Virtual Library

Abstract
The Cochrane Collaboration is an international, independent, not-for-profit organisation of over 28,000 contributors from more than 100 countries, dedicated to making up-to-date, accurate information about the effects of health care readily available worldwide. Cochrane contributors work together to produce systematic reviews of healthcare interventions, known as Cochrane Reviews, which are published online in The Cochrane Library. Cochrane Reviews are intended to help providers, practitioners and patients make informed decisions about health care, and are the most comprehensive, reliable and relevant source of evidence on which to base these decisions. Over 5,000 Cochrane Reviews have been published so far, online in the Cochrane Database of Systematic Reviews, part of The Cochrane Library. The Collaboration also prepares the largest collection of records of randomised controlled trials in the world, called CENTRAL, published as part of The Cochrane Library. Work from the Cochrane Collaboration is internationally recognised as the benchmark for high quality information about the effectiveness of health care. The Collaboration believes that effective health care is created through equal partnerships between researcher, provider, practitioner and patient. Cochrane Reviews are unique because they are both produced by, and are relevant to, everyone interested in the effects of human health care. Based on the best available evidence, healthcare providers can decide if they should fund production of a particular drug. Practitioners can find out if an intervention is effective in a specific clinical context. Patients and other healthcare consumers can assess the potential risks and benefits of their treatment. The Cochrane Collaboration's contributors are a mix of volunteers and paid staff who are affiliated to the organisation through Cochrane entities: healthcare subject-related review groups, thematic networks (called 'fields'), groups concerned with the methodology of systematic reviews, and regional centres. Many are world leaders in their field of medicine, health policy, research methodology or consumer advocacy, and our entities are situated in some of the world's finest academic and medical institutions. The Cochrane Collaboration is named after Archie Cochrane (1909-1988), a British epidemiologist, who advocated the use of randomised controlled trials as a means of reliably informing healthcare practice. The Collaboration is an independent, not-for-profit organisation, funded by a variety of sources including governments, universities, hospital trusts, charities and personal donations. The Collaboration is registered as a charity in the United Kingdom. To tie the organisation together, there are a number of overarching structures, led by the Steering Group, which provides policy and strategic leadership for the organisation. Members of this group are democratically elected from, and by, contributors. The Cochrane Operations Unit, is based in Oxford, UK, which manages the financial, legal and administrative work of the organisation, led by the Chief Executive Officer of the Collaboration; and a Cochrane Editorial Unit, based in London, UK, which supports Cochrane Review production, editorial processes, and training and methods development, led by the Editor in Chief of The Cochrane Library. There are annual conferences, known as "Colloquia", which are open to everyone. Colloquia are designed to bring people together in one place to discuss, develop and promote our work, and to shape the organisation's future direction In addition to the core mission of producing Cochrane Reviews, contributors are involved in a number of related activities, including advocacy for evidence-based decision-making, providing training in Cochrane Review preparation, developing the methodology for preparing reviews, and translating them from English into a variety of different languages. This session includes providing an introduction to developing a Cochrane Review and is kindly supported by the Cochrane Lung Cancer Review Group, based in Barcelona Spain (website ) and uses high quality training materials developed by the Cochrane Collaboration (grateful acknowledgement of for allowing the use of the training materials) delivered by volunteer Cochrane Collaborators. The session will address topics including; Introduction to systematic reviews, Writing a Cochrane protocol, Searching for studies, Collecting data, Risk of bias, Meta-analysis, Types of data, Heterogeneity, Analysing data and Interpreting results Other training resources include Online Learning Modules as part of a self-directed learning initiative of The Cochrane Collaboration. They provide an introduction to the core skills and methods required for new authors of Cochrane systematic reviews of interventions. The modules are intended to complement other learning opportunities such as face-to-face workshops and webinars, and the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions.

Abstract
The Cochrane Collaboration was set up in 1993 with the aim of providing a library of high quality systematic reviews of healthcare interventions. Over the past 20 years it has grown and now involves more than 28,000 people from around the world in its work. The Cochrane Library [1] is now published by Wiley as part of their Online system and includes the following databases: the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Methodology Register (Methodology Register), the Health Technology Assessment Database (HTA), and the NHS Economic Evaluation Database (NHS EED). The CDSR now contains over 5520 systematic reviews and it impact factor was 5.912 in 2011. Although the great majority of reviews address questions of therapy based on evidence from controlled trials, there are also reviews of diagnostic interventions. The Cochrane Lung Cancer Group (LCG) is one of over 50 Cochrane Review Groups and is dedicated to conducting systematic reviews on all aspects of primary prevention, therapy, supportive care, psychological interventions, biological therapy, and complementary therapy for the prevention, treatment and care of people with lung cancer and other intra-thoracic tumours. Established in 1998 it was originally hosted by the Ibero American Cochrane Centre (IACC) in Barcelona but has recently moved to the University of Besançon, France. Prof Virginie Westeel and Dr Fergus Macbeth are the Coordinating Editors, supported by an international group of clinical and methodological editors. There are currently 37 lung cancer reviews either published or being worked on, with topics ranging from screening to chemotherapy and palliative radiotherapy. The authors of new reviews have to submit a title proposal and a protocol to the Managing Editor. These are peer reviewed, formally approved, and published in The Cochrane Library allowing opportunity for anyone interested to comment on the proposed content and methods. The review process requires: · a thorough literature search · careful selection of the relevant publications · assessing each publication’s Methods for any sources of bias and completing a ‘Risk of Bias’ table · extracting the key data · carrying out a meta-analysis if appropriate · summarising the findings · writing conclusions including a summary in non-technical language for patients and public After the draft review is submitted, it is refereed by three editors with the appropriate expertise. An external peer review is also obtained. This process is designed to maintain the rigour and quality of the reviews to the level expected by The Cochrane Library. Before publication, there is a second review for language, style, and clarity. Carrying out a systematic review to the required standards is therefore a demanding and rigorous process and should be regarded as a research project in itself. This session explains the process in more detail and will I hope engender enthusiasm and lead to the recruitment of new authors. 1. http://www.thecochranelibrary.com

Abstract
The Cochrane Collaboration is an international network of more than 28,000 dedicated people in over 100 countries. Our vision is that healthcare decision-making throughout the world will be informed by high-quality, timely research evidence. We prepare, update and promote the accessibility of Cochrane Systematic Reviews. The Lung Cancer Group editorial team oversees the process of review development from title registration through publishing a protocol to completion of the final systematic review. The scope of topics covered includes prevention, early detection, diagnostic test, all modalities of treatment for both lung cancer and mesothelioma and complementary therapies. The first stage in preparing a review is to identify the topic and register this as a title with the Cochrane group. From this point the authors have a six month time frame to develop a protocol which is essentially the outline plan for the full review. The protocol defines the question to be addressed and specifies the process for identifying, assessing and analysing studies in the review. This will include the inclusion criteria for studies, the search strategy used, the comparisons to be made, any sub-group analyses and their justification and the outcomes to be reported. Once the protocol has been reviewed by the editorial team and confirmed as appropriate for development to a full systematic review, it will be published by Cochrane as a public record of an intended review. This registration helps to minimize bias in the subsequent conduct and reporting of the review and also reduces duplication of effort between groups. This presentation will describe the process of protocol development for a Cochrane review.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract
The Cochrane Collaboration celebrates its 20th anniversary this year. (1, 2) With around 28,000 people involved in 53 Cochrane Review Groups in about 100 countries and more than 5,000 systematic reviews, the Cochrane Collaboration has assisted clinicians, patients, researchers, policy makers and other health professionals to make decisions on a large number of health-related topics. Around 400 systematic reviews are on screening, prevention or treatment of different cancers, and they collectively analyse nearly 5,000 studies. (2) Forty-one systematic reviews are on lung cancer and mesothelioma: 21 of them deal with non-small cell lung cancer and 8, on small cell lung cancer; 7 are related to general aspects of treatment; 3 are about prevention and early detection; and 2 are about mesothelioma. (3) A Cochrane systematic review is the final product of a highly elaborated process. Today’s Workshop has gone through all this process starting with the definition of a question that needs to be answered with the highest certainty. The question is reflected in the TITLE of the review, the first submission to the review group editors that the potential authors do. Once the title has been approved, potential authors have to write and submit a PROTOCOL, a larger document that includes the background of the topic, the methodology to be used, with inclusion and exclusion criteria of studies and patients, the therapeutic interventions that will be included, the search strategy, and relevant references. After approval of this second phase of the process by the review group editors, the authors have to write the final document, the SYSTEMATIC REVIEW, which is internally and externally reviewed. Most systematic reviews analyse randomised clinical trials only, because this is the best research instrument we have in clinical practice. The conclusions derived from these reviews have a high level of evidence - that can even be increased if meta-analyses can be done combining data from the different studies. (4) The meticulous search of published and unpublished data, the careful identification of biases and the sound methodology provide reliable information on the effectiveness of a certain therapeutic intervention, that can be recommended to patients with similar characteristics to those of the patients included in the reviewed studies. (5) Many questions need to be answer in lung cancer therapy. However, randomized clinical trials are relatively few, especially in my specific field: thoracic surgery. We all should feel the responsibility to participate and include patients in clinical trials. No doubt, participation demands an extra effort from us: selecting patients, taking the time to explain the trial to the patients, abiding by randomization rules, sticking to the protocol and so on. But the effort pays off, because the conclusions we draw from randomized clinical trials are the most reliable and solid we can now have on therapeutic interventions. I would like to encourage the audience to participate in clinical trials. The more randomized clinical trials we complete, the more systematic reviews and greater the level of evidence on specific issues of lung cancer and other health-related problems. References 1. Friedrich MJ. The Cochrane Collaboration turns 20: assessing the evidence to inform clinical care. JAMA 2013;309:1881-1882. 2. Tovey D, Maclehose H, Clarke M. The Cochrane Collaboration, its mission and the value of systematic reviews. Cancer Control 2013;155-159. http://globalhealthdynamics.co.uk/cc2013/wp-content/uploads/2013/04/155-159-David-Tovey_2012.pdf Accessed on 27th July 2013. 3. The Cochrane Library. http://www.thecochranelibrary.com/view/0/browse.html Accessed on 27th July 2013. 4. OCEBM Levels of Evidence Working Group. “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed on 27[th] July 2013. 5. Cochrane Consumer Network. http://consumers.cochrane.org/what-systematic-review Accessed on 27th July 2013.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract
Over the last decade, combined modality therapy has been established as standard of care for patients with locoregionally advanced unresectable non-small cell lung cancer (1). Both induction chemotherapy followed by radiation as well as concomitant chemoradiotherapy have been shown to be superior to radiotherapy alone and both approaches extend progression-free and overall survival. In direct comparison, concomitant chemoradiotherapy has been shown to be superior to induction in several randomized phase III trials as well as meta-analyses, likely due to enhanced locoregional control due to the chemotherapy radiation sensitization effect (2, 3). Currently about 20 to 30% of patients can be cured. While there are established clinical prognostic factors, very little information exists to more precisely guide prognosis or therapeutic approach for individual patients. In trying to improve survival outcomes induction chemotherapy was added to concomitant chemoradiotherapy but failed to result in superior outcome compared to concomitant chemoradiotherapy alone.(4). Similarly, consolidation chemotherapy or maintenance therapy with erlotinib in patients unselected for molecular characteristics did not improve survival compared with concomitant chemoradiotherapy alone (5,6). Several chemotherapy regimens have been investigated in the concomitant setting including the mitomycin/vinblastine/cisplatin (MVP) regimen, carboplatin/paclitaxel given weekly (and this regimen has consolidation chemotherapy for two cycles built in) and cisplatin/etoposide. The latter two are frequently used standards in control arms for current randomized trials. There has also been interest in the combination of carboplatin and pemetrexed given the superior single modality activity of the platinum/pemetrexed regimen in non-squamous cell tumors (7). It has been demonstrated that this drug combination can be given at full systemic doses in combination with radiation, thus providing good systemic coverage to eradicate micro-metastases as well as locoregional radiation enhancement. Whether any of these regimens is superior to another is not clear and few direct comparisons have been completed. Japanese investigators compared carboplatin/taxol with carboplatin/irinotecan and the MVP regimen in combination with concomitant radiation and reported equivalent outcomes with these regimens(8). In a small trial comparing carboplatin/taxol with cisplatin/etoposide and radiotherapy, the platinum/etoposide regimen appeared to be superior; however, the number of patients was very limited at approximately 30 per arm (9). Cisplatin/pemetrexed vs. carboplatin/pemetrexed has also been compared in a randomized phase II format supporting a trend for superiority of cisplatin-based therapy as has been shown for other stages of non-small cell lung cancer as well (10). A large randomized phase III trial comparing cisplatin/etoposide with cisplatin/pemetrexed each with concomitant radiotherapy to 66 Gy has been completed. This study was closed after a futility analysis at near completion of planned accrual and a full analysis of this trial is awaited for the future. Targeted therapies have also been of interest. While they have matured to be standard therapy for many patients with stage IV disease their role in earlier stages remains under-investigated. In a number of uncontrolled trial, the addition of erlotinib or gefitinib to radiation therapy with or without additional chemotherapy has been shown to be feasible. In the Alliance Cooperative Group (formerly CALGB), a recent trial looking at induction chemotherapy with carboplatin and albumin-bound paclitaxel followed by erlotinib and concomitant radiotherapy for patients with poor-risk stage III non-small cell lung cancer was completed. Median progression-free and overall survival times of 11 months and 16 months respectively were encouraging. However, no comparative arm of radiotherapy alone was included in the trial design (11). Similarly, cetuximab has been integrated into this treatment approach. RTOG 0324 reported encouraging pilot data from the addition of cetuximab to carboplatin/paclitaxel-based concurrent chemoradiation and consolidation chemotherapy(12). A randomized trial comparing the base regimen vs. the base regimen plus cetuximab in this setting has been completed and mature results are expected in the near future. It should be cautioned however, that the larger clinical experience with the addition of cetuximab to concurrent chemoradiotherapy regimens to date has been disappointing. A randomized phase II study conducted by the CALGB (CALGB#30407) found no obvious clinically significant benefit from the addition of cetuximab to carboplatin/pemetrexed radiotherapy (7). Median survival times were 21.2 and 22.4 months respectively for the two study arms. Similarly, controlled trials investigating the addition of cetuximab in patients with esophageal or head and neck cancer to concomitant chemoradiotherapy have not shown a statistically significant benefit compared to chemoradiotherapy alone. Current research interest is focused on the treatment of patients with molecular abnormalities, in particular EGFR mutations or EML/alk translocation. For these patients, a study investigating induction chemotherapy with either erlotinib or crizotinib, respectively followed by standard concurrent chemoradiation vs concurrent chemoradiation alone is about to be activated. Similarly, immunological approaches are of interest. At present, no data from studies investigating CTLA-4 or PD1 inhibitors are available. However, a randomized trial investigating the BLP25 vaccine, a liposome MUC1-based vaccine, has recently been reported. This vaccine attempts to induce a proliferative T-cell response to the MUC1 antigen which is frequently overexpressed and hyper-glycosylated in non-small cell lung cancer. In this trial, patients completed standard combined modality therapy (either induction or concomitant chemoradiotherapy) and were then randomized to either a placebo or the active vaccine. For the overall study cohort a trend in survival was observed which was more pronounced in a planned subset analysis of patients receiving concomitant chemoradiotherapy (13). This study adds support to further investigations to vaccine-based approaches. While current standard therapy approaches do result in consistent cure rates of 20-30% of patients, further progress will depend on the development of more specific combined modality approaches. Immunological and molecularly driven clinical trials will be of particular interest in this regard.

Abstract
For years radiation oncologists have dreamed of being able to dynamically adapt treatment to the response of normal and tumor tissues observed during a protracted course of radiotherapy. An obvious goal is to adjust the PTV as the GTV shrinks during treatment, which may improve dose volume metrics in the organs at risk, especially lung. Reinflation of atelectatic lung in response to tumour size reduction may require adjustment of PTV size and position to avoid geographic miss. Cone beam CT (CBCT) has revolutionised the ability to regularly image soft tissue, although it is less useful for targets within the mediastinum or those defined primarily by FDG PET. The main limiting step is the time required to develop an adaptive treatment plan without interrupting treatment. Experience suggests that tumor reduction needs to be substantial to have a meaningful impact on the dose volume metrics. The use of serial FDG PET during treatment to detect residual activity and to use this as a surrogate for persistent disease for adaptive radiotherapy is under investigation. This is however based on an unproven assumption that such FDG activity is due to tumor and not inflammation. Tumor motion adds further uncertainty, affecting both SUV and intrafraction location of the residual FDG uptake. CBCT may also detect tumor progression. This seems to be uncommon.(1) When it occurs, apart from discontinuing futile treatment to avoid unnecessary toxicity, can anything else be done? Our group has investigated the use of PET tracers to detect functional changes in tumour during treatment, including FDG and the thymidine based tracer FLT which we hypothesise images tumour proliferation. Preliminary results indicate that FLT detects functional changes in the tumour earlier than FDG, but the clinical implications of this are unknown.(2) One patient with clinical progression had increased uptake of FLT detected at 20 Gy, suggesting accelerated repopulation. The rate of treatment was accelerated with twice daily fractionation, resulting in a reduction in FLT uptake, providing anecdotal proof of principle. Accelerated repopulation has also been indirectly observed with induction chemotherapy.(3) Imaging with FLT may present an opportunity to detect altered proliferation pre-radiotherapy which may benefit from accelerated fractionation.(4) A further change that may occur during fractionated treatment is reoxygenation. We have observed changes in uptake of the hypoxia PET tracer FAZA during a course of radiotherapy,(5) indicating that hypoxia is present in some tumors pre-treatment, although surprisingly little use is made of this knowledge in clinical practice. Changes observed in normal tissue response may also present opportunities for adaptive treatment. The patient can be used as a biological dosemeter, and the occasional patient will require truncation of treatment because of esophagitis. Is this increased sensitivity a surrogate for inherently increased radiosensitivity within the tumor, indicating that a higher tumor dose is unnecessary for such patients? Our group has observed changes in normal lung during treatment using ventilation/perfusion imaging, opening up prospects of avoiding functioning (as opposed to anatomical) lung with beam redirection.(6) Conclusions: A number of tools are now available to detect tumor and normal tissue response to radiotherapy during treatment. These changes may be anatomic or functional, including changes in tumor kinetics or the micro-environment. The challenge now is to turn these observations into clinically useful patient benefits. References 1. Lim G, Bezjak A, Higgins J, Moseley D, Hope AJ, Sun A, et al. Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy. J Thorac Oncol. 2011;6:531-6. 2. Ball D, Everitt S, Hicks R, Callahan J, Plumridge N, Collins M, et al. Differential Uptake of F18-fluoro-deoxy-glucose (FDG) and F18-fluoro-deoxy-l-thymidine (FLT) Detected by Serial PET/CT Imaging During Radical Chemoradiation for Non-Small Cell Lung Cancer (NSCLC). . J Thorac Oncol 2012;7:S238. 3. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer. 2003;89:2184-9. 4. Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76-85. 5. Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, et al. Imaging of hypoxia with (18) F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57:475-81. 6. Siva S, Callahan J, Hofman MS, Eu P, Martin O, Pope K, Ball D, MacManus M, Kron T, Hicks RJ. Technical considerations and preliminary experience of a pilot study of Gallium-68 VQ 4D-PET/CT in lung radiotherapy. J Thorac Oncol 2012;7: S1182.

Abstract

Abstract
There is no general agreement on the definition of the “borderline” patient with stage III non-small cell lung cancer (NSCLC). Patients judged to be unsuitable for standard treatment could be of advanced age, unable to undergo cisplatin-based chemotherapy, poor performance status, poor pulmonary function and/or bulky tumors requiring large radiation fields. Since the combination of chemotherapy and radiation therapy (RT) has been adopted as the standard of care, there has been an increased portion of elderly patients who receive it. [1]. Cooperative group studies have demonstrated that the elderly have more toxicity then their younger counterparts and that age is a negative prognostic factor for survival. [2, 3, 4] However, the elderly with good PF still have improved survival with combined chemoRT as opposed to radiation only. Prospective studies in the “borderline” patient by cooperative groups in North America and Asia have had various eligibility criteria. [5, 6, 7, 8]. Those studies accrued slowly or poorly, perhaps due to the 6-7 week RT required in most studies. One RTOG study combining celecoxib and RT did allow either 60 Gy in 6 weeks or 45 Gy in 3 weeks but few patients were treated with the short course. [8] A short of course of RT may be more acceptable to patients who are elderly or have a poor performance status. A retrospective study of patients who did not receive concurrent chemoRT showed that similar survival was seen in patients treated with 45 Gy in 3 weeks as in patients treated with >60 Gy in 6 weeks. [9] Few prospective studies have been done in patients with poor pulmonary function. A retrospective study found that pre-treatment FEV1 was not statistically correlated with symptomatic lung toxicity following concurrent chemoradiation.[10] However, the combination of poor FEV1, advanced age and high mean lung dose correlated positively with pulmonary toxicity. Prospective studies are also lacking in patients with bulky disease for whom large radiation fields are required. Retrospective studies suggest that bulky disease is associated with a higher risk for the early development of metastases and death. [11] Future efforts to improve the therapeutic ratio for borderline patients likely involve the improved ability to predict both benefit and risk for an individual patient. Studies are ongoing using molecular methods to better predict distant metastases-free survival and pulmonary toxicity. [12, 13] 1. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol. 2012;7(2):291-8. 2. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III non-small cell lung cancer. Cancer. 2007;110(2):363-8. 3. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173-81. 4. Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individuals patients from 52 randomized clinical trials.. BMJ. 7;311(7010) 1995: 8099-909. 5. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998;16(9):3078-81. 6. Atagi S, Kawahara M, Tamura T, et al. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Jpn J Clin Oncol. 2005;35(4):195-201. 7. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol. 2010;21(10):2040-4. 8. Gore E, Bae K, Langer C, et al. Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. Clin Lung Cancer. 2011;12(2):125-30. 9. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer. Radiat Oncol. 2012;7:33. 10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. 11. Wiersma TG, Dahele M, Verbakel WF, et al. Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. Lung Cancer. 2013;80(1):62-7. 12. Yuan X, Wei Q, Komaki R,et al. TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy. PLoS One. 2013;8(6):e65659. 13. Yin M, Liao Z, Yuan X, et al. Polymorphisms of the vascular endothelial growth factor gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy. Cancer Sci. 2012;103(5):945-50.

Abstract
ENDOBRONCHIAL ULTRASOUND The integration of ultrasound technology and flexible fiberbronchoscopy enables imaging of lymph nodes, lesions and vessels located beyond the tracheobronchial mucosa. Developed in 2002, the EBUS-bronchoscope looks similar to a normal bronchovideoscope, but is 6.9mm wide and has a 2mm instrument channel and a 30 degree side viewing optic. Furthermore, a curved linear array ultrasonic transducer sits on the distal end and can be used either with direct contact to the mucosal surface or via an inflatable balloon which can be attached at the tip. This allows a conventional endoscopic picture side-by-side with the ultrasonic view. US scanning is performed at a frequency of 7.5-12 MHz with tissue penetration of 20 – 50mm. An ultrasound processor processes the US image. Procedure: The actual TBNA is performed by direct transducer contact with the wall of the trachea or bronchus. When a lesion is outlined, a needle of 21 gauge (NA-201SX-4022; Olympus Corporation, Tokyo, Japan) can be advanced through the working channel and lymph nodes can be punctured under real-time ultrasound visualisation. At the same time colour Doppler can be used to identify surrounding vascular structures. Once the target lymph node or mass has been clearly identified with EBUS, the needle is inserted under real-time US guidance. Suction is applied with a syringe, and the needle is moved back and forth inside the lesion. Lymph node stations that can be reached via EBUS are the highest mediastinal (station 1), the upper paratracheal (2L and 2R), lower paratracheal (4R and 4L), the subcarinal (station 7), the hilar (station 10) as well as the interlobar (station 11) and the lobar nodes (station 12). The highest staging N should be biopsied first otherwise the needle needs to be changed each time. Results: In recently published meta-analysis EBUS-TBNA has been shown to have a high-pooled sensitivity of 93% and specificity of 100% . Multiple publications have shown that even in patients with lymph nodes under 1cm (which had been termed N0 by CT criteria), with the use of EBUS-TBNA a large percentage could still be shown to have N2/N3 disease (some despite also being negative on PET-CT). Complications such as bleeding or infection are very rare and have only been reported as case reports. Endoesophageal ultrasound Gastroenterologists have been using this technique for many years in the investigation of oesophageal and pancreatic malignancies. Mediastinal EUS-FNAs were first used in the early 1990s and have subsequently become a popular method to diagnose a variety of intra-abdominal and intrathoracic masses, including mediastinal lesion. Procedure The linear EUS-Scope (has the same basic architecture as the EBUS and uses a scanner of between 5 and 10 MHz. The penetrating ultrasound depth can be up to 8cm. Needles used for biopsy are 19 or 21gauge, again equipped with a stylet. The procedure is usually performed on an outpatient basis and takes approx 30min. However, EUS-FNA has limited access as only lymph node stations 2L, 4L, 7, 8 and 9 are accessible through a transesophageal approach. Lymph node station 5 is not routinely accessible via EUS, and may require transvascular FNA.. Results. EUS is especially useful in staging of the posterior mediastinum. Multiple publications and a meta-analysis on EUS-FNA have shown a high sensitivity and specificity. Even in patients without mediastinal lymph node enlargement on CT, EUS-FNA has been able to demonstrate metastases in 25% of lung cancer patients. Also, the left adrenal can be reached and identified in 97% of cases. It has a so-called ‘seagull’ shape on ultrasound and is particularly well visualised in cases of metastatic enlargement. Furthermore, the left lobe of liver can also be reached. The hilar and pre-carinal lymph nodes cannot be reached. EUS is also more accurate and has a higher predictive value than either PET scan or CT for posterior mediastinal lymph nodes. The procedure carries only a very small risk of mediastinitis or bleeding. . For both techniques it´s important to remember, however, that with EBUS and EUS the negative predictive value is limited and therefore samples which do not contain tumour cells require follow up with a more definitive procedure such as mediastinoscopy or VATS. Combining EBUS and EUS For tissue sampling of mediastinal lymph nodes after conventional TBNA, the present authors prefer minimally invasive methods such as EBUS-TBNA and EUS-FNA to more invasive procedures such as mediastinoscopy and VATS. EUS-FNA and EBUS-TBNA have been shown to prevent mediastinoscopies to a large extent. EBUS-TBNA and EUS-FNA have a complementary reach in analysing mediastinal nodes whereby EBUS has access to the paratracheal, subcarinal and hilar regions and EUS to the lower mediastinum and aortopulmonary window. As shown above, EUS and EBUS provide access to different areas of the mediastinum. In combining techniques, most lymph node stations as well as the left adrenal gland can be reached (apart from stations 5 and 6). In six recent series the accuracy of EUS-FNA and EBUS-TBNA used in combination for the diagnosis of mediastinal cancer was 95% . Using the EBUS-Scope for both endobronchial as well as endoesophagel sampling, the sensitivity for cancer detection could be shown to be as high as 96% (EUS 89%, EBUS 91%), specificity 100% and negative predictive value of 96% (EUS 82%, EBUS 92%). CONCLUSION Overall, EBUS and EUS are safe and effective techniques for the staging of the mediastinum. They are minimally invasive and reduce the number of invasive staging procedures. Currently, the main limitation for EBUS and EUS are that they are predominantly performed at centres of excellence and hence only on selected patients. Training of physicians and surgeons remains the issue and performance of an adequate amount of procedures per year is required in order to maintain competency. Reimbursement remains an issue in some countries as well as the actual implementation into cancer guidelines within the hospitals. Increasingly both techniques are being used in hospitals across the world improving the diagnostic yield. Combined EBUS and EUS ought to be regarded as the “first techniques into the mediastinum”, called “complete endo-echo staging”.

Abstract
There is a widely divergent clinical, radiologic, molecular and pathologic spectrum within lung adenocarcinoma. Remarkable advances in understanding of the genetic mechanisms that underlie lung adenocarcinoma have altered the diagnostic criteria that determine subsequent treatment. The use of the term bronchioloalveolar carcinoma (BAC) encompassed a broad spectrum of tumors ranging from solitary small peripheral lung tumors with a 100% 5-year survival to widespread advanced disease with a 10% 3-5 year survivals, with widely varying use of terminology even after publication of the 2004 WHO Classification. There are also clinical, radiologic, immunohistochemical, and molecular differences that are distinguishable among the subsets of mucinous and non-mucinous types of adenocarcinoma. In 2011, a new Classification of Lung Adenocarcinoma was therefore proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. The 2011 classification addressed three important weaknesses in the previous classification. First, it eliminated the term BAC. Second, it added new terminologies of carcinoma-in-situ, and minimally invasive adenocarcinoma to recognize that minimal invasion (< 5mm). Third, it replaced the terminology of mixed adenocarcinoma. The widespread availability of MDCT and abundance of new information obtained especially from low-dose CT lung cancer screening programs, have increased our understanding of the types and management of small peripheral lung nodules encountered in daily clinical practice, in particular, the importance and prevalence of subsolid pulmonary nodules (atypical adenomatous hyperplasia (AAH), ground glass nodules (GGN) and part-solid nodules). Thin section CT has emerged as a new biomarker for lung adenocarcinoma subtypes. The staging system is based solely on the anatomic extent of the disease. Other factors, such as clinical symptoms or molecular biological characterization of the tumor or attenuation of nodules on CT are not factored in the new TNM classification. Increasing T status reflects tumors that are larger or invasive. In lung cancer nodal staging depends on the location of involved nodes (as opposed to the number of nodes). The M descriptor defines the presence or absence of distant metastatic disease. In 2007, The International Association for the Study of Lung Cancer (IASLC) revised the lung cancer stage groupings based on newer survival data. In the 7[th] edition of TNM classification of lung cancer, following modifications were made: (a) Size cut points, in addition to the 3 cm cut point that traditionally separated T1 and T2 tumors, was introduced at 2, 5, and 7 cm. T1 tumors were now subdivided into T1a and T1b around the 2 cm cut point. T2 tumors were subdivided into T2a and T2b around the 5 cm cut point, and tumors larger than 7 cm. were classified as T3. (b) Cases in which additional tumor nodules are found were reclassified. Those in the same lobe as the primary tumor are now classified as T3, those in the other ipsilateral lobes are T4 and those in the opposite lung are now M1a. (c) Cases associated with pleural or pericardial nodules or effusions were reclassified from T4 to M1a. M1 disease due to distant metastasis was reclassified as M1b. A new IASLC nodal chart, with precise definitions was also agreed, reconciling the previous differences between the Japanese and Mountain-Dresler charts. The concept of nodal zones was introduced to make such classification relevant to those dealing with bulky nodal deposits that transgress the boundaries of individual nodal stations. Further improvements in stage discrimination and management of lung cancer could be expected in the future, as more robust data related to genetic make-up and biological behavior affecting survival of tumors becomes available.

Abstract
Background The origin of the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project took place during an international workshop on intrathoracic staging organized at the Royal Brompton Hospital, London, UK, in 1996. (1) At that time, the 6[th] edition of the tumour, node and metastasis (TNM) classification was in press, but its limitations and weaknesses were discussed in an international and multidisciplinary forum. The main conclusion was the need for a large international database that could be used to refine and update the TNM classification of lung cancer. Two years later, the IASLC Board approved the creation of an International Staging Committee (ISC), whose first co-chairs were Mr. Peter Goldstraw and the late Dr. Robert Ginsberg. An international call was made to promote participation and data sharing, and potential participants were summoned to subsequent meetings and workshops. Data on lung cancer patients diagnosed from 1990 to 2000 were collected from 46 different sources in 20 countries around the world. Data were stored, managed and analysed at Cancer Research And Biostatistics (CRAB), a biostatistics agency based in Seattle, WA, USA. By the end of 2005, 100,869 cases had been registered and 81,495 were analyzable: 68,463 non-small cell lung cancers (NSCLC) and 13,032 small cell lung cancers (SCLC). (2) The analyses of these cases allowed the IASLC to issue recommendations for changes to the 6[th] edition of the TNM classification. The recommendations were accepted by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC), and were introduced in the 7[th] edition of the TNM classification. (3, 4, 5) With the revision undertaken for the 7[th] edition, a new period of data-based revisions started, with the IASLC leading the revision process and informing the UICC and the AJCC of the potential changes in the classification based on the analyses of its growing international databases. The analyses of the retrospective IASLC database showed that a more detailed database, containing specific information on T, N and M descriptors, would be necessary to continue the revision process. Therefore, in 2009, a call was made for international participation in the prospective collection of data to inform the 8[th] edition of the TNM classification of lung cancer, due to be published in 2016. (6) The IASLC Prospective Phase of the Lung Cancer Staging Project This prospective phase of the project included a new retrospective collection of data from 1999 to 2010. 94,684 patients were collected: 78,640 analyzable cases of NSCLC and 5,912 analyzable cases of SCLC. These cases will be used to inform the 8[th] edition of the TNM classification and are now being analysed at CRAB. Expansion to Other Thoracic Malignancies The ISC incorporated mesothelioma in 2008 and thymic malignancies and oesophageal cancer in 2009. The structure of the ISC was modified to accommodate more tumours and members. Four domains were created: lung cancer domain (chaired by this writer), mesothelioma domain (chaired by Dr. Valerie Rusch), thymic malignancies domain (chaired by Dr. Frank Detterbeck) and oesophageal cancer domain (chaired by Dr. Tom Rice). To increase the participation of more specialists without increasing the number of ISC members and the budget, advisory boards for mesothelioma, thymic malignancies and oesophageal cancer were created. The retrospective database of mesothelioma contains 3,101 surgically treated patients, and its first analysis has been already published. (7) The International Mesothelioma Interest Group (IMIG) and the Mesothelioma Applied Research Foundation (MARF) collaborate with the IASLC Mesothelioma Staging Project. The prospective collection of cases is now ongoing, includes surgically and non-surgically treated patients, and is intended to inform the 8[th] edition of the TNM classification. A side-project on volumetric computerized tomography for clinical staging is also underway. The retrospective database of thymic malignancies has data on more than 10,000 cases, and the prospective collection of data is ongoing. The ISC works closely with the International Thymic Malignancies Interest Group (ITMIG) (8) and with thymic working groups of scientific societies, such as the European Society of Thoracic Surgeons, the European Association for Cardiothoracic Surgery, etc. The main objective is to device a data-driven, internationally acceptable TNM classification for thymic malignancies, both thymomas and thymic carinomas. The retrospective database of the oesophageal cancer is kept at the Cleveland Clinic, Cleveland, OH, USA, and contains data on more than 10,000 patients. Cases are provided by members of the Worldwide Esophageal Cancer Collaboration (WECC). (9) The revised 7[th] edition of the TNM classification of oesophageal cancer was based on the analyses of the surgically treated patients of this database. (10) Expansion to Prognostic Factors Given the importance of more precise prognostication, besides that provided by the TNM classification and staging system, the IASLC Board decided to expand the activities of the Committee to prognostic factors. To make this activity more patent, the name of the Committee was changed to Staging and Prognostic Factors Committee in February 2013. References 1. Goldstraw P. Report on the international workshop on intrathoracic staging, London, October 1996. Lung Cancer 1997;18:107-111. 2. Goldstraw P, Crowley JJ . The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006;1:281-286 3. Goldstraw P, ed. Staging manual in thoracic oncology. Orange Park, FL: Editorial Rx Press; 2009. 4. Sobin L, et al., eds. TNM classification of malignant tumours. 7[th] edition. Oxford: Wiley-Blackwell; 2009;138-146. 5. Edge SB et al., eds. Cancer staging manual. 7[th] edition. New York: Springer; 2010;253-270. 6. Giroux DJ et al. The IASLC lung cancer staging project. Data elements for the prospective project. J Thorac Oncol 2009;4:679-683. 7. Rusch VW et al. Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database. J Thorac Oncol 2012;7:1631-1639. 8. Detterbeck FC, Huang J. Overview. J Thorac Oncol 2011;6(Suppl 3):s1689-1690. 9. Rice TW et al. Worldwide esophageal cancer collaboration. Dis Esophagus 2009;22:1-8. 10. Rice TW et al. 7[th] edition of the AJCC Cancer Staging Manual: esophageal and esophagogastric junction. Ann Surg Oncol 2010;17:1721-1724.

Abstract
Tumor diagnosis, tumor staging, and patient treatment in clinical oncology depend on morphological and molecular imaging procedures, such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). Radiological and functional imaging studies, however, have well-known, inherent limitations that limit their diagnostic accuracy in assessing tumor stage and therapeutic response. Both CT and MRI provide mainly morphological information on the tumor and potential metastasis. However, the lack of functional information frequently limits the value of these studies when assessing lymph nodes metastasis. Accurate staging of patients with non-small cell lung cancer (NSCLC) is of paramount importance because stage significantly affects both treatment options and prognosis. The management of NSCLC often requires a multimodality approach for accurate diagnosis and staging and for patient treatment. Some of the most important advances in the treatment of lung cancer have been the development and implementation of accurate and functional imaging. In numerous studies the diagnostic capability of whole-body MRI, PET and PET/CT for cancer staging has been evaluated and compared. In the primary evaluation of pulmonary lesions, fluorodeoxyglucose (FDG)-PET scans are useful for distinguishing benign from malignant etiologies. Several studies investigating the accuracy of FDG-PET in diagnosing malignant pulmonary lesions have estimated its sensitivity and specificity to be 96.8% and 77.8%, respectively. In the same analysis, FDG-PET was found to be superior to CT for evaluating nodal and distant metastases and changed therapeutic management in 18% of the cases studied. However, PET has been shown to be less sensitive for characterizing smaller lung lesions. The positive predictive value (PPV) of FDG-PET is significantly lower for lesions smaller than 1 cm than for larger lesions (0.36 vs 0.90, p=0.015). The lower PPV for smaller lesions reflects a higher rate of false-positive FDG-PET scans. A comparison of the characteristics of PET-negative and PET-positive tumors has shown significant differences in lesion size (p < 0.001), histopathological type (p < 0.001), and pathological stage (p = 0.028). Both lesion size (p < 0.001) and histopathological tumor type (p < 0.001) were significant factors for determining whether PET results were negative or positive. This study established that negative PET findings were likely for lesions 2 cm or smaller and for adenocarcinomas (i.e., adenocarcinoma in situ and well-differentiated adenocarcinomas). A meta-analysis of 59 studies has shown that PET/CT is useful for detecting lymph node metastasis and extrathoracic metastasis. PET/CT is significantly more sensitive and specific than conventional CT alone and more sensitive than PET alone for staging NSCLC. Furthermore, PET/CT demonstrates excellent sensitivity (0.91) and specificity (0.98) for bone metastasis. However, PET/CT has high specificity but low sensitivity for detecting brain metastasis. The question of bone metastasis was most thoroughly answered by a recent meta-analysis of 17 studies comparing FDG-PET/CT, FDG-PET, MRI, and bone scintigraphy. The pooled sensitivity of each of the modalities in the detection of metastasis was 92%, 87%, 77%, and 86%, respectively, and the specificity was 98%, 94%, 92%, and 88%, respectively. When compared with other imaging modalities, FDG-PET appears to offer no additional information regarding the presence of metastatic disease in the brain. The current standard of care is to evaluate the brain metastasis with MRI in all patients, except those with clinical stage IA disease. A recent study of 1122 patients with PET-CT–determined stage I (T1-2N0) NSCLC suggests that invasive staging is not indicated for such patients, especially if a PET scan of the mediastinum is negative. Several studies have assessed the prognostic implications of mediastinal PET findings in patients undergoing curative resection of NSCLC. The rates of locoregional and distant recurrence are higher in patients with positive mediastinal PET findings than in patients with negative findings for the N0/N1 subset. The higher rate of locoregional failure in patients with positive preoperative PET findings in the mediastinum might lead to postoperative radiation therapy. Although chemotherapy is recommended for most patients with N1 disease, chemotherapy is generally not recommended for patients with N0 disease. The higher rate of distant failure in patients with positive preoperative mediastinal PET findings might lead to chemotherapy being recommended. On the other hand, pathologic confirmation with invasive mediastinal staging, either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy, is recommended if mediastinal lymph node abnormalities are detected with PET-CT. Several recent studies have shown that diffusion-weighted magnetic resonance imaging (DWI) has a higher specificity for N staging of NSCLC than does FDG PET/CT and has the potential to be a reliable alternative noninvasive imaging method for the preoperative staging of mediastinal and hilar lymph nodes in patients with NSCLC. Short inversion time inversion-recovery (STIR) turbo spin-echo (SE) MRI may be useful for distinguishing metastatic lymph nodes from nonmetastatic lymph nodes in patients with NSCLC. This imaging method might be more sensitive and accurate than CT, conventional T1-weighted MRI, FDG PET, or FDG PET/CT. We can prospectively compare the diagnostic capabilities of STIR turbo SE imaging, DWI, and FDG PET/CT for N staging in patients with NSCLC. In patients with NSCLC, quantitative and qualitative assessments of N staging obtained with STIR turbo SE MR imaging are more sensitive and more accurate than those obtained with DWI or FDG PET/CT. A new technology, PET-MRI, is now being established. To guarantee the clinically valuable, time- and cost-efficient use of PET/MRI, it is essential that appropriate indications be chosen, that cross-modality training be performed, that the acquisition protocols be optimized, and that the images be carefully reviewed, taking into account potential artifacts. Additional studies are needed to determine how PET/MRI might best be used clinically and to prospectively verify its clinical abilities. The increased use of FDG-PET will help clinicians to select the most appropriate treatments for each patient and thereby improve outcomes and avoid toxic therapies that are unlikely to be beneficial.

Background
Circulating tumour cells (CTCs) are considered the seeds of metastasis, and characterization of CTCs promises novel insights into metastasis, new targets for intervention, and less-invasive samples for assessing tumour status. CTCs however are rare in circulation and thus highly sensitive tools are required for their reliable capture and analysis. Antibody-based platforms using candidate gene-based approaches have begun to provide insights into CTCs. However tumour heterogeneity and the dependence of these methods on antigen expression has made antibody-independent methods of interest. The Clearbridge ClearCell System is a microfluidic-based platform that enables antibody-independent capture and retrieval of CTCs based on differences in the biomechanical characteristics of blood cells and CTCs. Next Generation Sequencing (NGS) has emerged as a tool to perform massive parallel sequencing of genomic regions with high efficiency and accuracy. The aim of this study was to perform NGS analysis of CTCs captured by antibody-independent methods, and their matched primary tumour or metastases samples, in patients with NSCLC.

Methods
Three matched CTC and primary tumour samples and three matched CTC and metastases samples were obtained from patients with NSCLC. Whole blood samples were also obtained from the patients for germline DNA. Five patients had adenocarcinoma and none of the patients had received targeted therapy prior to biospy of the metastatic lesions. CTCs were captured and retrieved from 2ml whole blood using the Clearbridge ClearCell System near the time of tumour sampling. DNA was extracted from CTCs, tumour tissue, and whole blood using the Qiagen QiaAMP DNA Micro Kit, DNAeasy Blood and Tissue kit , and Biorobot EZ1 workstation respectively. NGS was performed on the Ion Torrent PGM Sequencer using the AmpliSeq Comprehensive Cancer Panel targeted to 409 genes prominent in cancer. DNA variants were identified using Ion Torrent Software Suite v3.4, and pathway analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID).

Results
After subtraction of DNA variants found in whole blood, the average number of variants in CTC, primary tumour and metastases samples was 283 (range: 110-470), 433 (70-1002), and 242 (81-166) respectively. The concordance in variants between CTC and primary tumour samples was 22% (15-29%) and between CTC and metastases samples was 29% (20-38%). Genes frequently mutated in matched CTCs and primary tumours/metastases included NOTCH2, AKT1, and RET. Pathway analysis of genes with DNA variants revealed an enrichment of genes involved in mTOR signalling in both CTC/primary and CTC/metastases samples. In CTC/metastases samples, pathways including the JAK-STAT and B-cell receptor pathways were additionally enriched.

Conclusion
Our results have highlighted a high level of genetic variability between CTCs and their matched tumours, reflective of high tumour heterogeneity. Preliminary analysis has identified genes and pathways with alterations in CTCs that could be potential targets for systemic treatment.

Background
The feasibility of multigene testing in a clinical setting has been demonstrated by the Lung Cancer Mutation Consortium (LCMC) which has evaluated over 1000 cases from multiple institutions in a CLIA environment. The initial platforms used by the LCMC were SNaPshot and Ion Torrent, allele specific tests. More recently the sequencing by synthesis method (Illumina) used for whole genome sequencing has been scaled for sequencing of a limited number of targeted genes. In this study we compare the performance characteristics of Next Generation testing on the MiSeq platform with the older allele specific SNaPshot platform and evaluate the applicability of Miseq-based testing to a clinical, CLIA regulated setting.

Methods
Two Illumina kits, the TruSeq and TruSight evaluating 221 hotspots in 48 gene and 175 exons in 26 genes, respectively, were compared. To assess analytical sensitivity, cell lines with known mutations and SNPs were titered into liver DNA known to be wild-type for the selected mutations, at tumor cell concentrations ranging from 3% to 50%. In addition, 24 formalin-fixed paraffin-embedded lung tumors that had previously been evaluated by SNaPshot or direct sequencing were tested to compare sensitivities and specificities of methods. Paraffin embedded human tumor tissue samples were enriched for tumor cells by coring of paraffin block or macrodissection using a pneumatic cell collector. DNA was extracted by proteinase K digestion and column chromatography, end repaired and phosphorylated. Libraries were prepared from each sample by ligating index adapters that allow for mixing of samples and binding adapters that link DNA fragments to flow cell. Combined libraries were added to flow cells at an appropriate concentration, clusters generated, and sequencing reaction commenced. Results were evaluated by software developed by Illumina or locally at the University of Colorado.

Results
Spiking studies indicated that analytic sensitivity for Miseq at loading quantities of 100 to 300 ng (TruSeq) was ~5% for known KRAS and TP53 mutations and several synonymous polymorphisms in other covered genes, comparable to SNaPshot. For clinical samples, average depth of coverage was 5700 (+/- 2267). Unfiltered results using Illumina software supplied with the Miseq instrument showed an average of 88 heterozygous SNPs, 12 insertions and 17 deletions (uncurated for relevance). All of the mutations that were previously found by SNaPshot were also detected by Miseq TruSeq and TruSight protocols (100% concordance). Variants representing known polymorphisms, synonymous changes and variants identified in the context of low coverage were excluded. Data analysis using locally developed software indicated the presence of 1-9 SNPs in each sample that were not predicted by SNaPshot testing, attributable to the wider coverage of the Miseq platforms. None of the additional mutations represented treatable targets with currently available drugs.

Conclusion
Next-generation testing is feasible in a CLIA environment using the Miseq platform. However, rigorous software validation is necessary before this platform can be adopted by a busy clinical laboratory. Software limitations currently being addressed include long turnaround time, inadequate vetting of new and recurrent SNPs for clinical significance and limited software development resources.

Background
MicroRNAs are useful biomarkers for various disease states, and their preservation in formalin-fixed, paraffin-embedded (FFPE) tissue makes them particularly useful for clinicogenetic studies. Although global microRNA expression in FFPE samples is routinely measured with microarrays, the utility of RNA sequencing for such profiling has yet to be established. In this study, to appraise the suitability of RNA sequencing, microRNAs in RNA from lung cancer FFPE samples were quantified by both a microarray and a sequencing platform.

Methods
The affinity spin column–based Roche High Pure FFPE RNA kit was used to extract total RNA from 8 resected stage I lung adenocarcinoma FFPE tumor specimens (~3 mm[3]) with ≥50% tumor content. RNA was quantified by RiboGreen fluorometric and absorbance spectrometric analysis at 260 nm, and its quality was examined by electrophoresis on an RNA Pico chip in an Agilent Bioanalyzer 2100. MicroRNAs in 120 ng of RNA were profiled using the 8x60K Agilent Human miRNA Microarray (release 16.0) platform. MicroRNAs were also quantified by use of the Illumina HiSeq 2000 sequencing system (1x 50 bp reads), with multiplexed sequencing libraries prepared using 1 ug of RNA with the Illumina Truseq Small RNA Preparation Kit (version 2.0). Microarray data were processed using the AgiMicroRna Bioconductor package in R. Sequencing data were demultiplexed using CASAVA software and were mapped against mature human microRNAs in the miRBase database (version 16) using STAR aligner software. Absolute microRNA count values were then normalized among samples by use of the edgeR Bioconductor package.

Results
Results of RiboGreen fluorometric analysis suggested that an average of 16 ug (range, 6-35 ug; SD, 8 ug) of RNA was obtained from the FFPE specimens. Significant degradation of RNA was observed, as expected, with Bioanalyzer RNA integrity number values between 1.9 and 2.5. An average of 1.3 million sequencing reads (range, 9.1-16.9 million; SD, 3.5 million) were obtained, but only 1.4% (range, 0.4%-2.1%; SD, 1.4%) of them mapped to known microRNAs. Of the 1205 human microRNAs detectable with the microarray platform, 302 were identified as expressed in the 8-sample set, and 593 were identified as expressed in the sequencing platform. For the 177 microRNAs detected by both microarray and sequencing methods, the interplatform Spearman correlation coefficient was >0.5 for only 51 of them. Reverse-transcription PCR assays are being performed to identify the platform that yields the most accurate microRNA profile.

Conclusion
MicroRNA profiling by RNA sequencing and microarray techniques produced different results. The RNA sequencing method described here does not appear to be suitable for profiling microRNAs in RNA from FFPE samples. It is possible that depletion of ribosomal RNA fragments from FFPE RNA samples may improve the quality of data obtained from RNA sequencing.

Abstract not provided

Background
EGFR mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients who show an initial dramatic response to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy almost always acquire resistance due to secondary resistance mutations on EGFR or other mechanisms. Strategies to overcome such acquired resistance have therefore become critical to improve TKI-based targeted therapy. One strategy is the development of therapeutic agents to be used in combination with EGFR-TKI to treat EGFR mutation-positive relapsed patients. Although several candidate drugs targeting putative resistance pathways in NSCLC cells have been attempted in combination with EGFR-TKI, a systematic screening has not been reported. We seek to screen a small molecule library for compounds that would specifically enhance the cytotoxic effect of TKIs on EGFR mutation-positive tumor cells bearing acquired resistance mutations.

Methods
We have used MTS assay to screen a library containing about 1000 FDA approved drugs, 600 bioactive compounds, and 400 natural products, to identify compounds that when used in combination with 1µM Gefitnib, can result in significantly more toxicity to Gefitnib-resistant NSCLC cell line H1975 than either Gefitnib or the compound alone. The EGFR on H1975 contains both a TKI-sensitive mutation L858R and a resistant mutation T790M.

Results
The screening identified one candidate compound 18G06, an experimental natural product that belongs to a family of drugs currently used for heart disease. The compound has an IC50 of 270nM on H1975, and acts synergistically with Gifitnib to affect cell apoptosis, suggesting that the drug can overcome Gefitnib resistance in H1975. Test of 4 other known drugs in this family showed that they all have sub-microM IC50 values against H1975, but only Drug D had synergistic effect with Gefitnib, while other three drugs showed only additive effects. In addition, 18G06 or Drug D can overcome Gefitnib resistance of H1650 cells, a resistant NSCLC cell line with TKI-sensitive exon19 microdeletion and a TKI-resistant PTEN deletion. However, these two drugs, when used alone or with Gefitnib, had little effect on A549 cells, a resistant NSCLC line with wildtype EGFR. Biochemical evidence suggested that the improved Gefitnib sensitivities of H1975 and H1960 were correlated with specific synergistic inhibition of the ERK signaling pathway during combination treatment. Finally, combination therapy with Drug D and Gefitnib inhibited the growth of tumors formed by inoculated H1975 cells in nude mice to a greater extent than did treatment with either drug alone.

Conclusion
We identified two specific members of a family of therapeutics for heart disease that, when each combined with Gefitinib, have synthetic lethality effect on H1975 and H1960. The FDA-approved Drug D can be readily tested in clinical trials with Gefitnib to potentially reverse TKI-resistance of EGFR mutation-positive patients in targeted therapy.

Background
Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.

Methods
A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.

Results
Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.

Conclusion
Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.

Background
The management of non-small cell lung cancer (NSCLC) is becoming increasingly personalised with the identification of oncogenic drivers of cancer cell growth which are able to be targeted therapeutically. The paradigm of advanced non-squamous NSCLC treatment now incorporates assessment of epidermal growth factor (EGFR) mutations and treatment with EGFR tyrosine kinase inhibitors (TKIs) in cases where sensitising mutations are found, which results in significant prolongation of progression-free survival compared to empirical chemotherapy. However, the emergence of acquired resistance to EGFR TKIs is almost universal and the two most common mechanisms of resistance include the acquisition of a second mutation in EGFR, the T790M mutation, and c-MET amplification. Approximately one-quarter of cases of resistance are yet to be defined mechanistically and furthermore, optimal subsequent treatment remains unknown. Further research is required to understand the molecular origins of the development of acquired resistance in order to develop rational treatment strategies that incorporate both targeted and cytotoxic therapies. This study is evaluating, using in vitro models, pathways involved in the development of acquired resistance to EGFR TKI and chemotherapy and evaluating critical differences according to EGFR mutation status.

Methods
A panel of human NSCLC cell lines with varying clinically relevant molecular characteristics is being assessed and used to develop resistance to various cytotoxic agents and EGFR TKIs, through chronic low dose exposure, as outlined in the table below:

Cell Line	Mutation Status	EGFR TKI Sensitivity	Resistant Cell Line Generated
HCC827	EGFR Exon 19 deletion	Sensitive	Erlotinib; Cisplatin; Paclitaxel; Pemetrexed
H1975	EGFR Exon 21 Point Mutation (L858R) and T790M mutation	Resistant	Cisplatin; Paclitaxel; Pemetrexed
H1299	EGFR Wild-Type	Resistant	Cisplatin; Paclitaxel; Pemetrexed
A549	EGFR Wild-Type and KRAS Mutation	Resistant	Cisplatin; Paclitaxel; Pemetrexed, HDAC-inhibitor

Assessments of proliferation, cytotoxicity and key signalling pathways are being conducted to evaluate mechanisms of chemotherapeutic and targeted therapy resistance.

Results
Chronic low dose exposure has been successful in generating resistant cell lines to both chemotherapeutic agents and the EGFR TKI erlotinib. Cross-resistance to taxol in cisplatin-resistant cell lines has been observed, along with evidence of epithelial-to-mesenchymal transition in the development of EGFR TKI resistance. Antibody arrays of key signalling pathways are being conducted to confirm critical pathways of interest.

Conclusion
The panel of human NSCLC cell lines with parental lines harbouring various EGFR sensitising and resistance mutations and generated lines resistant to cytotoxic agents and EGFR TKI are a useful in vitro model to understand key pathways involved in the emergence of therapeutic resistance and to understand how both sensitising and resistant EGFR mutations influence response to cytotoxic agents. This will guide treatment strategies selected for evaluation in vivo that may influence future treatment selection for patients.

Background
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.

Methods
After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.

Results
From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.

Conclusion
EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1

Background
Lung cancer is the leading cause of death for cancer. Although impressive diagnosis and therapeutic achievements have been recently obtained, critical issues remain open. It is now believed that the generation of reliable preclinical models will provide the basis for new discoveries and to validate the clinical efficacy of known and novel compounds.

Methods
From 2010 to 2013, we have generated a biorepository of 190 frozen tumor samples and matched normal lung tissues, peripheral blood mononucleate cell collections, serum and plasma samples from patients who had undergone surgery with curative intentions (stage Ia, Ib, IIa mainly). This data set has been enriched with 480 additional archival tumors. The entire library, encompassing all major histotypes [adenocarcinomas (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)], covers the heterogeneous landscape of NSCLC. All tumors were characterized by immunohistochemistry (IHC) (TTF1, SPA, MUC5AC, CK5, CDX2, VILLIN, p53, p63, p16, ABCA3 and SOX2) and molecular analyses (EGFR, KRAS, BRAF and PI3K mutations). Considering that the pathogenetic role of many lesions is only in part elucidated, and that many lung cancers lack targetable mutations, we generated patient-derived tumorgrafts (PDTs), engrafting fresh and/or frozen tumor fragments in highly immunocompromised mice (NSG). Successfully grown tumors were propagated up to the third generation (T3). Primary versus PDT features were studied by histology, IHC and molecular profiling [Single Nucletoide Polimorphism (SNP), WES, RNA sequencing (RNAseq)] and HTP proteomic analyses.

Results
A known distribution of mutations within the first 300 ADCs samples (17% EGFR; 35% KRAS; 2% PI3K; 1% BRAF) was observed. 26 PDT lines (9 adenocarcinoma, 14 squamous, 2 sarcomatoid, 1 mixed) have been propagated, showing that the time growth average required from engraftment was significantly longer for the ADC-lines than SCC-lines (ADC-lines 20 weeks vs SCC-lines 11 weeks). We demonstrated the strong correspondence of primary cancers and PDT tumors, highlighting primary tumor’s specific features or biomarkers. The SNP analysis has revealed the occurrence of stress engrafment events (i.e. loss of heterozigosity LOH) at the first PDT passage; these alterations, once acquired remain relatively stable along later passages. Preliminary data from proteomic profiling are demonstrating stable Phospho-Tyrosine-Kinase profiles in primary tumors compared to PDTs, reinforcing the idea that this PDT tumors aren’t drifted so far from primary cancer architecture.

Conclusion
To improve bio-molecular stratification, pathological classification and clinical treatments of lung cancers, a multiparametric approach is needed; this should depict a complete and integrated cancer network in each cancer patient. Nonetheless, reliable preclinical models are required to define the best treatment choices and to overcome the boundaries between basic knowledge and the clinical requirements.

Abstract not provided

Background
The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.

Methods
A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.

Results
33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.

Conclusion
GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.

Background
Preclinically, arginine deprivation has shown activity as a novel antimetabolite strategy for MPM patients who are deficient for the rate-limiting enzyme in arginine biosynthesis argininosuccinate synthetase (ASS1). Here, we examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 (Polaris Group, San Diego, US) among patients with MPM.

Methods
We performed a multicentre randomised phase II clinical trial, based on patients with good performance status (0 or 1), non-resectable disease, ASS1-deficient MPM, and measurable disease. Patients were randomized 1:2 to receive best supportive care (BSC) or BSC+ADI-PEG20, stratified by: gender, histology (sarcomatoid versus non-sarcomatoid), prior treatment (chemonaive or previous platinum combination therapy), and centre. The primary endpoint, progression-free survival (PFS), is assessed by modified RECIST, and secondary endpoints include overall survival, tumor response rate, and toxicity. Translational endpoints included measurement of plasma arginine, citrulline and ADI-PEG20 antibody levels, assessment of metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and ASS1 methylation status using Illumina’s 450K DNA methylation array. The target sample size was estimated to detect a PFS hazard ratio of 0.60. [Trial funded by Cancer Research UK].

Results
ASS1 deficiency was detected in 98 of 214 patients (46%) of which 68 were randomized on the trial (44 ADI-PEG20+BSC and 24 BSC alone). 66 patients have progressed so far (42 ADI-PEG20+BSC vs. 24 BSC alone), and 32 patients were alive (23 ADI-PEG20+BSC vs. 9 BSC alone). The hazard ratio for PFS was 0.53 (95%, CI 0.31 to 0.90, p=0.02) with a median PFS of 98 days for patients randomized to ADI-PEG20+BSC compared with 59 days for patients receiving BSC alone. ADI-PEG20 toxicity in patients with MPM has been consistent with previous trials of ADI-PEG20 in melanoma and liver cancer: commonly skin injection site reactions (grade 1-2), infrequent episodes of neutropenia (range: grade 1-4), anaphylactoid reactions (2 patients with grade 3 episodes) and serum sickness (1 patient). The best response by modified RECIST was stable disease. Metabolic responses (in 39 evaluable ADI-treated patients) were as follows: 46% with partial response (18/39), 31% with stable disease (12/39), 15% progressive metabolic disease (6/39) and 8% mixed metabolic response (3/39) by FDG-PET assessment. There was a significant difference between IHC assessed ASS1-negative and ASS1-positive patients and the methylation status of the ASS1 gene (p=0.025).

Conclusion
ADI-PEG20 is generally well tolerated and shows evidence of clinically significant activity in patients selected for arginine-dependent MPM demonstrating differential methylation of ASS1. Arginine deprivation may have a role in the future management of MPM either alone or in combination with selected therapies.

Background
Malignant pleural mesothelioma is an incurable thoracic neoplasm for which combination chemotherapy offers limited improvement in survival. Novel agents that offer synergy with standard systemic cytotoxic therapy are under investigation. Among these agents are a variety of immunotherapeutics which can be administered either locally or in a systemic fashion.

Methods
We conducted a Phase I/II “in situ vaccination” clinical trial commencing in March2011 involving repeated intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x10[11 ]viral particles concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib). This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival.

Results
We completed accrual (n=25) in the first-line chemotherapy arm, in which all patients received pemetrexed-based chemotherapy regimens. This group included patients who previously received pemetrexed chemotherapy but did not subsequently receive this agent for >6 months. In the second-line chemotherapy arm, 13of a planned 15 subjects have enrolled (with 12 evaluable), all of whom received gemcitabine-based chemotherapy (Table 1). In both arms, the combination of intrapleural Ad.IFN-α2b vector, high-dose celecoxib, and systemic chemotherapy proved safe. Adverse events during the chemotherapy portion of the study were comparable to historical controls.Most patients experienced expected mild toxicities from vector (cytokine release syndrome, interferon production), including nausea, fatigue, anemia, lymphopenia (grade 3-4) and hypoalbuminemia. Serious adverse events included: pleural catheter infection (n=2); hypoxia (n=2); supraventricular tachycardia (n=1); and esophagitis (n=1), none directly attributable to the vector or vector administration. Serial chest CT and PET/CT scans demonstrated an overall response rate of 31% by Modified RECIST criteria and disease control rate (DCR) of 78% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Partial responses were seen in 9/25 evaluable patients with pemetrexed-based chemotherapy and 1/12 with gemcitabine. Patients who received first-line pemetrexed-based chemotherapy (n=14) had a median survival of 10.5 months, 95% ci=(5.5,inf), whereas second-line patients (n=21; 12 gemcitabine)had a median survival of 15.0 months, 95% ci=(9.0,inf).

	Pem/Platin (N=25)	Gemcitabine (N=13)
Male %	64% (16/25)	84.6% (11/13)
Median Age	67 (51-86)	65 (43-81)
Histologic Subtype %	Epithelioid - 17 (68%) Biphasic - 4 (17%) Sarcomatoid - 4 (17%)	Epithelioid - 11 (84.6%) Biphasic - 2 (15.4%) Sarcomatoid - 0
Stage	I - 2 (8%) II - 6 (24%) III - 13 (52%) IV - 4 (16%)	III - 4 (30%) IV - 9 (70%)
Prior Treatment	Chemotherapy - 4 (16%) RP/PDT - 4 (16%) XRT - 5 (20%)	Chemotherapy - 13 (100%) RP/PDT - 7 (53%) XRT - 2 (15%)
Platin Agent	Cisplatin - 12 Carboplatin - 10 Cis-Carbo - 1 None - 2	Cisplatin - 0 Carboplatin - 2 None - 8
Median Cycles of Chemo	6 (1-6)	3 (0-6)

TABLE 1

Conclusion
The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe. Disease control rates observed in this study compare favorably with historical data andthe especially encouraging OS in the second-line chemotherapy group argue strongly for proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus chemotherapy alone.

Background
Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.

Methods
All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1

Results
During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.

Conclusion
Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.

Abstract not provided

Background
The National Lung Cancer Audit is run jointly by the Royal College of Physicians and The Information Centre for health and social care with the aim of recording outcomes in lung cancer (and mesothelioma) on a population scale, explaining the wide variations seen within the UK and between the UK and other countries and ultimately improving outcomes. This abstract presents results for England only, focusing on mesothelioma.

Methods
All patients with mesothelioma seen in in secondary care 2006-2011 were analysed. A hierarchy of diagnosis from surgical histology to non-surgical histology to clinical diagnosis was used to exclude patients with potentially conflicting diagnoses. These records were further analysed to extract data on age/sex distribution, referral source, histological subtype, treatment regime and survival rates.

Results
There were 8,503 patients with mean age 72yrs (83% male), representing around 65% of expected incident cases (a substantial number diagnosed at autopsy and not included in the audit). 45% have right-sided disease, 28% were left-sided, and 1% were bilateral (data missing in 26%). The majority of patients (47%) were referred by their primary care physician, but at least 20% present to secondary care as emergencies. Overall, 89% of cases were histo-cytologically confirmed with that figure appearing to rise slowly over the audit period from 81% (2006) to 92% (2011). Survival data is shown below.

	n (%)	Median survival (days)	1 year survival (%)
All patients	8,503 (100%)	278	41
Survival was slightly better in females (median 304 days vs 274 days HR 0.91, p=0.002)
Subtype	n (%)	Median survival (days)	1 year survival (%)
Unspecified	3,798	276	39.5
Epithelioid	2,300	388	53.2
Sarcomatoid	439	123	16.4
Biphasic	268	274	36.0

37% of patients received no anti-cancer treatment, but 28%, 26% and 30% of patients received “surgery”, chemotherapy or radiotherapy at any time. Most surgical operations (60%) were pleurodesis. Median survival varied by first treatment modality: surgery 378 days, chemotherapy 399 days, radiotherapy 308 days, no anti-treatment 140 days. Survival was highest in patients having “surgery” and chemotherapy (491 days). Use of chemotherapy varied across 28 regional cancer networks from 14% to 41% of patients, but overall increased over the audit period from 13% to 34%.

Conclusion
Mesothelioma is predominantly a cancer of elderly males, with a striking tendency for right-sided disease. Only 11% have no histological confirmation, but where this is obtained, the epithelioid subtype has best prognosis. Low rates of anti-cancer treatment may reflect therapeutic nihilism as well as patient fitness, but there is an encouraging trend towards wider use of chemotherapy which was associated with a greater than doubling in survival compared with no treatment.

Background
Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.

Methods
We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.

Results
We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.

Conclusion
In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM patients.

Background
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and estimates indicate that the incidence of MPM will peak in western world within the next 10-15 years. Untreated, MPM has a median survival time of 6 months, with poor survival rates for most patients after 24 months of diagnosis. Nuclear Factor kappa B (NF-kB) is a pro-inflammatory transcription factor which is activated in many cancer types, including MPM. The NF-kB pathway regulates important cellular processes including survival and proliferation signals, which are often found to be dysregulated in cancer. Furthermore, we and others have shown that increased NF-kB activation is linked to development of cisplatin resistance. We aim to outline the potential role of NF-kB as a mediator of cisplatin resistance in MPM and determine its value as a potential candidate for therapeutic intervention.

Methods
NF-kB expression was examined in a cohort of MPM patients (n=200) by IHC, and correlated with clinicopathological variables and survival. NF-kB expression was examined in both a panel of MPM cell lines and isogenic parent/cisplatin resistant cell lines by Western blot analysis. The effect of NF-kB inhibition on cellular proliferation was measured by BrdU assay, in a panel of MPM and isogenic parent/cisplatin resistant cell lines, using the novel NF-kB inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ). In addition, the effect of DHMEQ on nuclear translocation of NF-kB was examined by high content screening (HCS).

Results
Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NF-kB was seen in only 11% cases. Kaplan-Meier survival analysis showed that nuclear NF-kB expression correlated with reduced survival (p=0.05). There was no significant correlation between the level of expression of NF-kB and standard clinicopathological parameters. NF-kB was expressed in all MPM cell lines tested to a varying extent (n=20), with no associations to histology. NF-kB levels were shown to be elevated in cisplatin resistant cell lines when compared to the isogenic parent from which they were derived. DHMEQ was shown to reduce nuclear translocation of NF-kB, inhibiting cell proliferation in all cell lines but to a lesser extent in NCI 2596 cells which have low NFkB expression.

Conclusion
Nuclear NFkB expression is a poor prognostic factor in MPM. DHMEQ, which inhibits nuclear translocation of NF-kB, inhibits cell proliferation in MPM cell lines. Furthermore, increased NF-kB expression in resistant cells suggests this pathway may play a role in development of cisplatin resistance in MPM. Inhibition of NF-kB may therefore prove to be of potential therapeutic benefit in MPM treatment and re-sensitisation of resistant MPM to cisplatin.

Abstract not provided

Background
Tumor response criteria provide a framework for therapeutic decisions and clinical trials management in oncology. The standard response classification categories (partial response (PR), stable disease (SD), and progressive disease (PD)) were defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines based on relative changes in linear measurements of tumor diameter on computed tomography (CT) scans. An increase in linear dimension of at least 20% is categorized as PD, a decrease in linear dimension of at least 30% is categorized as PR, and a change in linear dimension not great enough to exceed either of these thresholds is categorized as SD. With improvements in imaging technology and enhancements in computer algorithms, the extraction of tumor volume from CT scans has become more practical. The possibility that tumor volume may eventually become the preferred tumor measurement metric rather than linear dimension necessitates the development of volumetric response criteria. Although extrapolation of the RECIST response criteria to volume is straightforward for spherical nodules, tumors as non-spherical as mesothelioma likely will require unique volumetric response criteria.

Methods
A semi-automated computerized method was used to determine the mesothelioma tumor volume from CT scans (baseline and all available follow-up scans) retrospectively collected from 70 patients undergoing standard-of-care chemotherapy. Relative changes in tumor volume from baseline were categorized as PR, SD, or PD based on different combinations of percent change thresholds. Overall patient survival was correlated with best response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria.

Results
The process that systematically evaluated various combinations of response criteria identified an increase in tumor volume of at least 58% and a decrease in tumor volume of at least 17% for PD and PR, respectively, as the criteria that were best correlated with patient survival. These criteria yielded a C statistic of 0.76, where a C statistic value of 1.0 would indicate perfect separation of response groups with respect to subsequent survival times. This result may be compared with the C statistic value of 0.61 obtained when volumetric response criteria extrapolated directly from the RECIST criteria (+73% for PD and -66% for PR) were applied to this cohort.

Conclusion
The evolution toward volumetric assessment of tumor burden and response to therapy necessitates the derivation and validation of volume-specific tumor response criteria to distinguish among PR, SD, and PD. The present study motivates such response criteria for mesothelioma and indicates that mesothelioma volumetric response criteria differ substantively from a simplistic extension of the RECIST criteria to three dimensions. Future prospective studies will be required to validate these criteria.

Background
Clinical T classification of Malignant Pleural Mesothelioma involves qualitative estimation of tumor involvement of the thorax and does not accurately predict prognosis (JTO 7(11):1631-9, 2012). We explored whether novel quantitative assessment of standard CT images might improve the prognostic accuracy of clinical T classification.

Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with available preoperative CT for retrospective review were included. Tumor volume was derived using Vitrea software (Vital) and binned into 3 categories (≤75cc, >75≤500cc, >500cc). Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival were computed for each combination of volume and septum thickness categories. Combinations with similar estimated survival functions were combined to create criteria for T classification levels. Cox regression was used to evaluate the relative hazard for death and disease recurrence associated with classification levels.

Results
406 patients met inclusion criteria (278 EPP, 128 PDC; 317 male; 297 epithelial histology on biopsy; median age 64). Alignment of survival functions yielded combinations of volume and septum thickness categories defining T1 through T4. These classifications were associated with progressively increasing hazard for death and recurrence (Table).

		Overall Survival			Time to Recurrence
T status	N	Median(mths)	HR	95% C.I.	Median(mths)	HR	95% C.I.
T1	85	37	1.0	-	16	1.0	--
T2	118	21	1.5	1.0 - 2.1	11	1.6	1.1-2.1
T3	105	14	2.5	1.7 - 3.5	8	2.3	1.7 -3.2
T4	98	10	4.2	3.0 - 6.1	5	4.1	3.0 - 5.8

Conclusion
Tumor volume and septum thickness are readily measured on standard CT imaging and provide robust prognostic information not accounted for by current clinical T classification criteria. As quantitative measurements, they should be minimally affected by inter-observer variability. The feasibility and value of these simple and cost effective adaptations to clinical staging should be evaluated as the TNM staging system is revised.

Background
Little is known about the significance of metastases to the posterior intercostal lymph nodes, located within the intercostal spaces at the level of the rib heads, in patients with malignant pleural mesothelioma. These nodes are not part of any staging system. This report is an initial attempt to determine the significance of these lymph nodes.

Methods
We sampled posterior intercostal lymph nodes from 48 patients undergoing radical pleurectomy for malignant pleural mesothelioma. Statistical analyses were then performed correlating metastases to these lymph nodes with progression free and overall survival.

Results
26/48 (54%) patients had positive posterior intercostal lymph nodes. Standard staging revealed: 6/48 (13%) N0, 3/48 (6%) N1, 39/48 (81%) N2, 9/49 (19%) stage III and 39/48 (81%) stage IV. Presence of positive posterior intercostal lymph nodes was not associated with stage (Fisher exact P=0.48), but was associated with N status. N1 and N2 were associated with higher rates of positive posterior intercostal lymph nodes (Fisher exact P=0.011). At a median follow-up of 9.6 months, progression-free survival was 0.83 years, 95% CI: (0.74, 1.30) years; median overall survival was 1.89 years, 95% CI: (1.29, ND) years. Patients with negative posterior intercostal lymph nodes had a median progression-free survival of 1.25 years, 95% CI: (0.95, 1.95) years, while that for patients with positive posterior intercostal lymph nodes was 0.73 years, 95% CI: (0.61, 1.40) years (p=.017 by log-rank test). Patients with negative posterior intercostal lymph nodes had a median overall survival of 3.43 years, 95% CI: (1.89, ND) years, while that for patients with positive ICLNs was 1.01 years, 95% CI: (0.61, 1.40) years (p=.007 by log-rank). In a Cox regression model that adjusted for stage, positive posterior intercostal lymph nodes were associated with an increased risk of failure (HR=2.71, 95% CI=1.15.6.39, P=.048) and death, (HR=3.3, 95% CI: 1.3, 8.1, P=0.0098. Figure 1

Conclusion
Bearing in mind the limitations of this retrospective study with short-term follow-up, these results suggest that the posterior intercostal lymph nodes may have independent prognostic significance. This data has served as a trigger for us to now routinely include the posterior intercostal lymph nodes in our thoracic lymphadenectomies in patients undergoing surgery for malignant pleural mesothelioma. Further investigation of this nodal station is indicated and it is likely that these nodes should be included in any future staging system for malignant pleural mesothelioma.

Background
Studies have assessed correlation between radiographically estimated tumor volume (TV) and outcomes for malignant pleural mesothelioma, no standard radiographic model exists for estimating TV. Although radical pleurectomy yields a surgical specimen essentially all cancer, thereby allowing accurate determination of TV, empirically-derived intraoperative TVs have never been reported. We compare multiple radiographic estimates of TV with TVs determined at resection to determine which radiographic approach most accurately predicts intraoperative TV, and we correlate TV with survival.

Methods
Actual TVs were measured for 41 consecutive radical pleurectomy specimens by volume displacement. Radiographic TV estimates were performed by radiologists/radiation oncologists blinded to intraoperative TVs. Radiographic estimates were obtained with: Live Wire algorithm (automated tumor delineation after manual algorithm training), radiology TeraRecon (tumor automatically circumscribed with subsequent manual tracing corrections), and radiation oncology Eclipse (non-automated tumor delineation).

Results
Median age was 63yrs, with 80% male and 83% having epithelial histology. Stage distribution was: 3-Stage I (7%), 4-Stage II (10%), 29-Stage III (71%), and 5-Stage IV (12%). Median (interquartile range) intraoperative TV was 600(400,800)cm[3]. Median TV of 800(575,1100)cm[3] among nonepithelial compared to 500(350,838)cm[3] for epithelial was not significantly difference (p=0.099). TVs were largest for stage III (p=0.01). Median TVs for Live Wire, TerraRecon, and Eclipse were 260(147-452), 293(161-465), and 447(247-559)cm[3], respectively. Pearson correlation coefficients were 0.60, 0.75, and 0.78, with all models underestimating intraoperative TVs (Figure 1A). Among 34 epithelial patients (mean/median follow-up 9.8/8.0mo), median survival was not reached (only 9 recurrences). Epithelial patients with large (>500cm[3]) intraoperative TVs had numerically worse progression-free (p=0.148) and overall (p=0.161) survival than patients with TVs ≤500cm[3](Figure 1B), but limited events precluded statistical significance. Larger radiologic TVs similarly correlated with shorter survivals. Figure 1

Conclusion
This is the first study to compare radiographic estimates of TV to actual TV determined by volume displacement of radical pleurectomy specimens, arguably the TV measurement gold standard. This study is also the first to compare estimated TVs using multiple established and previously reported radiographic techniques. Our results demonstrate a clear trend toward greater overall and progression-free survival for actual TVs <500cm[3]. All radiographic techniques underestimated actual TV, with estimates progressively closer to the actual volume with each technique as they became less automated and more manual. Further analysis is ongoing to determine if any radiographic method can serve as an accurate surrogate for actual TV and if models correlate as closely with outcomes as actual TVs.

Abstract not provided

Background
Response assessment using conventional RECIST criteria after SABR of lung targets can be confounded by fibrotic response. The purpose of this study was to evaluate the utility of 4D-FDG-PET/CT and CT perfusion scans in the response assessment of single fraction SABR for inoperable pulmonary oligometastases.

Methods
This is a prospective ethics approved clinical study of patients undergoing single fraction SABR with 26Gy for pulmonary metastases. Eligible patients had 1-2 metastases with no extrathoracic disease on staging FDG-PET. Serial 3D / 4D-FDG-PET and CT perfusion studies were performed at baseline, 14 days and 70 days after therapy. Two radiologists independently reported CT perfusion scans.

Results
At a median follow-up of 16 months (range 3-27), 10 patients with 13 metastases received SABR. A further 7 patients (41%) were screened from the study due to interval progression of disease between the time of the original FDG-PET and trial 4D-FDG-PET / perfusion CT. The mean time between the original FDG-PET and trial scans was 62 days. No patient progressed locally, 7/10 patients progressed distantly of which 2/7 received subsequent SABR. At the end of study period, 5/10 patients are alive without disease. The median progression free survival was 14 months. The change in SUVmax from baseline was higher on 3D than 4D-PET by a mean of 20.6% (range 0.2%-47.2%) at 14 days and 14.8% (range 0-37.8%) at 70 days. Overall, the SUVmax increased at 14 days (mean 104.9%, p<0.01) and decreased at 70 days (mean=55.5%, p<0.01), despite persistent morphological lesions on the concurrent late timepoint CT. There was strong level of inter-observer agreement of CT perfusion interpretation with a median intraclass correlation coefficient of 89% (range 57%-98%). Perfusion parameters of Time to Peak Blood Flow and Blood Volume showed a median increase of 18.8% and 23.0% at 2 weeks post-therapy and decreased below baseline by a median 7.0% and 14.0% at 70 days (non-significant).

Conclusion
High rates of interval progression between staging scans indicates a need to expedite management of oligometastases in a timely fashion. Increased tumour perfusion and FDG-PET intensity at 2 weeks post-RT is likely due to an inflammatory response to large single dose SABR. Late PET response was associated with tumour control despite CT apparent morphological lesions. Conventional 3D PET may overestimate change in PET intensity post SABR as compared to 4D PET. These findings, in particular CT perfusion findings, require a larger patient cohort for validation.

Background
The standard of care worldwide for radiation dose scheduling in NSCLC has historically been 2Gy per fraction treating once daily over six weeks. The CHART regimen of accelerated hyperfractionated treatment first demonstrated significant survival benefit from a two week radical course, attributed to reduced repopulation and improved local control. A recent individual patient data meta-analysis confirms significant survival benefit from accelerated radiotherapy[1]. Meantime the evolving data on stereotactic radiotherapy treating early stage lung cancer over two weeks or less suggests marked improvement in local control rates compared with historical populations treated with conventional fractionation[2]. The latest challenge to 2Gy per fraction comes from the early stop to the dose escalation arm of RTOG 0617 with 74Gy actually appearing inferior to the 60Gy arm. We postulate that overall treatment time is a key factor in lung cancer radiotherapy outcomes and that standards of care need to be reviewed. This paper examines the current international guidelines on radical radiotherapy schedules, evaluates the supporting evidence and proposes new priorities for research.

Methods
Five international guidelines on the management of lung cancer were reviewed. All were published 2010-2013: ESMO Clinical Practice Guideline on early stage and locally advanced lung cancer 2010, NICE guideline (England and Wales) 2011, Australian Government Clinical Practice Guideline for treatment of lung cancer 2012, Cancer Care Ontario evidence based series lung cancer guideline 2013, National Comprehensive Cancer Network (NCCN) Lung Cancer guideline v2.2013. Recommendations on radical radiotherapy dose and fractionation for NSCLC were collated from each guideline together with the references cited in support of these recommendations to assess levels of evidence.

Results
Two guidelines specifically recommended hypofractionated SBRT for early stage inoperable disease -NICE and NCCN. The Australian guideline stated uncertainty over relative benefit SBRT versus conventional fractionation in stage I disease. England, Ontario and Australia all included CHART regimen as treatment of choice for stage II/III radical patients not receiving chemotherapy. Cancer Care Ontario undertook specific review of altered fractionation schedules identifying lack of evidence for hyperfractionation but suggesting possible benefit for hypofractionation. All five guidelines specified standard care, if given with chemotherapy, of conventional fraction size 2Gy: Ontario, ESMO and Australian guidance was a minimum of 60Gy in 30 fractions. NCCN offered a range of 60-74Gy at 2Gy/fraction. NICE alone proposed alternative standard of 55Gy in 20 fractions, a common UK schedule, or the option of 64-66Gy at 2Gy/fraction

Conclusion
International guidelines lag behind the emerging evidence for lack of benefit from dose escalation at 2Gy/fraction and apparent benefit from shorter treatment courses . We propose that accelerating treatment with hypofractionation and shorter overall treatment times should be the priority for radiotherapy development. We discuss current and pending trials examining this approach. 1. Mauguen A, Le Pechoux C, Saunders M et al: Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 30:2788-2797, 2012 2. Timmerman R, Paulus R, Gavin J et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070-1076, 2010

Background
Reported non-small cell lung cancer (NSCLC) nodal failure rates following stereotactic body radiotherapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesize that this effect is due to incidental prophylactic nodal irradiation.

Methods
A prospectively collected group of medically inoperable early stage NSCLC patients (n=179) from 2004 to 2010 was used to identify a patient cohort with nodal relapses (n=19). These cases were matched, 1:2, to controls, controlling for tumour volume (i.e. same or greater) and tumour location (i.e. same lobe). Reference (normalized total) point doses at the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical record. Multivariate logistical regression analyses determined variables of interest.

Results
The case and control cohorts were well matched with respect to age, sex, method of nodal staging, SUVmax, histology subtype, dose and length of follow up.. The controls, as expected, had larger gross tumour volumes (p=0.02). The mean hilar doses were 9.6 and 22.4 Gy for cases and controls, respectively (p=0.014). Similarly, the mean carinal doses were 7.0 and 9.2 Gy, respectively (p=0.13). The mean ipsilateral hilar doses were 19.8 and 3.6 Gy for ipsilateral non-hilar and hilar nodal relapses, respectively (p=0.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse (Figure 1).Figure 1

Conclusion
Incidental hilar dose greater than 20 Gy (normalized to 2Gy/fraction) appears to be correlated with lack of hilar relapses in inoperable early stage NSCLC patients treated with SBRT.

Background
Fiducial markers enable lesion tracking and localization with radiosurgery. Complications with percutaneous insertion are very common with pneumothorax rate reported as high as 67%, chest tube insertion 22% and migration of marker 19%. The purpose of this study was to assess complications associated with the bronchoscopic placement of a new commercial fiducial marker, designed for bronchoscopic insertion and to reduce migration. Twenty-one consecutive patients are reviewed in which 60 Cobra® (SuperDimension) fiducial markers were placed using electromagnetic navigational bronchoscopy. Accuracy of placement, utility of each marker, complications and migration are reported.

Methods
The use of these markers was approved by a advisory committee at our institution. Records of 21 consecutive patients (12 men, 9 women; mean age 61) referred to the Interventional Pulmonary Division for fiducial marker placement before initiation of cyber knife radiosurgery (Accuray, Sunnyvale CA) between December 15, 2012 and June 15, 2013. Indications for radiosurgery included non-surgical patients with nonsmall cell lung cancer and metatatic disease to the lungs from colorectal carcinoma and renal cell carcinoma. Our institution's radiation oncologist requested between one and three fiducials placed within or adjacent to each lesion. A total of 60 Cobra® fiducial markers were placed. In each insertion procedure, a computerized tomogram of the chest was used to preplan ideal insertion site and fiducial location in relation to tumor mass. Bronchoscopy was performed, using the SuperDimension planning and navigation, 1 to 3 Cobra® fiducial markers were placed in proximity to 22 different tumors.

Results
There were no instances of pneumothorax, with patient followup to one week. There no instances of fiducial migration greater than 3 mm from insertion site. There were 7 episodes of post procedure events, which included cough, dyspnea and hypoxemia. All events resolved prior to patient discharge from the outpatient treatment area. Imaging included chest radiograph, post procedure, on same day and CT chest within 1 week of procedure.

Conclusion
In this limited series, the Cobra® fiducial marker, using bronchoscopy and SuperDimension planning and navigation resulted in no instances of pneumothorax and no significant fiducial migration. This contrasts many reports of percutaneous fiducial placements regarding complications and migration.

Background
SBRT is an accepted safe and effective treatment modality for peripheral (P) stage I NSCLC tumors. Concern of excessive toxicity, however, limits its use for central (C) tumors. This study evaluates outcomes and toxicities after cone-beam CT (CBCT) image-guided SBRT for central vs. peripheral NSCLC.

Methods
959 lung tumors were treated with lung SBRT from 1998-2012 at five international centers participating in the Elekta Collaborative Lung Research Group; 98% underwent online CBCT IGRT. 100 cases were classified as Central (C) and 869 Peripheral (P), defined as ≤2cm vs. >2cm from the proximal bronchial tree, respectively. Staging included chest CT and routine chemistry for all; 93% had PET staging (mean time PET to SBRT 6.4 weeks); 6% had mediastinal sampling (mediastinoscopy or endobronchial ultrasound). 61% had tumor biopsy (84% C vs. 59% P, p<0.001). 89% were medically inoperable with mean baseline FEV1 of 1.6L (63% of predicted) and mean baseline DLCO of 12.1 ml/min/mmHg (56% of predicted). Mean age was 74y (42-93) with a large range in ECOG performance status (27%; 47%; 23%; 26% for 0-3, respectively). Clinical stage was T1aN0 44%, T1bN0 30%, T2aN0 23%, T2bN0 32%. Mean tumor maximum dimension was 2.5cm (range 0.5-8.5cm); C tumors were larger (mean 3.lcm vs. 2.4 cm, p<0.001). Mean SBRT prescription dose was 51.5±6.4 Gy, with mean dose per fraction of 14.5±4.0 Gy in 3.9±1.5 fractions. Mean biological equivalent dose (BED) was 126.6±26.6 Gy, higher for P vs. C tumors (129.2 vs. 104.0 Gy, p<0.001. Chemotherapy was administered more for C (9%) than P tumors (2%), p<0.001. Groups were compared with t-test & chi-square. Competing risks analyses were used, accounting for the competing risk of death.

Results
Mean follow-up for all cases was 1.8y (0.1-7.7y; mean potential follow-up 3.4y), similar for C&P. C tumors had higher Local Failure (LF) (3y-LF 16.2%C vs. 5.9%P; 5y-LF 20.4%C vs. 8.3%P, p<0.001), similar regional nodal recurrences (RR) (3y-RR 12%C vs.12%P, p=0.69) and distant metastases (DM) (3y-DM 19%C vs 20%P, p=0.75), lower cause-specific survival (CSS) (3yr-CSS 75%C vs. 88%P, p<0.001), but similar overall survival (OS) (3y-OS 50%C vs. 51%P, p=0.70). Grade > 2 pneumonitis was higher for C tumors (8%C vs. 1%P, p<0.001). Incidence of grade 3 pneumonitis, chest wall pain/myositis, rib fracture, and skin dermatitis were rare (0.8%, 0.5%, 0.4%, 0.6% respectively for all) with no differences between C&P. No grade 4 toxicities were noted, though 2 cases (1C & 1P) of fatal pneumonitis were potentially attributable to SBRT. On multivariate analysis, BED (HR:0.975, p<0.001) predicted CSS, and both BED (HR:0.978, p=0.002) and baseline SUVmax (HR:1.04, p=0.001) predicted LF. Weeks from PET-staging until SBRT (HR:1.25, p=0.004) and the percent of lungs receiving >20 Gy (HR:1.063, p=0.001) were the strongest independent predictors of OS.

Conclusion
In this large data set, pneumonitis was higher for central tumors, but both central & peripheral SBRT were safe with similar overall and cause-specific survival. LF was higher for central tumors, which were larger, had higher baseline SUVmax, and received lower dose. Results of the ongoing RTOG 0813 dose-finding study for central tumors are awaited.

Abstract not provided

Background
In the framework of a coverage with evidence development program on innovative radiotherapy techniques in Belgium, the cost of stereotactic body radiotherapy (SBRT) was calculated and compared to the cost of more standardized 3D-conformal (3D-CRT) and intensity-modulated (IMRT) radiotherapy treatments.

Methods
Activity-Based Costing methodology was used to calculate resource costs of radiotherapy treatments delivered in ten operational Belgian departments. Cost inputs were defined as personnel costs (number of full-time equivalents (FTE) devoted to the actual radiotherapy process times reference wages according to the guidelines of the Belgian Health Care Knowledge Centre (KCE)), equipment costs (including maintenance and upgrade) and specific material costs. Following KCE guidelines, overhead was accounted at 56% of global costs excluding physician wages. The activities in scope comprised all activities performed during the radiotherapy process from the first consultation, over treatment preparation, delivery and quality assurance until completion of the treatment. Products included all radiotherapy treatments delivered in each specific department and combined indication with treatment site and technical complexity. In view of the comparative analysis, products were aggregated into larger categories.

Results
The average cost of all SBRT treatments was calculated at 6,221€ (range 3,104€ - 12,649€) and compared favorably to the average cost of standard fractionated 3D-CRT (5,919€, range 4,557€ - 6,564€) and IMRT (7,379€, range 5,054€ - 8,733€). The average cost of hypofractionated 3D-CRT and IMRT was lower (3,993€ res. 4,730€). Apart from differences in investment costs, the relatively larger variability in fraction number and in time requirements for individual personnel types performing the radiotherapy activities explain the larger spread in treatment cost of SBRT compared to more standardized radiotherapy treatments. The figure demonstrates these differences for various technical SBRT solutions and for different 3D-CRT and IMRT fractionation schedules. The overall averages are shown by the bars, minimum and maximum center averages by the error bars. The number of centers is mentioned between brackets. Activity times shown combine time per personnel with number of FTE. Figure 1

Conclusion
Cost calculation of radiotherapy treatments at the multi-institutional level using Activity-Based Costing is feasible. SBRT shows larger variation in cost than more standardized radiotherapy approaches in line with the larger variability in technical solutions, time requirements and resource consumption. Its average cost however does not exceed the average cost of standard curative radiotherapy. Careful interpretation of these variables within the applicable economic context is required when using such cost data for determining financing levels.

Background
In early stage non-small cell lung cancer (NSCLC) stereotactic body radiotherapy (SBRT) has become standard of care for inoperable patients. Tumor size >3cm was reported to be a predictor of local recurrence (LR), suggesting a dose-volume effect. Recently, the dose effect relation was questioned[1]. We used a Tumor-Control-Probability (TCP) model on a large pooled multi-center cohort to test this.

Methods
850 patients were analyzed from our five institutes. Patients received a 4D CT-scan and plans were inversely optimized using advanced dose calculation algorithms. Treatment was delivered using online cone-beam CT guidance. Immobilization, margins, dose prescription and treatment planning was performed according to institute specific protocols. Median tumor diameter was 2.2 cm (range:0.7-8.0), median prescribed dose was 54 Gy (range:18-64) and median number of fractions were 3 (range:1-10). LRs were either biopsy proven or defined as a FDG-PET positive growing mass on CT-scan. The Web-Nahum TCP-model[2] was fitted to LR-data using maximum-likelihood estimation by optimizing its parameters: α representing the population-average radio-sensitivity, σ~α~ representing the population-variation in α and ρ the clonogen density. Input variables were the patient specific Gross Tumor Volume (estimated from the tumor diameter), for the dosimetric parameter PTV-D~min~, D~max~, D~mean~, D~1~, D~99~ were evaluated after conversion to Biological-Effective-Dose (BED) using the LQ-model with α/β=10Gy. We tested the optimized TCP model against a random model in which TCP was fixed independent of dose and volume. The optimal model was selected based on the Akaike-Information-Criterion (AIC).

Results
After a median follow up (FU) of 17 months (range:0-93), 43 LRs (5%) were diagnosed at 14 months FU (range:2-56), of which 25 tumors were biopsy proven and 18 recurrences diagnosed on PET-CT. The PTV-BED~mean~ based TCP model showed the best fit with parameters α=0.43Gy[-1] (CI:0.33–0.75) and σ~α~=0.17 Gy[-1] (CI:0.11–0.37). The model-fit was insensitive to ρ and set to literature values: 10[7]/cm[3]. The AIC of the optimal model was 12 units higher than the random model indicating a clear dose-volume-effect. At high PTV~mean~-BEDs, however, the volume effect is modest. Additionally, the AIC of the BED corrected model was 9.4 units higher than the BED uncorrected model. Figure 1

Conclusion
A dose-volume-effect relation in SBRT for early stage NSCLC for local control was derived in a large cohort of patients. This dose-effect relation requires validation in independent datasets and prospective trials. 1.van Baardwijk,Rad.Onc.,2012. 2.Web&Nahum,PMB,1993.

Background
Stereotactic body radiotherapy (SBRT) is an effective treatment for early-stage non-small cell lung cancer (NSCLC) and lung metastases. However, increased toxicity has been observed for SBRT to lesions near the proximal airways or mediastinal structures. Reported toxicities have primarily pertained to pulmonary complications, but little is known about the risk for esophageal toxicity. Therefore, we sought to evaluate dosimetric predictors of esophageal toxicity in this patient cohort at our institution.

Methods
We identified 125 patients who received SBRT for single lung tumors within 2 cm of the proximal bronchial tree (n=81) or whose planning target volume (PTV) intersected mediastinal structures (n=44). Ninety-one patients had primary NSCLC, 12 had recurrent NSCLC, and 22 had metastatic tumors involving the lung. Patients with prior thoracic radiotherapy were excluded. Toxicity was scored using the Common Terminology Criteria for Adverse Events v.4.0. Biological equivalent doses (BED) were calculated using the linear quadratic formula with either α/β=3 or 10 Gy. Dose-volume histogram variables for the esophagus (D~v~, minimum dose to the hottest volume v and V~d~, volume receiving doses greater than d) were then examined for all patients and correlation with toxicity was assessed using logistic regression. Log rank tests were performed using median splits for variables that were significant in logistic regression.

Results
With a median follow-up of 14.3 months, the overall rate of grade ≥2 esophageal toxicity was 12.8% (n=16), including two grade 3 events. The median prescription dose was 45Gy. The most common fractionation schemes were 45Gy in 5 fractions (n=56), 48Gy in 4 fractions (n=21), or 50Gy in 5 fractions (n=14). Highly significant logistic models were generated on the basis of D~3.5cc~, D~5cc~, and D~max ~(p<0.001). For a complication rate < 20%, D~3.5cc~ ≤ 29.4 Gy~10~, D~5cc~ ≤ 25.4 Gy~10~, and D~max~ ≤ 50.1 Gy~10~ was observed based on these models (BED~10~). Log rank tests showed that at 2 years, the probability of complication of those with a BED~10~ D~3.5cc~ > 16.6 Gy was 25% (p<0.001), D~5cc~ > 15.1 Gy was 26% (p<0.001), and a D~max~ > 29.6 Gy was 21% (p=0.032). The probability of complication for those with a D~3.5cc~, D~5cc~, and D~max~ (BED~10~) less than or equal to the above limits were 2%, 2% and 7%, respectively. The analysis was insensitive to α/β, and the same D~v~ variables were found to be significant using α/β =3.

Conclusion
This is a novel quantitative analysis providing dose guidelines for significant esophagitis in the setting of SBRT. Dose to the hottest 3.5cc, 5cc and D~max~ were the best parameters for prediction of esophageal toxicity. Converting the BED~10~ limits to physical doses, D~3.5cc ~to the esophagus should be kept less than 18.3, 19.7 and 20.8 Gy for 3, 4, and 5 fractions, respectively, to keep the esophagitis rate < 20%. However, these guidelines must be weighed against clinical considerations and potential compromise of target coverage. This information will be valuable for treatment planning and identifying patients at risk for esophageal complications from SBRT.

Background
Treatment-related radiologic change occurs commonly following stereotactic ablative radiotherapy (SABR) and often confound the interpretation of follow-up CT scans. SABR is frequently delivered using both fixed-beams and rotational-arcs, resulting in different dose distributions and it is unclear how this influences radiological change. We studied the morphology, timing and severity of radiologic change after both delivery techniques.

Methods
Twenty-nine patients with early stage non-small cell lung cancer receiving SABR by arc delivery, without clinical evidence of local recurrence, and a follow-up of more than two years, were assessed using a published scoring system [Dahele M, JTO 2011]. Here, the morphology of acute (within six months) radiologic change was characterized between ‘patchy (less than 5 cm) ground glass opacity’, ‘patchy consolidation’, ‘diffuse (more than 5 cm) ground glass opacity’, or ‘diffuse consolidation’. The late (after 6 months) morphology was characterized between ‘scar-like’, ‘mass-like’ and ‘modified conventional’. Additionally the severity of radiologic change was scored as ‘pronounced’ (more than expected), ‘expected’, ‘mild’ (less than expected) and none. These outcomes were compared to 54 patients treated with SABR by fixed-beam delivery, who we previously assessed using the same scoring system.

Results
Baseline characteristics of the arc and fixed-beam cohorts were well matched and respective median follow-ups were no different, 31.7 vs. 28.4 months (p=0.20). Patients treated by arc delivery trended towards being more likely to have any radiologic change (p=0.06). This was strongly time-dependent (p<0.001) and more pronounced early, as by two years radiologic changes were almost universally present irrespective of delivery technique. Figure 1 shows the morphology of these changes with time. Acute changes were not technique dependent (p=0.23). After six months, arc delivery resulted in a modified-conventional morphology throughout follow-up, while fixed-beam delivery resulted in an increasing probability of scar-like or mass-like morphologies. The predicted probabilities of a modified-conventional pattern following SABR by arc and fixed-beam delivery were 96.3% vs. 68.9% (p<0.001) respectively. Following arc delivery, radiologic changes were more likely to be scored as pronounced or expected (p=0.009) than mild or none, a finding that became more evident with longer follow-up (p=0.014). The predicted probability of pronounced or expected changes two years following arc or fixed-beam delivery was 83.1% and 26.2%, respectively. Figure 1

Conclusion
Patterns of radiologic change more than six months post-SABR are influenced by delivery technique. Diagnostic algorithms used to differentiate suspected local recurrence and benign change should therefore consider the delivery technique used.

Background
SABR has become a standard treatment option for medically inoperable, peripherally located early-stage NSCLC. However, using SABR for centrally located lesions remains challenging because of the potential for severe side effects. Here we sought to validate our previous experience with SABR (50 Gy in 4 fractions) for central lesions, including the dose-volume constraints, and explore a new regimen of 70 Gy in 10 fractions for cases in which dose-volume constraints cannot be met with the previous regimen.

Methods
We used 4D-based, volumetric image-guided SABR to treat 101 patients with biopsy-proven and PET/CT-staged centrally located (within 2 cm of bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus or vertebral body) T1-2N0M0 tumors (n=82) or isolated lung-parenchyma recurrent lesions (n=19). The treatment period spanned February 2005 through May 2011; follow-up visits (every 3 months for 2 years and every 6 months for the next 3 years) included chest CT or PET/CT. Endpoints were toxicity (CTCAE v3.0), survival, local control, regional control, and distant metastasis.

Results
At a median follow-up time of 30.3 months for all patients (40.5 months for those alive), median overall survival time was 56.5 months and 5-year overall survival rate was 49.0%. Three-year actuarial local, regional, and distant control rates were 96.5%, 87.2% and 77.3%. The most common toxicities were chest-wall pain (18% grade 1 and 13% grade 2) and radiation pneumonitis (10.9% grade 2 and 1.9% grade 3). No patient experienced grade 4 toxicity and one patient with tumor invading bronchial tree who received 70 Gy in 10 fractions died from hemoptysis 13 months after SABR. The distance between tumor and chest was associated with chest wall pain (≤1 cm 45% vs >1 cm 17%, p=0.002). Univariate and multivariate analyses showed that for the 82 patients receiving 50 Gy in 4 fractions, mean total lung dose (MLD) >5 Gy or ipsilateral lung V~20~ (iV~20~) >16% were independent predictors of radiation pneumonitis; 3 of 9 patients in that group with D~max~ to brachial plexus >35 Gy experienced brachial neuropathy versus none of the 73 patients with brachial D~max~ ≤ 35 Gy (p=0.001).

Conclusion
SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected. For 50 Gy in 4 fractions, we recommend MLD ≤5 Gy, lung iV~20~ ≤16%; bronchial tree D~max~ ≤ 38 Gy, V~35~ ≤1 cm[3]; major vessel D~max~≤ 56 Gy, V~40~≤1 cm[3]; esophageal D~max~ ≤35 Gy, V~30~≤1 cm[3 ]; brachial plexus D~max~ ≤35 Gy, V~30~≤0.2 cm[3] and spinal cord D~max~ <25 Gy. Giving 70 Gy in 10 fractions is another option for challenging cases but can produce severe toxicity if significant amounts of critical structures are exposed to ≥70 Gy. Proper selection of cases (based on tumor location and normal tissue constraints) and SABR regimens and volumetric image-guided delivery are all crucial to avoid overdosing critical structures. Typically, a minimum 5-10 mm distance between critical structures and gross tumor is required to meet dose-volume constraints.

Abstract not provided

Background
[68]Ga-macroaggregated-albumin ([68]Ga-MAA) perfusion PET/CT is a novel molecular imaging technique for the assessment of functional lung volumes. This prospective study aims to investigate the utility of four-dimensional (4D) [68]Ga-perfusion PET/CT for functional adaptation of radiation therapy (RT) planning in patients with non-small cell lung cancer (NSCLC).

Methods
An interim analysis was performed of a prospective clinical study of patients with NSCLC who underwent 4D-perfusion PET/CT scanning prior to curative intent RT. All patients were planned to 60Gy in 30fx with or without concurrent chemotherapy based on conventional anatomical lung volumes. Subsequently, a single nuclear medicine physician in conjunction with a single radiation oncologist contoured the functional ‘perfused’ lung using a visually adapted threshold. Functional lung was defined as lung parenchyma with Ga-MAA uptake. A second volume labeled as ‘high-perfused’ lung was created based on a visually adapted 30% max SUV threshold (figure 1). A single RT planner optimised the 3D conformal radiotherapy plan to spare the functionally ‘perfused’ and ‘high-perfused’ lung volumes respectively. Dose volumetrics were compared using mean lung dose (MLD), V5, V10, V20, V30, V40, V50 and V60 parameters. Figure 1 figure 1 - RT Plans optimised to each of the conventional, 'perfused' and 'high perfused' lung volumes.

Results
14 consecutive patients had RT plans adapted to functional lung volumes based on perfusion PET/CT. This patient cohort consisted of ex-smokers with pre-existing airways disease, with a mean FEV1 of 1.87L (0.83L-2.82L) and DLCO of 54% (27%-87%). The average MLD of the original treatment plans was 11.44Gy using conventional anatomical lung measurements. When considering the functional ‘perfused’ lung and ‘high perfused’ lung, the original plan produced an average MLD of 11.12Gy and 12.41Gy respectively. Plans optimized for ‘perfused’ lung only showed significant improvement of the V60 dose parameter (median 1.00Gy, p=0.04). However, plans optimized for ‘high perfused’ lung improved MLD, V30, V40, V50 and V60 (all p-values <0.05). The MLD was improved by a median of 0.86Gy, p<0.01. The largest improvement was found in the V30 parameter, with a median difference of 1.76Gy.

Conclusion
This is the first study of [68]Ga perfusion PET/CT for planning the treatment of lung cancer patients. RT plans adapted to ‘high perfused’ but not ‘perfused’ functional lung volumes allows for significant technical improvement of conventional RT for NSCLC patients. The clinical impact of this improvement in planning technique should be validated in the context of a prospective study measuring patient toxicity outcomes.

Background
Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. As radiosensitivity varies between patients, genetic correlations have been investigated, which appear to be difficult to repeat in validation studies. This may be due, in part, to differences in methods for measuring RILD across studies. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed.

Methods
Hounsfield Unit (HU) changes before vs. 3 months post-radiotherapy were correlated per voxel with the radiotherapy dose. Deformable registration was used to register pre and post CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2.

Results
95 lung cancer patients were studied. Radiation dose was linearly correlated with the change in HU (mean R[2]=0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo-radiotherapy were observed. In the whole patient group, 33/95 (34.7 %) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3 %) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1 %) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. Figure 1

Conclusion
HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

Background
The Dutch Society for Radiotherapy and Oncology (NVRO) aims to ensure transparency regarding clinical outcome, quality and safety of lung cancer treatments in radiotherapy departments throughout The Netherlands. Auditing is considered the best instrument to achieve this. The quality of the radiotherapy will become transparent by using objective and reliable data from accurate registration of clinical outcome linked to patient and treatment characteristics The results of the audit are communicated to the health professionals that supplied the data. This outcome registration will provide the local health professionals with a robust instrument to compare and improve their lung cancer treatments. The decision was made to seek collaboration with the thoracic surgeons as their group were already committed to the DICA (Dutch Institute for Clinical Auditing) .

Methods
The Quality Assurance Committee of the NVRO, in collaboration with a platform of Dutch radiation oncologists dedicated to lung cancer treatment, received a grant to set-up a quality assurance program for lung cancer treatment. Quality indicators to be collected were defined within the platform of Dutch radiation oncologists and a database was setup in October 2012. All patients receiving primary thoracic radiation treatment with curative intent for (primary or recurrent) stage I-IIIB lung cancer will be included in the registry. Information will be collected on patient, tumor and treatment characteristics, the incidence and severity of acute toxicity, mortality within three months of radical radiotherapy and the time interval between diagnostic work-up and start of radiotherapy The adherence to the NVRO and Dutch guidelines will be registered and analyzed, as well as the use of new treatment techniques like stereotactic radiotherapy and image-guided radiotherapy. A pilot phase was initiated to test the feasibility of enrolling patients from six participating centers.

Results
The pilot-database was tested in 6 Dutch centers: NKI-AVL (Amsterdam), MAASTRO clinic (Maastricht), RIF (Leeuwarden), RISO (Deventer), UMC Radboud (Nijmegen) and ARTI (Arnhem). A total of 196 patients were entered from January to June 2013. Analysis of the patients entered is ongoing. We expect to have a national roll-out in October 2013. The patient records were very complete with a few exceptions: lung function tests, the Mean Lung Dose / Lung V20, gross tumor volume (23% missing) and the non-mandatory follow-up items. The mean age was 68 years (range 41-90) with 57% males. Charlson comorbidity index ≥ 2 was scored in 39% of patients. Most patients (66%) were cN+ with 14% T4 tumours. Most patients received IMRT or VMAT irradiation. Ninety-five percent of patients completed treatment. All registered patients had position verification during irradiation, mostly 3D (70%). Acute 3-month toxicity (grade≥ III) was registered in 18% of patients and 3-month mortality was 4.4%.

Conclusion
This national audit on outcome after radiotherapy is directed towards an improvement of care for lung cancer patients and will help to direct evidence into clinical practice. It is expected to have an important impact on quality assurance ,safety and possibly patient mortality.

Background
CONVERT is an international randomised phase III trial comparing 45Gy in 30 fractions twice-daily and 66Gy in 33 fractions once-daily (given concurrently with cisplatin/etoposide) for good performance status patients with limited stage small cell lung cancer. A QA programme was set-up to standardise radiotherapy (RT) delivery across all centres.

Methods
The pre-trial QA exercise (PQE) involved completion of a questionnaire and treatment planning exercise. Each participating clinician was asked to select a previously treated patient, who fitted the entry criteria for the trial, and provide disease and organs at risk (OAR) outlines and a treatment plan for both arms of the trial. QA guidelines, including an atlas for OAR outlining, were distributed to participating centres. Additionally, at least one RT plan per centre was randomly collected during the trial (ongoing QA exercise-OQE). A comparison was made between the PQE and OQE for each centre, including a review of eligibility criteria, OAR and gross tumour volume (GTV) outlining, expansion to clinical target volume (CTV) and planning target volume (PTV).

Results
Twenty nine clinicians from 28 centres who had completed both the pre-trial QA and the ongoing QA were included in the analysis. From the pre-trial questionnaire it was reported that 3 centres were using beam energies of 10MV or more which was not permitted as per protocol. Subsequently the PQE showed that these all used acceptable beam energies. Four clinicians submitted ineligible patients for the PQE and none for the OQE. Twenty five clinicians (86.2%) used the correct GTV to CTV and CTV to PTV expansions for the PQE and OQE. Table 1 shows a comparison of adherence to protocol regarding OAR outlining between the PQE and OQE. Table 1

	Oesophagus outline	Spinal canal outline	Heart outline	Lung-PTV outline
PQE-OAR outline as per protocol (n=29)	19 (65.5%)	14 (48.3%)	4 (13.8%)	20 (68.9%)
OQE-OAR outline as per protocol (n=29)	21 (72.4%)	18 (62.1%)	8 (27.6%)	20 (68.9%)

Organ at risk doses were found to be within the tolerances specified in the trial protocol for both PQE and OQE.

Conclusion
A PQE improves clinicians’ compliance to trial protocol, and has been found in the OQE to reduce deviations across the participating centres that may confound the results of the study. Despite the fact that consistency of OAR outlining remained an issue in both the PQE and the OQE an overall improvement was seen following the PQE.

Background
CONVERT is an international randomised phase III trial, comparing 45Gy in 30 fractions twice-daily or 66Gy in 33 fractions once-daily (given concurrently with cisplatin/etoposide) for good performance status patients with limited stage small cell lung cancer. A survey was sent out to 69 clinicians who had randomised patients into the trial with the aim of establishing how radiotherapy techniques for lung cancer have changed over the 5 years since the trial opened.

Methods
As part of the pre-trial quality assurance process each centre was asked to complete a facility questionnaire giving details of treatment planning, delivery and verification techniques. Recruitment to the trial began in April 2008 and in January 2013, a further facility questionnaire was sent to centres. The survey was completed using an on-line survey tool.

Results
This analysis includes answers from the 34 clinicians who responded to the questionnaire. Changes in treatment planning techniques and verification since the beginning of the trial are summarised in table 1. Table 1 Figure 1 *Note that some centres reported using more than one beam arrangement, beam energy, planning algorithm or treatment verification technique. Out of the 34 clinicians who answered the questionnaire, 14 (41.1%) are currently using 4DCT, 3 (8.8%) are using breathold techniques and 16 (47.1%) are not using any technique to account for respiratory motion for simulation and treatment planning of lung patients. Data on management of respiratory motion were not available in 2008.

Conclusion
During the 5 years the CONVERT Trial has been open there have been significant advances in radiotherapy treatment technology. Major changes include the use of Type B treatment planning algorithms and PET CT for planning, IMRT for treatment and CBCT for treatment verification of patients with small cell lung cancer.

Abstract not provided

Background
Manual target volume delineation using CT/FDG-PET is the standard method used for radiotherapy treatment planning of non-small cell lung cancer (NSCLC) patients. Since manual delineation is prone to inter-observer variability and is time consuming, many FDG-PET auto-contouring methods were proposed in literature. The purpose of this study was to investigate to what extent a gradient-based FDG-PET auto-contouring method reduces observer variation, reduces delineation time and influences delineation behavior in radiotherapy treatment planning for NSCLC patients.

Methods
Seven radiation oncologists (observers) dedicated to lung cancer treatment delineated the primary tumor (PT) and involved lymph nodes (LN) for 10 patients with stage IIA-IIIB NSCLC on a co-registered CT/FDG-PET scan. The study was separated in two phases. In the first phase, the observers manually delineated the PT and LN for all patients. For the second phase (four months later), auto-contours were generated for both the PT and LN using a gradient-based FDG-PET segmentation method. Bone and air tissue were removed from these auto-contours using CT thresholding. These auto-contours were provided as initial delineation and were adapted by the observers. Delineation times, delineated contours and agreement with the auto-contour were analyzed. Delineated contours were analyzed based on volume, the ratio between the common volume and the encompassing volume (C/E), Dice Index (DI), local standard deviation (SD) and the local distance between median surface and delineated surface. Regions were identified where the observers did or did not change the provided auto-contours.

Results
The observers agreed with the provided auto-contour for 37.3% of the PT and for 42.6% of the LN. Notable regions of agreement were the tumor/bone and tumor/air interfaces. The mean delineation time was reduced by 23.9% from 25.5 minutes in phase 1 to 19.4 minutes for phase 2 (p=0.000). The mean delineated volume was smaller in phase 2 compared to phase 1: 8.9% for the PT (155.8 to 142.0 cm[3], p=0.000) and by 9.1% for the LN (13.2 to 12.0 cm[3], p=0.001), respectively. The C/E ratio and DI both did not change significantly and were 0.79 and 0.88 for the PT and 0.54 and 0.67 for the LN in both phases. The mean local SD for the PT was 1.7 mm and 1.5 mm and for the LN was 1.5 mm and 1.4 mm and both did not change significantly, for both phases respectively. The mean distance between the median surface and PT delineations was slightly reduced from 2.1 to 1.8 mm for phase 2, and was 2.0 mm for the LN in both phases.

Conclusion
The gradient-based FDG-PET auto-contouring method reduced delineation time by 24%, but was sufficient in only 37.3% of the primary tumors and 42.6% of the involved lymph nodes; most notably at the tumor/bone and tumor/air interfaces segmented using the CT scan. The results suggest the FDG-PET auto-contour is currently primarily used for localization, and not so much for delineation. Multi-modal auto-contouring has the potential to reduce inter-observer variation when further developed in close collaboration with radiation oncologists.

Background
The use of CBCT is essential for precise treatment delivery of radiotherapy for lung cancer. The current work practice at many centres is to use bony landmarks to match on-treatment CBCT to the radiotherapy planning CT to verify treatment. To take full advantage of this imaging modality for lung cancer, soft-tissue matching is preferred as it ensures that the actual lung cancer is within the radiotherapy fields regardless of bony anatomy. However Radiation Therapists (RTs) are trained in bony matching and not soft tissue matching. The purpose of this study was to determine the level of inter-observer variability in lung cancer gross tumour volume (GTV) delineation on CBCT and alignment of the CBCT with a planning GTV between Radiation Therapists (RTs), a Radiation Oncologist (RO) and a Radiologist (RD)

Methods
Ten RTs, one RO and one RD independently delineated the lung cancer GTV for fifteen lung cancer patients on Elekta Synergy CBCT image datasets taken on the first treatment fraction. The window and level settings used by each observer were recorded. Each observer then performed an alignment of the CBCT GVT to the radiotherapy planning GTV and translational errors were recorded. The difference in the isocentre corrections for the alignment shifts and Centre of Volume, Volume and Concordance Index (CI) for the contoured volumes were calculated to determine the level of agreement between the RT’s and the RD and between the RTs and the RO, in comparison to the variation between the RD and RO. In an ideal setting the difference between the RTs and the RO and the RTs and the RD would be at least equivalent to the difference between the RD and RO.

Results
The difference between the RT’s and RO and RD was found to be not statistically equivalent to the difference between the RD and RO. The mean isocentre difference between the RO and RD was 0.40cm, compared with 0.42cm and 0.51cm between the RT’s and the RO and RD respectively. The mean CI between the RD and RO was 0.56 (0.44,0.69), which was smaller than the lower bound of the 95 % confidence intervals (95%) of the RT’s compared to the RD (0.5, 0.56) and RO (0.52,0.59). The mean log COV difference was -0.82cm between the RD and RO and -0.54 and -0.65cm between the RT’s and RO and RD respectively. The volume results showed that only 6 of thirty comparisons were equivalent. The mean volume difference between the RD and RO was 0.44cm[3] and 4.73 cm[3] and 5.7cm[3] between the RT’s and RO and RD respectively.

Conclusion
The variation between the RTs and the RO and RD was greater than the variation between the RO and RD. Advanced training is necessary to educate the RTs on soft-tissue matching on CBCT for lung cancer radiotherapy.

Background
Cone beam-CT (CBCT) guidance is routinely used for setup verification of lung cancer patients treated with radiotherapy. CBCT’s frequently show intra-thoracic anatomical changes (ITAC) during treatment. We developed a protocol as a decision support system to guide the radiation technologist in prioritizing these changes. The purpose of this study was to quantify these ITAC during the radiotherapy course and evaluate the current decision protocol.

Methods
The CBCT-scans (made the first 3 fractions and weekly thereafter) of all lung cancer patients treated in 2010 in our institute with radical radiotherapy were evaluated. Each CBCT-scan was visually compared with the planning-CT and all visible ITAC were scored. Additionally, our decision protocol called “traffic-light protocol” was retrospectively applied to all CBCT-scans. The traffic-light protocol has three urgency levels: 1) red: ITAC that likely have a considerable impact on the delivered dose to the primary tumor and/or involved lymph-nodes such as tumor shifts outside the high dose region, large in- or decrease of atelectasis; 2) orange: ITAC with likely moderate impact on the dose distribution such as tumor progression, minor in- or decrease of atelectasis, pleural effusion and post obstructive pneumonia; 3) green: ITAC with likely negligible impact on the dose distribution such as tumor regression without considerable centre of mass displacement or other anatomical changes. For level red changes, the radiation oncologist needs to be consulted immediately before the treatment fraction is delivered. For level orange, the radiation oncologist will be informed by email and a response is required before the next fraction. For level green, the radiation oncologist is informed but no response is required.

Results
In total 1500 CBCT-scans of 177 patients were evaluated. All patients received radical radiotherapy (≥50 Gy); 97 patients with concurrent chemoradiation, 23 with sequential chemoradiation and 57 with radiotherapy only. In 128 patients (72%) ITAC were observed with maximum level red, orange and green in 12%, 36% and 24% respectively. Fourteen patients (10%) required a new CT and treatment plan to account for the changed anatomy. Most ITAC occurred in the first week (55%). Of all patients with ITAC during treatment, 45%, 36% and 17% had 1, 2, and ≥3 ITAC respectively. Types of observed ITAC were evident regression (36%), considerable tumor baseline shift (28%), changes in atelectasis (15%), tumor progression (11%), pleural effusion (7%) and pneumonia (3%). Progression seen on the CBCT had a significant correlation with changes in week 1 (p<1e3), and level red changes (p=0.01).

Conclusion
ITAC have been observed in 72% of all lung cancer patients during radical radiotherapy. In 12% of the patients the radiation oncologist needed to respond immediately and in 10% of the patients a new planning-CT was made to mitigate the risk of tumor under dosing. Volumetric image guided radiotherapy in combination with a decision protocol is recommended for lung cancer patients treated with radical radiotherapy. In our institute we implemented daily CBCT guidance for accurate patient alignment and simultaneously capture ITAC as soon as possible.

Background
FDG-PET/CT based selective lymph node (LN) irradiation is the standard when using 3D-conformal techniques (3D-CRT) for locally advanced NSCLC. With 3D-CRT, adjacent LN not included in the target volume still receive a substantial radiation dose. With current new techniques (IMRT/VMAT), the radiation dose to non-involved LN decreases, which raises the question whether selective nodal irradiation based on PET/CT is still safe. We therefore evaluated the impact of adding EBUS-TBNA (endobronchial ultrasound guided transbronchial needle aspiration)-mapping of the mediastinal LN to PET/CT in avoiding geographical miss, and on the size of nodal GTV (gross tumor volume).

Methods
Consecutive NSCLC-patients referred for radiotherapy (RT) in 2012 who underwent EBUS-TBNA were included. False negative (FN) LN for different constellations of PET, CT and EBUS-TBNA based on literature data were calculated, to evaluate the safety of excluding LNs based on CT, PET and EBUS findings. A practical algorithm when to include LN in the GTV was made, and tested on our patients. Results are expressed as mean +/- SD and range.

Results
Twenty-five consecutive patients with a full EBUS-TBNA mapping before RT were included: 11 women, 14 men; 17 adenocarcinoma, 8 squamous cell carcinoma; 14 right-sided and 11 left-sided tumors. Mean age: 62.5 +/- 9.7 years. All patients had stage III-disease based on PET-CT. LN stations 1,2R,2L,3,4R,4L,5,6,7,8,9,10-11L,10-11R were analyzed on CT- and PET-scan (=325 LN). Sixty-seven were enlarged (≥10mm), of which 63 were PET-positive. Twelve normal-sized LNs were PET-positive. Fifty LNs were investigated with EBUS-TBNA (mean: 2/patient +/-0.96;1-5): 28 were malignant, 22 normal. EBUS-TBNA detected 1 cancer-containing normal-sized LN without FDG-uptake, thus 1/25 geographical miss (4%). The cancer prevalence, taking into account the FN rate of EBUS of 20%, was calculated (Fig.1). With addition of EBUS, in PET-negative patients FN decreases with 10% for enlarged LN, and with 5% for normal-sized LN. An algorithm when to include a LN in the GTV is proposed (Fig.1). According to this algorithm, in our population 3/79 (4%) enlarged or PET-positive LN would be excluded from the GTV. At patient level, this was a GTV decrease in 3 (12%) patients.

Conclusion
When incidental nodal irradiation is low such as in IMRT or VMAT, EBUS-TBNA should be added to FDG-PET/CT for mediastinal staging. This avoids geographical miss in 4% of patients, and decreases the radiation volume in 12% of patients. A practical algorithm is proposed.

Background
A modern treatment approach for non-resected NSCLC comprises radiation dose intensification and short overall treatment times. We report on patients treated within a prospective trial, correlating doses to tumor volume, combined with chemotherapy sequentially.

Methods
Radiation doses to primary tumors were aligned along increasing tumor size within 4 groups (<2.5 cm/ 2.5-4.5 cm/ 4.5-6.0 cm/ >6.0 cm; mean number of three perpendicular diameters). ICRU-doses of 73.8 Gy/ 79.2 Gy/ 84.6 Gy/ 90.0 Gy, respectively, were applied. Macroscopically involved nodes were treated with a median dose of 59.4 Gy, nodal sites about 6 cm cranial to involved nodes electively with 45 Gy. Fractional doses were 1.8 Gy twice daily (bid). 2 cycles chemotherapy were given before radiotherapy; the interval between chemotherapy and radiotherapy was preferentially shorter than 8 days. With a median follow up time of 56.1 months (range 43.2 – 97.1 ) for patients alive, mature results for locoregional tumor control, survival and toxicity are presented.

Results
Between 2004 and 2009,123 continuously referred, unselected patients with 127 histologically/ cytologically proven NSCLC were enrolled; Stage II: 6 pts.; IIIA: 70 pts.; IIIB: 47 pts. Weight loss >5%/ 3 months: 26%; Karnofsky Index ≤ 70%: 46% of the patients. The local tumor control rate at 2-/ 5 years is 73%/ 70%, respectively; the regional tumor control rate 91%/ 89%, respectively. The median overall survival time is 24.6 months, the 2- and 5-year overall survival rates are 52% and 19%, respectively. 2 treatment-related deaths (progressive pulmonary fibrosis) occurred in patients with pre-existing pulmonary fibrosis. Further toxicity was mild or moderate: Pneumonitis grade 2/ 3 (n=10/ 6); esophagitis grade 2/ 3 (n=16/ 7). Lung late grade 2 (n=13), esophagus late grade 3 (n=1).

Conclusion
Locoregional tumor control is high; as are survival times for this unselected patient cohort. In all outcome parameters DART-bid seems to compare favourably with simultaneous chemo-radiotherapies, at present considered ‘state of the art’; simultaneous treatments however are applicable only to a minority of referred patients, patients in good general condition.

Abstract not provided

Abstract
Small cell lung cancer represents about 12% of new case of lung cancer in the USA. It has a unique presentation and natural history compared to other types of lung cancer and is highly responsive to first-line treatment. Unfortunately, the cancer typically relapses after a short period of time and exhibits resistance to cytotoxic and targeted therapeutic agents with a poor median survival. The last 2 decades witnessed significant improvement in our understanding of the molecular basis of small cell lung cancer with identification of several potential therapeutic targets leading to application and evaluation of novel chemotherapeutic, targeted and immunotherapeutic agents in a large number of clinical trials. In this presentation, we will summarize the data from the recent and ongoing clinical trials in this disease and understand the challenge that it poses. However, the results have overall been disappointing and the combination of a platinum compound with etoposide remains the most effective treatment for this patient population. Despite the advent of new cytotoxic and targeted agents, which have shown significant activity in other types of cancer including non-small cell lung cancer, their use in SCLC has not had any impact on survival. The differences in efficacy observed with agents such as amrubicin and irinotecan in patients from different ethnic or racial groups indicate the importance of the understanding the tumor genetic makeup and individualizing treatment regimens. The landscape of genetic alterations of SCLC is more complex than in other types of cancer. To date, no specific mutation, abnormal fusion protein secondary to chromosomal translocation or aberrant signal transduction pathway has been validated and proven to be critical for the continuation of the carcinogenesis process and survival of the SCLC tumor cells. SCLC remains one of the most challenging tumors to treat with our current standard of care. The recent advances in sequencing and high throughput technologies have started to yield useful information about the molecular abnormalities of SCLC. We need to refine the recently acquired knowledge of SCLC biology and apply that knowledge in innovative clinical trials to have a breakthrough in the treatment of SCLC.

Abstract not provided

Abstract
Whilst the incidence of small cell lung cancer (SCLC) has reduced over the last 20 years, the prognosis of the disease remains poor. Major advances in SCLC include improvements in radiotherapy (RT) techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC and the improved integration of chemotherapy and RT. It is unlikely that future advances in the treatment of SCLC will relate to standard chemotherapy. The role of thoracic RT is well established in the management of stage I-III SCLC [1,2,3,4]. There is increasing evidence in the literature in favour of early concurrent chemo-radiotherapy (CTRT), and a gold standard of care for patients with a good performance status is twice-daily thoracic RT (45 Gy in 3 weeks) with concurrent cisplatin and etoposide [5]. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies, essential questions related to the optimisation of thoracic RT remain unanswered. These questions include i) optimal total dose, ii) fractionation, iii) timing and sequencing of radiation, iv) volume of irradiation, v) concurrent chemotherapy/targeted therapy combinations, and vi) the importance of the time between the start of any treatment to end of RT. PCI reduces the incidence of brain metastases and improves survival in all stages of SCLC [6,7]. As a result of the implementation of best standard of care the 5 year survival of stage I-III SCLC patients has increased from less than 10% with chemotherapy alone to 25-30% with early concurrent CTRT and PCI. It is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to continue to improve the survival of this disease. Clinical trials aiming to establish a standard dose/fractionation in the stage I-III setting include the European/Canadian CONVERT and the US intergroup (CALGB 30610/RTOG 0538) studies. The results of the CREST study investigating the role of thoracic RT in stage IV SCLC are eagerly awaited. Molecular studies are ongoing aiming to gain improved insight into the molecular biology of SCLC, discover and/or validate candidate biomarkers for response, resistance to or toxicity of systemic treatment and radiation. There is now a concerted effort within the research community to understand the molecular mechanisms that underpin the molecular pathways in cancer. It is hoped that this understanding will lead to the development of targeted therapies that will not only prove efficacious, but also less toxic than more conventional treatments. In combination with newer techniques such as conformal RT and better imaging, it is hoped that the rates of long term survivors will increase significantly in the future. References 1 Bayman NA, et al. Radiotherapy for small-cell lung cancer-Where are we heading? Lung Cancer. 2009;63(3):307-14. 2 Sørensen M, et al. ESMO Guidelines Working Group. Small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Supplement 5):v120–v125. 3 Stahel R, et al. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer. Ann Oncol. 2011;22(9):1973-80. 4 Pignon JP, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-22. 5 Turrisi AT, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-71. 6 Auperin A, 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(7):476-84. 7 Slotman B, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664-72.

Abstract not provided

Background
Japanese researchers have reported good correlation between radiologic and pathologic findings in early lung adenocarcinomas. For negative margin confirmation, we found a technique using lavage and cytological examination. The objective of this study is to confirm limited resection efficacy as radical surgery in patients with high-resolution (HR) computed tomography (CT) indicated minimally invasive lung cancer, and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.

Methods
Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients with a malignancy history within the past 5 years or those unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with 50 ml saline. Washing saline was centrifuged and sediment stained using Papanicolaou’s method and examined for cancer cells. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. Patients are followed up every 6 months by chest CT for the first 3 years, and annually thereafter for at least 5 years. The initial endpoint was 5-year local recurrence free survival rate, but we are now looking at 10-year rate.

Results
This prospective study started in November 2003, and 101 patients were enrolled as of November 2009. This was 4.5% of all resected lung cancer patients during this period, and 99 of them were eligible for analysis. There were 39 men and 60 women, aged 30-75, with an average 62 years. Tumor sizes ranged from 7 to 20 mm on high-resolution CT, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, one atypical adenomatous hyperplasia, one atypical cuboidal cell hyperplasia, one alveolar hyperplasia, and 3 inflammatory fibroses. All cancers showed no vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 69 months, there have been no recurrences.

Conclusion
So far, HRCT scans appear to predict non- or minimally invasive GGO lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.

Background
The size of solid component is much more important for predicting survival than maximum tumor dimension on thin-section CT scan in lung cancer. Moreover, the presence of ground-glass nodule (GGN) is the other significant predictor of pathologic lymph node-positive status. Our previous study showed that tumors with the absence of GGN, i.e. pure-solid, have more pathologically invasive nature than tumors with the presence of GGN, i.e. part-solid, even if both tumors have the same size of solid component on thin section CT. Therefore, it could be estimated that part-solid tumors with the small size of solid component have less frequency of nodal involvement, regardless of the maximum tumor dimension for resectable lung cancer patients.

Methods
Between February 2008 and April 2013, 306 consecutive patients with part-solid tumors that measured less than 30 mm in diameter of solid component and had clinically negative nodal involvement (cN0) on thin-section CT underwent surgical resection at our hospital. The findings of preoperative thin-section CT scan were reviewed for all 306 patients and part-solid tumors were defined as a tumor containing both solid and GGN component. Consolidation tumor ration (CTR) of those tumors showed 0 < CTR <1.0 and both pure GGN and pure solid tumors were excluded from this study. Univariate and multivariate analyses were performed by the logistic regression procedure to determine the relationship between pathological lymph node positive status and clinical or radiological findings.

Results
Of the 306 patients, 14 (4.6%) had pathological lymph node metastasis. Nodal involvement was observed in 3(1.9%) out of 156 patients with the maximum tumor dimension less than 20mm, i.e. cT1a tumors, 5 (4.4%) out of 113 cT1b tumors and 6 (16.2%) out of 37 cT2a tumors. The size of solid component on thin-section CT scan and consolidation tumor ratio (CTR) were significant predictors of pathological nodal involvement in both univariate and multivariate analysis (p<0.05, respectively). Part-solid tumors with the size of solid component ≤ 17mm and CTR ≤ 0.7, which were obtained as cutoff values of predicting pathological lymph node metastasis based on the result of Receiver operating characteristics curves, 1(1.4%) in 73 patients with these criteria had pathological lymph node positive status even in the c-T1b and c-T2a part-solid tumors on thin-section CT scan.

Conclusion
Among part-solid tumors with cN0 status, even cT1b and cT2a tumors with small size of solid component on thin-section CT scan have less frequency of nodal involvement and less invasive nature on pathological examination. These tumors could be candidates for limited surgical resection such as segmentectomy with nodal dissection only when enough surgical margin is warranted.

Background
Although the standard operation for lung cancer is lobectomy, precise preoperative diagnosis of the “very early” lung carcinomas may identify patients that can be treated by limited resection. Previous reports on limited resection included patients who were not candidates for lobectomy. The survival of non-small cell lung cancer (NSCLC) patients who were fit for lobectomy and underwent limited resection has not been studied in a large enough scale.

Methods
A nationwide multi-institutional project collected clinical data of patients who underwent limited resection (segmentectomy or partial resection) for clinical T1-2N0M0 non-small cell lung carcinoma, who were 75 years old or younger at the time of operation and were considered fit for lobectomy by the physician. Overall and disease free survival, freedom from recurrence were analyzed and factors affecting survival or recurrence were identified.

Results
The median age of 1963 patients was 63 years. The mean maximal diameter of the tumor was 1.4 ± 0.6 cm. The overall and recurrence free survival after limited lung resection was 93.7 % and 90.4 % at 5 years, respectively. The recurrence free proportion and local recurrence free proportion were 93.3 % and 98.4 % at 5 years, respectively. Prognostic factors in overall survival were pathologically proven lymph node metastasis, interstitial pneumonia, male gender, older age, complications (cardiac disease, diabetes etc.), radiological invasive cancer, and multiple lesions. The consolidation/tumor ratio on CT of ≤ 0.25 predicted good outcome especially in cT1aN0M0 disease. Prognosis and recurrence was not affected by the method of limited resection (segmentectomy (n=1225) or partial resection (n=738)).

Conclusion
If the patient was 75 years old or younger and was judged fit for lobectomy, the result of limited resection for cStage I NSCLC was excellent and was not inferior to the reported result of lobectomy for small sized NSCLC. The radiological noninvasive carcinomas rarely recur and are especially good candidates for limited resection.

Abstract not provided

Background
The patients for NSCLC with IPF are having at a high risk of pulmonary resection. The objective of this study was to compare the survival rate after sublobar resection and lobectomy or more resection for NSCLC among patients with IPF.

Methods
The total 80 patients with IPF from 1995 to 2012 at Asan Medical Center had received pulmonary resection for NSCLC. Predictors of overall survival and disease-free survival were evaluated. Statistical analyses included Kaplan-Meier estimates of survival, log-rank tests of survival differences and multivariate Cox proportional hazards models.

Results
Lobectomy or more resection (lobectomy group) was performed in 65 patients and sublobar resection (sublobar group) in 15 patients. The median age was 66 years (range, 42 to 86 years), The median follow-up was 17 months (range, 0.4 to 96.5 months). The postoperative early mortality rate was higher at lobectomy group than sublobar group (15.4% versus 6.7%, p<0.3), but there was no difference in postoperative late mortality between sublobar group and lobectomy group. (60.0% versus 56.9%, P<0.8) Lung cancer related death rate was higher at sublobar group than lobectomy group. (50.0% versus 23.4%, p=0.089), but the respiratory problem related death rate was higher at lobectomy group than sublobar group. (76.6% versus 50.0%, p=0.089) There was no difference in local recurrence between two groups (20.0% versus 7.7% P=0.15) Distant metastasis was higher at sublobar group than lobectomy group. (46.7% versus 10.9%, p<0.001) There was no difference in overall survival between two groups with a hazard ratio of 0.51 (95% confidence interval, 0.21 to 1.2). A disease-free survival of sublobar group was significantly lower than lobectomy group, with an increased hazard ratio of 4.7 (95% confidence interval, 1.1 to 20.2, p=0.03).

Conclusion
Although sublobar group was associated with increased incidence of distant metastasis compared with lobectomy group but there is no difference in overall survival. Therefore, sublobar resection might be considered as one of the strategy for lung cancer with IPF.

Background
The VIO soft-coagulation system is a new device for tissue coagulation. This system regulates the temperature rise below boiling point without generating sparks, which is high enough to denature protein. The purposes of this study are to evaluate the effect of intersegmental air leak repair by the use of Vio-soft coagulation mode (ERBE Elektromedizin GmbH, Germany) during thoracoscopic segmentectomy and to show how to use the device.

Methods
Between 2007 and 2013, we have performed 162 thoracoscopic segmentectomies for early stage primary lung cancer (In this period, 805 thoracoscopic lobectomies have been performed.). Among these patients, 36 underwent anatomical intersegmental plane dissection only using electrocautery without any staplers. Inclusion criteria for thoracoscopic segmentectomy are as follows: 1) c-stage IA peripheral non-small cell carcinoma, 2) No prior chemotherapy or radiation therapy, and 3) Confirmation of N0 status by intraoperative frozen examination. Furthermore, indication criteria for anatomical intersegmental plane dissection using electrocautery followed by any sealing to repair air leak from dissected intersegmental plane include the above-mentioned criteria and as follows: 1) Non-emphysematous lung, and 2) No pleural adhesion. In this series, we divided the intersegmental plane along the intersegmental vein and inflation-deflation demarcation line with an electrocautery (monopolar coagulation mode, 80W) and vessel sealing system. Soft coagulation was set at Effect 5 and 80W for divided intersegmental sealing. The massive air leak from the divided intersegmental plane was repaired with suture pneumorrhaphy or bronchiororraphy before the coagulation. These patients were assigned into two groups: group A consisted of 19 patients with air leak repair using Vio-soft coagulation system and group B consisted of 21 patients not subjected to the system.

Results
There was no case of conversion to thoracotomy. The mean operative time was 229 + 73 vs 238 + 48 min (group A vs group B; P=0.69), and accordingly, the mean intraoperative blood loss was 104 + 112 vs 115 + 115 ml (P=0.77). Total number of endostapler cartridges was 1.3 vs 1.4 (P=0.99). Of course, the cartridge number used for intersegmental division was zero in both groups. Most importantly, the fibrin sealant was used in 5 patients (26.3%) vs13 patients (61.9%) to repair air leak from intersegmental division (P=0.031). There were no major postoperative complications in both groups. There were one cases of prolonged air leak in group A and one (requiring redo surgery) in group B (P>0.99). The median chest tube duration and postoperative stay were 2.0 + 1.7 (range 1-8 days) vs 2.4 + 0.8 days (range 2-5 days) (P=0.41) and 7.9 + 1.9 vs 7.9 + 2.3 days (P>0.99), respectively.

Conclusion
The VIO soft-coagulation system is safe and feasible for repair of dissected intersegmental plane in patients during thoracoscopic segmentectomy. It enables reduction in the use of fibrin sealant and number of endostapler cartridges in this procedure without any postoperative increased air leak problem.

Background
Lung cancer with small nodules(≤3cm) have less tendency of local regional lymph node metastasis. We investigate the value of preoperative clinicopathological characteristics in predict regional lymph node metastasis of cT1 lung cancer patients.

Methods
A retrospective review of database identified 384 patients with cT1N0M0 lung cancer, diagnosed by CT/PET-CT/MRI and pathologically confirmed as primary lung cancer. All the patients underwent surgery (include sublobar resection, lobectomy and pnemonectomy) and systemic mediastinal lymphadenctomy, and receive no preoperative chemotherapy or radiotherapy. The correlation between clinicopathological factors and the nodal status was analyzed by logistic regression model.

Results
The prevalence of lymph node metastasis is 69/384 (18.0%) . Univariate analysis identified tumour size, elevated CEA level and Standar uptake value(SUV)≥2.5 affect nodal status. Shown in Table1. In multivariate analysis, only tumour size (≤1cm vs >1-≤2cm vs >2-≤3cm，P=0.000) was found to be independent predictors of nodal metastasis. Shown in Table 2.Figure 1Figure 2

Conclusion
Tumour size is the only predictive factor of nodal metastasis for patients with cT1 lung cancer. Futher invastigation is recommend in omission of mediastinal lymphadenctomy in cT1 patients with tumour size of <2cm and SUVmax<2.5.

Abstract not provided