and 4 cases of IA, IB, IIB, and IIIB, respectively.

Results:
The overall 5-year survival rates (OS) of the PW and NW groups were 100% and 59.4%, while the disease-specific 5-year survival rates (DS) were 100% and 82.6%, respectively. The indications for (number of) limited resections in the NW group were low respiratory function (15), other malignancies (4), cardiac disease (4), cerebral disease (3), and other (5). The OS/DS of the NW group were 57.1/85.7 for IA; 71.4/100 for IB; 0/0 for IIB; and 50/50 for IIIB. There were 9 cases of death due to other diseases. There were 6 cases of death due to lung cancer recurrence. Among the patients with c-stage I tumours, 7 died of other disease, while only 2 died of lung cancer distant metastasis recurrence (Table). Table

Death due to lung cancer	6	Death due to other diseases	9
1st recurrence site		Other malignancy	4
bone	3	Cardiovascular disease	2
pleura	2	Cerebral disease	1
brain	1	Liver failure	1
		Hemorrhagic enteritis	1

Conclusion:
Wedge resection is positively indicated in PW cases. Negative wedge resection should be positively indicated in NW cases of c-stage I disease because treatment for other diseases must start as quickly as possible to maximize quality of life.