Virtual Library

Abstract:
Advances in lung cancer diagnosis and treatment are enabling many metastatic cancer patients to live months or years longer than ever before. Best practices in lung cancer detection, diagnosis, and treatment are changing so fast that keeping current with new developments is difficult for many healthcare providers-- more new drugs have been approved for lung cancer in the past five years than in the previous five decades. While testing for useful biomarkers such as EGFR, ALK and ROS1 is becoming more common, such tests are not yet standard procedure in many settings. Some patients who have limited tissue or who are interested in pursuing clinical trials might benefit from liquid biopsies or next generation sequencing (NGS) panels, but such tests might not available to them for a variety of reasons: the healthcare provider may be unfamiliar with the test or unconvinced of its merits, the facility may not have the technology or expertise to conduct the testing, or insurance may not cover the test. Even if the testing finds an actionable biomarker, patients may have difficulty obtaining novel therapies if those therapies are not approved or covered by insurance, or they may have trouble identifying and accessing appropriate clinical trials. Some biomarkers, such as PD-L1, are also less ‘definitive’ or standardized than others. This presentation discusses ways that patient access to molecular testing and novel therapies can not only improve lung cancer outcomes, but also help engage patients as partners in their own care and accelerate research through patient-driven data sharing.

Abstract:
A significant proportion of lung cancer patients are first diagnosed with their disease as part of an emergency presentation (EP) to acute medical services. EP includes patients attending the emergency department (ED), primary care referrals to acute services, and emergency admissions to secondary care. This route to diagnosis is more common in lung cancer than other malignancies[1]. Initial studies focused on the United Kingdom, where 40% of lung cancer patients were found to present in this fashion[1], but it occurs in all European countries, with rates up to 52%[2]. Lung cancer patients presenting via EP tend to be older, have lower socio-economic status and greater social deprivation, display worse overall health, and have a lower performance status[3]. They are more likely to present with advanced stage disease~,~ and are less likely to have surgery or other treatments with curative intent[2]. The emergency route to diagnosis is associated with poorer patient experience and is a significant additional burden on acute medical services[4]. Most importantly, EP lung cancer patients have poorer survival[1]: the risk of dying in the first month post-diagnosis is four times higher for EP compared to non-EP patients[2]. For the majority of lung cancer patients, there are opportunities for earlier diagnosis and prevention of EP[5]. Most have a relatively long history of symptoms, often more than 12 weeks, and three-quarters have been to their general practitioner (GP) with their symptoms, usually on several occasions. There is also a group of patients who delay consulting a doctor, and they are more likely to report barriers to presenting to healthcare services[5]. Novel methods of lung cancer diagnosis, focusing on symptom recognition, early involvement of primary care and prompt assessment in secondary care, have the potential to address this important problem. In the UK, the issue of late diagnosis and EP of cancer is increasingly recognised in cancer strategies. A number of innovative approaches have been brought together by the ACE (Accelerate, Coordinate and Evaluate) program, which aims to improve early diagnosis of cancer across a range of tumour types by learning from current best-practice and trialling new projects, many of which focus on lung cancer[6]. These are now informing health policy. Prominent independent reports have also addressed the EP of lung cancer, and have produced a series of recommendations[7]. At a national level, campaigns to raise public awareness of the signs and symptoms of lung cancer can help promote earlier presentation to primary care, whilst the adoption of lung cancer screening programmes has the potential to reduce the number of lung cancer patients diagnosed late. Lung cancer risk assessment and clinical decision support tools can assist the GP. System-based tools use patients’ current symptoms to provide an indication as to who should be referred for further investigations, whilst lung cancer risk prediction models identify high risk individuals without symptoms for CT screening. These require further testing and validation, but if proven successful, should be available in primary care practices. Improving communication between primary and secondary care is critical. Direct telephone or email access between GPs and secondary care consultants would speed discussion about high risk cases. Meanwhile GPs should be able to make direct referrals for CT scans for patients with suspected lung cancer without the need for specialist authorization. Other innovative schemes have pioneered open-access patient self-referral for chest radiographs. The ED is often used as a safe and quick access point to secondary care, even for those patients who do not require emergency medical care. Developing new outpatient pathways can prevent EP by providing GPs with access to rapid-access clinics for patients with, for example, clinical suspicion of cancer but who are too unwell to wait 2 weeks for an urgent outpatient appointment, or those in whom the likely tumour type is not clear[6]. The Danish pathway for patients with serious but non-specific symptoms and signs of cancer is one of the pioneers in this area[8]. To support the patient through their whole journey and expedite the diagnostic process, a clinical nurse specialist (CNS) should be available to all patients undergoing investigations for suspected lung cancer. Those who present via EP should be seen within 24 hours by a CNS who then acts as their key worker. The patient should be registered on a timed, multi-disciplinary pathway, so that diagnosis is efficient and the patient is afforded the same treatment opportunities as those presenting via elective routes. Although there is not one solution to the problem of EP in lung cancer, and different approaches are needed for different health systems, there are common themes by which survival can be improved by changing the system for this vulnerable patient group. References: 1. Elliss-Brookes L, McPhail S, Ives A, et al. Routes to diagnosis for cancer - determining the patient journey using multiple routine data sets. British journal of cancer 2012;107(8):1220-6. doi: 10.1038/bjc.2012.408 2. Newsom-Davis T, Berardi R, Cassidy N, et al. Emergency diagnosis of lung cancer: an international problem. American Society of Clinical Oncology Annual Meeting. Chicago, 2015. 3. Mitchell ED, Pickwell-Smith B, Macleod U. Risk factors for emergency presentation with lung and colorectal cancers: a systematic review. BMJ Open 2015;5(4):e006965. doi: 10.1136/bmjopen-2014-006965 4. NHS England. High quality care for all, now and for future generations: Transforming urgent and emergency care services in England - Urgent and Emergency Care Review End of Phase 1 Report: NHS England Leeds, 2013. 5. Forbes L, Sarafraz-Shekary N, Kaushal A, Ramirez A-J, Hughes C, Newsom-Davis T.[. ]What explains diagnosis of lung or bowel cancer as an emergency? 10th NCRI Annual Conference; 2014; Liverpool. 6. Cancer Research UK: ACE Programme: Cancer Research UK; 2016 [Available from: http://www.cancerresearchuk.org/health-professional/early-diagnosisactivities/ace-programme accessed May 2016. 7. Expert Lung Cancer Working Group. Tackling emergency presentation of lung cancer: An expert working group report and recommendations. London: British Lung Foundation, 2015. 8. Ingeman ML, Christensen MB, Bro F, et al. The Danish cancer pathway for patients with serious non-specific symptoms and signs of cancer-a cross-sectional study of patient characteristics and cancer probability. BMC Cancer 2015;15:421. doi: 10.1186/s12885-015-1424-5

Abstract:
WCLC Extended Abstract: Establishing a Paradigm for High Quality Lung Cancer Treatment David LeDuc Due to the complexities of diagnosing and treating lung cancer, and the high mortality rate of the disease, lung cancer specialty care is more important than ever. Proper and timely diagnosis and development of a patient-specific treatment plan can impact patient outcome and quality of life with vulnerable populations, such as those who are uninsured or who live in rural and remote places, often not having access to the quality of care and multi-disciplinary approach to treatment found at leading academic institutions. This dynamic results in vulnerable populations being diagnosed in later stages, with limited treatment options and poorer outcomes than those patients with access to quality multi-disciplinary care. The Addario Lung Cancer Foundation (ALCF) Community Hospital Centers of Excellence Program (COE) directly addresses this need by partnering with community hospitals, where 80% of cancer patients are treated, to deliver standard of care lung cancer screening, diagnosis and treatment. The COE program currently includes 13 hospitals and serves thousands of patients each year in regions of high unmet need. The program aims to improve the standard of care, patient experience and patient outcome by offering patients and caregivers the same type of multi-disciplinary and comprehensive care provided at leading academic centers. ALCF also provides lung cancer education and services to patients, caregivers and the community. The COE program helps to bridge the health-equity disparity and lung cancer information gap by establishing a standard of care (SOC) to improve health outcomes and quality of life through an approach that is personalized, multi-disciplinary/-institutional, considers the totality of each individual’s cancer, and is coordinated by an onsite Patient Navigator (PN) cognizant of the unique medical, economic, emotional, and cultural needs of their unique population. The COE approach embodies a support and engagement strategy that targets the patient, caregiver, family, healthcare team, and community. The goals of the program are to: Improve outcomes, survival and quality of life for patients. Implementation of SOC best practices enable a comprehensive and fully integrated multidisciplinary team (MDT) of doctors (oncologist, pulmonologist, radiologist, pathologist, immuno-oncologist, etc.) that personalizes treatment based on each patient’s specific disease state. SOC includes: tumor board review; timely biopsy; molecular testing; consideration for targeted and immunotherapies and access to clinical trials. Successful implementation of COE standards of care helps to improve patient outcome and quality of life. Provide on-site Patient/Nurse Navigator (PN/NN) to manage each patient’s cancer journey. Navigators build a trusted relationship with patients, families/caregivers, and physicians to better ensure patient retention, engagement, and utilization of comprehensive specialty care and support services. Patient oversight includes guidance on molecular testing to identify unique genetic profile of the individual’s cancer to determine the best first-line treatment and develop a treatment strategy. The PN also provides support by connecting patients to all ALCF programs and helps address non-clinical challenges. The PN oversees MDT coordination, data tracking, patient surveys, and other monitoring tools to measure patient satisfaction, outcomes, and program success. Educate and empower patients/families/caregivers. Education empowers patients/caregivers to self-advocate and communicate with their physician team to ensure access to the full breadth of treatment and care options including access to new diagnostic technologies and tests, clinical trials, symptom management & palliative care among other resources. Patients and providers have access to ALCF’s free support programs: Patient Education Handbook, “Navigating Cancer 360° of Hope” (in English, Spanish, Chinese and hard copy, downloadable, mobile App); Patient Web Portal; and monthly Living Room Education/Support & Speaker Series available 24/7 Video Library (with Spanish and Chinese subtitles to ensure access to diverse populations). The COE program also provides patient educational materials and outreach to help promote the program in the local community and drive awareness. Track program progress & metrics through database tools. A key element of the program is the ability to collect and analyze COE data and provide COEs with access to de-identified patient/population data and reports and insights that drives interventions and improved patient outcomes. Participating COE hospitals provide metrics that demonstrate adherence to the COE SOC and to patient care and outcome. Metrics include: survival rates; quality of life as defined by NCCN guidelines; time from diagnosis to treatment; patient referrals to ALCF education/support services; and patient-specific data such as percentages with: an early diagnosis; who complete molecular testing; are referred to clinical trials; and reviewed by tumor board. Insights derived from this data help demonstrate progress toward patient survival, and delineate outcomes by care facility, geography, treatment approach, and ethnic group. Data is used to benchmark against other COE sites as well as compared to national data/statistics. ALCF conducts an annual review, sharing all findings with ALCF partners and community hospital COE sites. The COE model has already demonstrated proof of concept and positive impact on patient care and outcomes. Several sites are already reporting servicing patients at levels above community hospitals reported in the National Cancer Database. The COE data collection and analytics tools will enable ALCF to demonstrate impact on the screening, diagnosis, treatment and survival of lung cancer patients. Further, as the COE program adheres to SOC and produces data, it is anticipated that more patients will be diagnosed at earlier stages when survival rates are highest; more patients will receive molecular and genetic testing steering them towards targeted and immunotherapies that improve outcome; and clinical trial participation rates will go up.

Abstract:
WCLC abstract December 2016 Title: The role of the Lung Cancer Nurse Service within the Lung Foundation Australia (LFA) Introduction: The presence of a Lung Cancer Nurse within a dedicated Lung Foundation is rare, nationally and internationally. In response to the need to improve national lung cancer services, Lung Foundation Australia (LFA) successfully secured funding through the Cancer Australia grant initiative “Supporting people with cancer”. LFA directed these funds toward addressing challenges identified by Cancer Australia within the lung cancer community through the appointment of a Lung Cancer Nurse to provide support and information across all stages of a lung cancer patient’s experience – not only at diagnosis, but also as a consistent point of contact throughout an extremely stressful and uncertain time. The service is intended to be an extension of existing health services, supporting both patient and carer throughout their journey. The role of the LFA Lung cancer nurse has evolved with the launch of the National Lung Multidisciplinary Team (MDT) directory in June 2016. This directory, currently representing 64 Lung MDTs, provides a detailed understanding of the services each hospital can provide for a patient, from diagnostics through to various treatment modalities. These two key initiatives - the Lung Cancer Nurse Service and National Lung MDT Directory - service have become intertwined, supporting the needs of patients and, importantly, navigating them towards achieving the best level of care whilst ensuring the patient, their family and carers feel supported, informed and respected. The most significant aspect of the Lung Cancer Nurse Service is that of patient advocate, reflecting and representing the needs of patients nationally and, where appropriate, linking patients back into the health care system. Lung cancer specialist nurse roles are pivotal in representing patient needs within Lung MDT meetings as well as referring them into community support services. However, with the development of the National Lung MDT directory it has become evident there are significant variations among Lung MDT operations: including representation of the different professional disciplines involved in caring for patients with lung cancer; formal communication channels to primary care providers; and providing patients with access to a dedicated Lung Cancer Support Nurse. For example, data from the commencement of the Lung Cancer Nurse Service in July 2015 confirms that not every patient has access to a specialist Lung Cancer Nurse – currently the National Lung MDT directory has highlighted the existence of 30 dedicated Lung Cancer Nurses nationally, which currently equates to one specialised nurse per 400 patients diagnosed with lung cancer. Overall the National Lung MDT Directory and Lung Cancer Nurse Service have become a vital link in delivering efficient, up-to-date information for patients and carers seeking support and guidance. Ultimately the objective of the Lung Cancer Nurse Service is to continue to address the principles of best practice management in lung cancer ensuring: the patient and carer feel supported, informed and respected; all patients receive timely access to all components of their care regardless of location: and patients have access to all relevant treatment and supportive options and, importantly, have well-coordinated lung cancer care. This Service complements the support structures that are already in place, so clinicians can continue to strive to ensure the needs of lung cancer patients can be addressed and increase much-needed support and resources. The experience in establishing this new role within LFA, forming collaborations with national Lung Cancer MDTs and the measurable impact of the role on outcomes for lung cancer patients, will be presented in both qualitative and quantitative terms.

Abstract:
*Seda Kansu Founder Member Pembe Hanım - *Beril Koparal, Vice President Pembe Hanım - * Cengiz MD Gemici Dr Lutfi Kirdar Kartal Training and Research Hospital Department of Oncology - * Hasan Fevzi Batirel MD Marmara University Medical FacultyDepartment of Thoracic Surgery - *Rıza Çetingöz MD.Professor in Medicine Turkish Lung Cancer Society President - *Ahmet Özet MD.Professor in Medicine Turkish Medical Oncology Society President References Pembe Hanım Cancer Patients Society Turkish Society of Medical Oncology Turkish Lung Cancer Society Dr Lutfi Kirdar Kartal Training and Research Hospital Department of Oncology Marmara University Medical FacultyDepartment of Thoracic Surgery The incidence of cancer in Turkey is 267 and 186 in a hundred thousand in men and women respectively. Lung cancer is the number one cause of cancer death in men in Turkey and its incidence is increasing in women in recent years as well. It is the fifth common cause cancer after breast, colon, thyroid and gynecologic malignancies in women in Turkey.The number of cancer cases directly related with smoking is expected to be 31.000. The incidence of lung cancer in men and women is 21.9 and 5.3 in a hundred thousand respectively. Namely there are 50.000 lung cancer patients in Turkey. And each year a new 30.000 patients are added to this number. Between 2009-2013,the incidence of lung cancer among men has decreased from 56 to 51 in a hundred thousand. However the number has increased from 16 to 18 in a hundred thousand among women. This decrease among men is the positive result of effective smoking cessation campaigns as the main cause of lung cancer in Turkey is smoking. The second reason is air pollution in workplaces. Lung cancer is diagnosed generally at late stages in Turkey as well as in the west, and more than 50% of the patients present with metastatic disease at diagnosis. Only minority, less than 20% present with localized disease and these cases are generally detected incidentally for other health reasons. Curative surgery can be offered to only 15% of the patients. There is no effective prevention other than smoking cessation and screening which is becoming more popular for certain risk groups in the west but it is not a proposed method actually in Turkey. Treatment decisions in high volume centers are taken by multidisciplinary way including radiologists, pathologists, nuclear medicine specialists, surgeons, medical and radiation oncologists. Surgery is the primary treatment modality in early stages of disease, and lung cancer surgeons are well experienced throughout the country being able perform all sort of surgical techniques including robotic one with high success. Cancer chemotherapy and radiotherapy are well developed in the country with the availability of recent FDA approved targeted drugs and immunotherapeutic agents as well. Certain centers in Turkey are also included in multinational studies involving new agents in treatment of this disease. Radiation oncology centers are equipped with high technology radiotherapy machines being able to perform image guided intensity modulated radiotherapies and stereotactic radiotherapies in treatment of lung cancer. For the last years prevention programs in Turkey has increased. Two main actions for this are smoking cessation and fight against air pollution. The effectiveness of early diagnosis programs in lung cancer has not been proved. There has been an initiation of screening programs by low dose BT in high-risk patients. The diagnosis and treatment of lung cancer is in line with global standards considering surgery, radiotherapy and chemotherapy. The global improvements in lung cancer is closely followed by oncologists and scientists in Turkey and rapidly integrated into clinical practice by means of prevention, diagnosis, treatment and follow-up. However the patient care in terminal stage should be improved. The set up of Turkish Cancer Institute has been initiated and targets for 2023 are the determination of molecular genetic targets for diagnosis and the treatment of lung cancer, the identification of cellular therapies and immunotherapy and other targeted therapy modalities. In Turkey it is not possible to talk about early diagnosis. But we can talk about early stage diagnosis. The rate of early stage lung cancer patients in Turkey is less than 1/5. Unfortunately population based screening programs for lung cancer has not been approved by Ministry of Health yet. With a screening program a tumor of 1 cm can be diagnosed. However a patient with symptoms being diagnosed has a tumor of 3 cm and the rate of cure between these patients is really different. 5 year survival for a patient with a tumor of 1 cm is 100% and a patient with a tumor of 3cm is 65-70%. Under screening programs for high- risk patients, the risk of death from lung cancer decreases 20%. On the patient organization side Pembe Hanım Association has made the first attempt in Turkey to raise awareness in the public for lung cancer. For four years a Project called “MegaLung” has reached many people talking about the prevention, diagnosis and treatment of lung cancer. This was the first and only project about lung cancer. “MegaLung” had its place in many organizations open to public to reach as many people as possible as lung cancer is a wide range cancer and it has a preventable cause namely smoking. At the moment with the collaboration of members of Pembe Hanım Association, mainly Seda Kansu and Turkish Lung Cancer Society, a patient organization for lung cancer called “Nefes (Breath)” is being set up with the aim of raising awareness among public and lung cancer patients about the all the issues related with lung cancer. * As Pembe Hanım Cancer Patients Society we would like to thank Turkish Society of Medical Oncology,Turkish Lung Cancer Society, Dr Lutfi Kirdar Kartal Training and Research Hospital Department of Oncology and Marmara University Medical FacultyDepartment of Thoracic Surgery for their valuable support. Seda Kansu IASLC Patient Advocates Committee Member References Pembe Hanım Cancer Patients Society Turkish Society of Medical Oncology Turkish Lung Cancer Society Dr Lutfi Kirdar Kartal Training and Research Hospital Department of Oncology Marmara University Medical FacultyDepartment of Thoracic Surgery

Abstract:
The importance of mediastinal downstaging during induction therapy of N2 disease P. De Leyn*, H. Decaluwe*, C. Dooms** and J. Vansteenkiste**. Department of Thoracic Surgery*, Department of Pneumology**, University Hospitals Leuven, Belgium Patients with preoperative pathological proven N2 disease have a dismal prognosis after surgery. Neoadjuvant chemotherapy or chemoradiotherapy is a therapeutic option that is used in patients with baseline resectable stage IIIA-N2 non-small cell lung cancer. Mediastinal downstaging is an important prognostic factor for long term survival. Different restaging techniques are available. The mediastinum can be restaged by CT scan, remediastinoscopy, VATS, PET-CT and EBUS-EUS fine needle aspiration. In primary staging, CT scan has proved to have a low accuracy. It is not surprising that the accuracy of CT scan in restaging the mediastinum is also low. In a Spanish study of 24 patients who underwent neoadjuvant chemotherapy for N2 non-small cell lung cancer, staging was performed by CT scan and remediastinoscopy (1). CT scan had a sensitivity of 41%, a specificity of 75% and an accuracy of 58%. In a prospective study of 93 patients who were restaged by integrated PET-CT after induction chemoradiotherapy, repeat PET-CT was found to be more accurate than CT alone for pathological stages. However, there were 20 false negative and 25 % false positive cases. So, in case of suspicion of residual mediastinal disease, nodal biopsies are still required (2). We evaluated in a prospective single center study repeat mediastinoscopy and PET-CT after induction chemotherapy for N2 disease. PET-CT had a sensitivity of 77% and a specificity of 88% (3). Repeat mediastinoscopy, technically much more difficult than the first procedure, offers the advantage of providing histological evidence of response after induction therapy. Although some centers obtain good results (4), most surgeons will accept that remediastinoscopy is technically difficult and often incomplete. We performed a prospective study to evaluate the accuracy of remediastinoscopy and PET-CT in restaging the mediastinum after mediastinoscopy proven N2 disease (3). The first mediastinoscopy was thoroughly performed with a mean lymph node level of 3.6 per patient biopsied. In our experience, remediastinoscopy was technically feasible, but inaccurate due to severe adhesions and fibrosis. The sensitivity to detect residual mediastinal lymph nodes was only 28,6% with an accuracy of 58,3%. Minimally invasive endoscopic technique EUS and EBUS also obtain histological diagnosis. Their accuracy is very good in baseline mediastinal staging. In the study Herth et al (5) EBUS-FNA was performed for restaging after induction chemotherapy or chemoradiotherapy for N2 disease in 124 patients. The sensitivity was 76% but the negative predictive value was as low as 20%. The largest series in the literature is reported by Szlubowski (6). They combined EBUS-EUS FNA for restaging N2 disease in 106 patients. Sensitivity was 67% with a negative predictive value of 73%. Some recent smaller studies showed better results for EBUS-EUS to prove persistent nodal disease. Most of the new lesions that appear after induction chemotherapy on PET-CT are not malignant (7). We know that some patients with minimal persistent N2 disease (mainly single level) can have a good prognosis after surgical resection (8). In a study published by Dooms et al (9) patients with less than 10% viable tumor cells in mediastinal lymph node sampled at mediastinoscopy and s with more than 60% decrease of SUV~max~ of primary tumor had a five year survival of over 60%. Therefore, we believe that a new staging algorithm could be used to select patients for radical therapy after induction chemotherapy for N2 disease. At baseline staging, pathological N2 disease should be proved by EBUS-EUS fine needle aspiration. PET-CT should be done to exclude distant metastasis and to evaluate SUV~max~ of the primary tumor. At restaging, mediastinoscopy with nodal dissection should be performed. Also repeat PET-CT should be done. In patients with major pathological response in lymph nodes and a major SUV drop of the primary tumor, surgery can be performed with good outcome. References (1)Mateu-Navarro M, Rami-Porta R, Bastus-Oiulats R, Cirera-Noqueras L, Gonzalez-Pont G. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-5. (2)Cerfolio R, Bryant A, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006;131(6):1229-1235. (3)De Leyn P, Stoobants S, Vansteenkiste J, Dewever W, Lerut A.. Prospective study of accuracy of redo videomediastinoscopy and PET-CT in detecting residual mediastinal disease after induction chemotherapy for NSCLC. Lung Cancer 2005;49 Suppl 2 : S3. (4)Rami-Porta R, Call S. Invasive staging of mediastinal lymph nodes: mediastinoscopy and remediastinoscopy. Thorac Surg Clin 2012: 22:177-89. (5)Herth F, Annema J, Eberhardt R, Yasufuku K, Ernst A, Krasnik M, Rintoul R. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008;26(20):3346-3350. (6)Szlubowski A, Zielinski M, Soja J, Filarecka A, Orzechowski S, Pankowski J, Obrochta A, Jakubiak M, Wegrzyn J, Cmiel A. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothor Surg 2014;46:262-266. (7)Collaud S, Lardinois D, Tischler V, Steinert H, Stahel R, Weder W. Significance of a new fluorodeoxyglucose-positive lesion on restaging positron emission tomography/computed tomography after induction therapy for non-small-cell lung cancer. Eur J Cardiothorac Surg 2012;41:612-616. (8)H. Decaluwé, P. De Leyn, J. Vansteenkiste, C. Dooms, D. Van Raemdonck, P. Nafteux, W. Coosemans, T. Lerut. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothoracic Surg 2009 ;36 :433-9. (9)Dooms C, Verbeken E, Stroobants S, Nackaerts K, De Leyn P, Vansteenkiste J. Prognostic stratification of stage IIIA-N2 non-small-cell lung cancer after induction chemotherapy: a model based on the combination of morphometric-pathologic response in mediastinal nodes and primary tumor response on serial 18-fluoro-2-deoxy-glucose positron emission tomography. J Clin Oncol 2008;26(7):1128-1134.

Abstract:
Approximately 30% of patients with non-small cell lung cancer (NSCLC) are found to have locally advanced stage III tumours at initial diagnosis. For these patients the curative therapeutic options include definitive high-dose radiotherapy with concurrent chemotherapy or, alternatively, induction treatment followed by surgery. Preoperative chemotherapy or combined radiochemotherapy protocols followed by resection result in cure rates of 25-35 percent at 3 years for locally advanced NSCLC. However, surgical resection in patients with stage IIIa N2 remains an issue of controversy depending on the extent of lymph node involvement. Neoadjuvant chemo- or radiochemotherapy is being used to reduce disease burden in the mediastinum before surgery since patients who are downstaged via neoadjuvant therapy and then undergo resection experience a significantly longer 5-year survival of 40% to 50% than those who are found to have residual N2 disease at the time of surgery. Thus, identification of patients who are N2 negative after completion of their neoadjuvant therapy is a critical component for patient selection for thoracotomy. However, clinical restaging in these patients often is challenging. Endoscopic ultrasound guided biopsies (EUS/EBUS-FNA) have increasingly become available and are currently preferred procedures for staging and restaging before surgery due to their high diagnostic accuracy.(1) Serial PET-CT imaging captures anatomical changes and additionally offers semiquantitative information about morphometric and metabolic tissue changes during induction treatment. Issues of PET-CT performance and quality assurance concerning standardization have been clarified during recent years and the validity of repeated measurements has been approved.(2) Successful induction treatment regimes have been frequently found to reduce 18F-FDG uptake and thus PET-CT allows to assess the therapeutic response. Reduction in FDG-uptake of mediastinal lymph nodes after induction therapy has been shown to correlate well with histopathologic response (3), while postinduction PET avidity taken alone was not consistently found to be associated with pathological N2 involvement (4). In the direct comparison of EUS-FNA with PET-CT for restaging after induction chemoradiotherapy, concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases was observed in 63% patients treated within a prospective study but the diagnostic accuracy of PET-CT was limited.(5) Nevertheless, serial FDG-uptake measurements seem to provide prognostic information during induction therapy. Data collected in prospective trials suggest that a decrease in SUV~max~ between 45% to 60% optimally separates between responders and non-responders (6-9). In a recent large retrospective analysis, a decrease in SUV~max~ greater than 60% in the involved mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary tumour site. (10) An analysis of a randomized trial in potentially resectable stage III NSCLC of induction treatment (including a hyperfractionated accelerated radiotherapy phase) and definitive radiochemotherapy compared with induction treatment followed by surgery confirmed that as early as after two cycles of cisplatin-based induction chemotherapy percentage of SUV~max~ remaining represents a significant prognostic parameter.(9) PET-response was of higher importance than all other clinical factors. Cut-off levels between 0.45 and 0.55 were predictive for freedom from extracerebral progression in all randomized patients. No important differences in the predictive value were observed comparing resection versus definitive radiochemotherapy. PET-response was closely related to extracerebral distant metastases but not to local recurrences, independent of treatment. One might conclude that less PET-responsive tumors are successfully controlled by intensified hyperfractionated accelerated radiochemotherapy or neoadjuvant radiochemotherapy and resection at loco-regional sites so that the highest risk of relapse remains at extracerebral distant sites. Therefore, a selection or intensification of the local therapy according to SUV-decrease is not warranted by these data. Functional imaging has not yet been fully established for treatment guidance but prospective evaluation is underway. In the group of poor-responding patients, treatment intensification by independent systemic options such as targeted therapy or immunomodulating therapy may become emerging new treatment options within clinical trials. References: 1) De Leyn EJCTS 2014, 2) Young, EJC 1999, 3) Pöttgen CCR 2006, 4) Ripley JTCS 2016, 5) Stigt, Lung Cancer 2009, 6) Hoekstra, JCO 2005, 7) Eschmann, Lung Cancer 2007, 8) Dooms, JCO 2008, 9) Pöttgen, JCO 2016, 10) Barnett ATS 2016

Abstract not provided

Abstract:
Rationale for restaging after induction therapy Persistent mediastinal nodal involvement after induction therapy is an independent prognostic factor associated with poor prognosis [1]. Based on the results of two phase III clinical trials on multimodality treatment for pathologically proven N2 non-small cell lung cancer (NSCLC) [2,3], patients with persistent mediastinal involvement do not benefit from surgical resection in terms of survival. The assessment of an objective response after induction therapy continues to be a diagnostic challenge. For this reason, the use of ‘mediastinal downstaging’ as a criterium to select patients for surgery requires a reliable restaging method to predict pathologic stage before lung resection. Algorithm for mediastinal restaging The European Society of Thoracic Surgeons guidelines for preoperative lymph node staging for NSCLC recommend histological confirmation of objective response after induction therapy. This confirmation can be done with ultrasound-guided endoscopic techniques. However, the use of an invasive surgical technique is still recommended when the results of endoscopic procedures are negative [4]. The role of mediastinoscopy Mediastinoscopy in restaging can be performed in the following situations: 1) after induction therapy with no pretherapeutic invasive diagnosis; 2) after induction therapy with mediastinal histological confirmation by endoscopic techniques; 3) after induction therapy preceded by staging mediastinoscopy. In this case, mediastinoscopy is a reoperation: a remediastinoscopy. The use of first mediastinoscopy for restaging is addressed in a small series [5]. In this article, a negative predictive value (NPV) of 90% with a prevalence of ypN2 of 46% were reported. Theoretically, this approach could be a good strategy to perform an easier and safe mediastinoscopy due to the absence of adhesions in the mediastinum. Remediastinoscopy (reMS) is a technique that does not differ much from a conventional mediastinoscopy. However, reMS is technically more demanding because of peritracheal adhesions, resulting in a lower accuracy in comparison with the first procedure. The main goal of this procedure is to take new biopsies of those nodes that had been positive at first mediastinoscopy. Moreover, if it is technically feasible, other nodal stations should be reached to rule out subclinical progression of the disease. Although reMS is not a common procedure, several authors have reported its feasibility and consistent results (see table 1). In addition, its results do not seem to depend on the type of the induction therapy (chemotherapy or chemoradiation) or on the level of thoroughness of the initial mediastinoscopy [6]. Morbidity rate ranges from 0% to 4%, and complications are not specific of reMS because they can also occur at first mediastinoscopy [1,6-8]. Regarding mortality, only one death has been reported. Based on the four largest published series, this intraoperative death represents a mortality rate of 0.2% [1,6-8]. The role of transcervical lymphadenectomies During the last decade, two new surgical staging procedures were developed: videoassisted mediastinoscopic lymphadenectomy (VAMLA) and transcervical extended mediastinal lymphadenectomy (TEMLA). The main difference between these procedures is that VAMLA is an endoscopic technique performed through a videomediastinoscope, and TEMLA is an open procedure assisted by a videomediastinoscope or a videothoracoscope, depending on the nodal station dissected. Both techniques imply the removal of all the lymph nodes of the explored nodal stations, allowing the identification of minimal nodal disease that is not identified on computed tomography (CT) or positron emission tomography (PET). Therefore, after a properly performed transcervical lymphadenectomy, the restaging of the mediastinum is unnecessary because there is no material left for a new biopsy. Focusing on the use of these procedures for restaging after induction therapy, only TEMLA has been validated on two retrospective studies conducted in the same institution. In the first series with 63 patients, the diagnosis of N2-3 disease before induction treatment was confirmed with invasive techniques in 27 patients (20 with endosonography and 7 with mediastinoscopy), and with CT in 36. Sensitivity, specificity and accuracy of restaging TEMLA were 95.5%, 100% and 98.3%, respectively [9]. In the second series with 176 patients treated with chemo- or chemotherapy, the restaging values of endobronchial endosonography (EBUS) and/or esophageal ultrasonograpy (EUS) (88 patients) were compared with those of TEMLA (78 patients). There was a significant difference between EBUS/EUS and TEMLA for sensitivity (64.3% and 100%; p < 0.01) and NPV (82.1% and 100%; p < 0.01) in favor of TEMLA [10]. Regarding their use for primary staging, VAMLA and TEMLA represent a new paradigm. Firstly, transcervical lymphadenectomies could also be considered part of the induction treatment because the mediastinum is staged and downstaged by these operations. Secondly, due to the fact that nodal restaging is unnecessary, new parameters should be used to select patients for lung resection after induction such as the stability of the primary tumor and the absence of extrathoracic disease based on the results of postinduction CT or PET. Finally, intraoperative pathologic study of the remaining lymph nodes should confirm the absence of nodal involvement before proceeding with lung resection, especially if pneumonectomy is required. Conclusions In multimodality treatments for patients with stage IIIA(N2) tumors, pathologic restaging after induction therapy is essential to decide on subsequent treatment. ReMS is a useful procedure regardless of the induction treatment used or the intensity of the first mediastinoscopy. The role of transcervical lymphadenectomies in staging and restaging should be implemented in clinical practice and validated in future clinical trials. References 1. De Waele M, Serra-Mitjans M, Hendriks J, et al. Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients. Eur J Cardiothorac Surg 2008;33:824-8. 2. Van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50. 3. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non- small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. 4. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787–98. 5. Lardinois D, Schallberger A, Betticher D, et al. Postinduction video-mediastinoscopy is as accurate and safe as video-mediastinoscopy in patients without pretreatment for potentially operable non-small cell lung cancer. Ann Thorac Surg 2003;75:1102–6. 6. Call S, Rami-Porta R, Obiols C, et al. Repeat mediastinoscopy in all its indications: experience with 96 patients and 101 procedures. Eur J Cardiothorac Surg 2011; 39:1022-7. 7. Stamatis G, Fechner S, Hillejan L, et al. Repeat mediastinoscopy as a restaging procedure. Pneumologie 2005;59:862-6. 8. Marra A, Hillejan L, Fechner S, et al. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg 2008;135:843-9.
 9. Zieliński M, Hauer L, Hauer J, et al. Non-small-cell lung cancer restaging with transcervical extended mediastinal lymphadenectomy. Eur J Cardiothorac Surg 2010;37:776–80. 10. Zielinski M, Szlubowski A, Kołodziej M, et al. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol 2013;8:630-6. Table 1. Staging values of the largest published series of remediastinoscopies for restaging after induction therapy.

Author	Year	N	S	NPV	DA
Stamatis et al. [7]	2005	160	0.74	0.86	0.92
De Waele et al. [1]	2008	104	0.71	0.73	0.84
Marra et al. [6]	2008	104	0.61	0.85	0.88
Call et al. [8]	2011	84	0.74	0.79	0.87

Abbreviations: N: number of patients; S: Sensitivity; NPV: Negative predictive value; DA: Diagnostic accuracy

Abstract:
The optimal strategy for patients with stage III non-small cell lung cancer (NSCLC) is not well-established and significant variation in practice exists across the United States and Europe. In the U.S., the majority of National Comprehensive Cancer Network (NCCN) member institutions consider surgery to be indicated in stage IIIA patients with involvement of a single N2 lymph node station smaller than 3 cm who have undergone induction chemotherapy. However, there is no agreement among institutions regarding treatment for other manifestations of stage IIIA-N2 involvement (e.g., multi-station or bulky disease) and both NCCN and European Society of Medical Oncology (ESMO) guidelines recommend that the role of surgery be discussed in a multidisciplinary tumor board setting. The use of induction chemotherapy vs induction chemoradiotherapy is currently of great interest worldwide, and the use of the latter is still common despite the results of numerous clinical trials and meta-analysis. The lack of consensus regarding treatment strategies for stage III NSCLC is in part due to the relatively low number of randomized studies available to guide decision-making, as well as institutional biases despite evidence. One important issue is the role and methods of restaging after induction therapy for patients with potentially resectable Stage IIIA (N2) disease. While all would agree that pathologic confirmation of N2 disease prior to induction chemotherapy is mandatory, using EBUS or mediastinoscopy, not all surgeons believe that restaging after induction therapy to confirm response to chemotherapy is necessary, despite evidence that the overall and cancer-specific survival of non-responders is quite low. There are 2 dominant strategies for staging and restaging patients with N2 disease: EBUS prior to induction therapy and restaging with videomediastinoscopy or mediastinoscopy prior to induction therapy and restaging with thoracoscopy or repeat mediastinoscopy. There may be a role for each strategy depending on individual patient characteristics. Advantages of thoracoscopic restaging after induction therapy include the ability to resect all ipsilateral nodes to most accurately assess response and the resection of nodal tissue at thoracoscopy is the first step in thoracoscopic resection and thus greatly facilitates the procedure. The role of thoracoscopic restaging after induction therapy will be reviewed, and the technical aspects for successful restaging and thoracoscopic lobectomy after induction therapy are demonstrated in videos. References 1. Martins RG, D'Amico TA, Loo BW, Jr., et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. Journal of the National Comprehensive Cancer Network : JNCCN. 2012;10(5):599-613. 2. Vansteenkiste J, De Ruysscher, D, Eberhardt WEE, Lim E, Senan S, Felip E, Peters s. Early-Stage and Locally Advanced (non-metastatic) Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines. Annals of Oncology. 2013;24((suppl 6)):vi 89-98. 3. Ettinger DS, Wood DE, Akerley W, et al. Non-small cell lung cancer, version 6.2015. Journal of the National Comprehensive Cancer Network : JNCCN. 2015;13(5):515-524. 4. Weeks JC, Uno H, Taback N, et al. Interinstitutional variation in management decisions for treatment of 4 common types of cancer: A multi-institutional cohort study. Annals of internal medicine. 2014;161(1):20-30. 5. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. 6. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. 2012;118(24):6126-6135. 7. Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer. 2010;69(1):86-93. 8 Jaklitsch MT, Gu L, Harpole DH, D'Amico TA, et al. Prospective phase II trial of pre-resection thoracoscopic restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer: Results of CALGB 39803. J Thorac Cardiovasc Surg 2013;146: 9-16 9. Yang CF, Gulack BC, Gu L, et al. Adding radiation to induction chemotherapy does not improve survival of patients with operable clinical N2 non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery. 2015;150(6):1484-1492; discussion 1492-1483. 10. Shah AA, Berry MF, Tzao C, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg. 2012;93(6):1807-1812.

Abstract:
Introduction The pathological differential diagnosis of in a patient with synchronous multiple tumors has a similar thought process for classic morphology as for DNA analysis. Metachronous multiple lung cancers are not discussed here, as the provided title implies a clinical situation at moment in time. In the end of the text the usefulness of clinical context is mentioned.[1–5] Morphology In the setting of obvious metastatic dissemination, histologic appearance is generally conserved. This implies that most metastases look alike and in most instances also have a similar morphologic appearance as the primary tumor. However, dedifferentiation occasionally occurs in metastases. Thus it is reasonable to conclude that lesions of different histological types, e.g. squamous cell and adenocarcinoma, are two separate primary cancers. Recently, it was suggested that differences in a comprehensive histologic assessment may provide an argument for separate primary cancers. However, resection specimen analysis is required for this assessment, making this approach only useful in about 15-20% of the cases. Moreover, an evidence based data set supporting comprehensive histologic assessment is currently lacking. Reproducibility has to be taken into account.[6] In contrast to different morphological types, in case of two tumors with similar morphology a conclusion for same lineage (primary tumor- metastases relation) or different lineage (two primary tumors) is not easy to reach. The reason for this is that within an individual the genetic predisposition and etiologic factors are the same and may lead to separate tumors with the same morphology, which may still represent two lineages (thus two primary tumors) or alternatively, the same morphology in metastatic setting is one lineage. In case of multiple adenocarcinoma in-situ lesions, they are assumed to be separate primaries. In summary , in comparing two tumors differences in morphologic types is conclusive for second primary tumors, but demonstration of the same morphology is not sufficient for lineage analysis. DNA changes Demonstration of specific driver mutations by widely available PCR sequencing techniques may have use in establishing lineage.[7]In case of different driver mutations between two tumors, this obviously provides a strong argument for two primary (lung) cancers. However the frequency of discordant driver mutations is not so high. Noteworthy is that the demonstration of different passenger mutations does not have any use for lineage determination. In case of equal driver mutations a conclusion about lineage is not easy to reach.[8,9]Not only because the genetic predisposition and etiologic factors are the same, but also because in certain genes hotspot mutations occur. Thus simple demonstration of the same mutation does not provide definite evidence for lineage analysis. On this matter more research is needed with posterior probability analysis involving a relevant number of similar mutations. A detailed genetic assessment such as in comparative genomic hybridisation (CGH) may have greater discriminative power but has been used in only a few small studies.[10]In array CGH the number of data points is orders of magnitude greater than in mutation analysis. Array CGH encompasses the predisposition and etiologic factor related copy number variations (CNV) as well as lineage specific CNV. In this sense comparison of exact breakpoints in gene rearrangements is useful. Although the data are limited as the assessment was in the past complex, nowadays arrayCGH in the form of shallow sequencing can reliable be performed on small biopsies as well. To which extend NGS with a large mutation panel may be useful remains to be seen. In summary , different driver mutations is conclusive for second primary tumors, but demonstration of the same driver mutation is not sufficient for lineage analysis. Clinical context Adding clinical context provides interesting arguments. 1) Imaging may show multiple ground glass opacities (mGGO) and lack of enlarged lymph nodes. Although the morphology may be similar (lepidic pattern with AIS, MIA, Invasive adenocarcinoma) the mGGO lesions are considered to be separate primaries. In case of part solid component the morphological equivalent is usually infarction (=benign) or invasive cancer. 2) Imaging may show multiple consolidations (pneumonic type) with mostly the morphological correlate of invasive mucinous adenocarcinoma. 3) Abundance of nodular lesions, provides an argument for metastases (although rare exceptions exist, e.g. DIPNECH, Carney’s triad), while lack of nodal or systemic metastases provides an argument of two primary lung cancers. 4) Clinical follow-up is in hindsight only partly useful: lack of nodal or systemic metastases provides an argument of two primary lung cancers, while presence of local and/or distant metastases may be due to one of the two or both lung cancers. Conclusion If morphological and/or DNA analysis provides differences between two tumors it is relatively easy to establish that these pulmonary foci of cancer are separate primary tumors. Many commonly used characteristics are associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended. References 1. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J. Thorac. Oncol. 11, 639–50 (2016). 2. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 681–92 (2016). 3. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth. J. Thorac. Oncol. 11, 666–680 (2016). 4. Kozower, B. D., Larner, J. M., Detterbeck, F. C. & Jones, D. R. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, e369S–99S (2013). 5. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 651–65 (2016). 6. Thunnissen, E. et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod. Pathol. 25, 1574–83 (2012). 7. Vignot, S. et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J. Clin. Oncol. 31, 2167–72 (2013). 8. Arai, J. et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer 77, 281–7 (2012). 9. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science (80-. ). 346, 251–256 (2014). 10. Macintyre, G., Ylstra, B. & Brenton, J. D. Sequencing Structural Variants in Cancer for Precision Therapeutics. Trends Genet. 32, 530–42 (2016).

Abstract:
The Surgical Choices for Patients with Multifocal Lung Cancers Surgery for patients with multiple lung lesions is a growing domain. CT scans are obtained frequently and have high resolution such that any lesion in the lung that is 2 millimeters or larger can be identified. Also, it appears that multifocal lung lesions are more common now. At the same time, surgical technique and technology (minimally invasive) have evolved so identifying and resecting small lesions is straightforward and associated with very little morbidity and pain. In most cases there is one lesion (primary lesion) that is more concerning and others that are smaller, less solid or relatively unchanged over time. Often a diagnosis of all of the lesions is not known at the time of surgical intervention and in many cases no diagnosis is known ahead of time. Thus, the surgeon must integrate many factors when operating on multifocal lung findings. What are risk factors that the patient will have lung cancer, what are the patient’s co-morbidities and underlying lung function? When is it important to establish a pre-operative diagnosis? How important is it to resect all of the pulmonary lesions seen on CT scan? Will other therapy be needed? In general, our approach is to obtain a pre-operative diagnosis when possible if the surgery will be particularly challenging based on the location and number of the lesions and/or if the patient has very compromised lung function. The most important point is to anatomically resect the primary lesion; that nodule which is largest, most solid and/or growing the fastest. If the lesion is 2 centimeters or smaller and located within a segment that is straightforward to resect (superior segment lower lobe, lingula or upper division of the left upper lobe, posterior segment of the right upper lobe, medial basilar segment of the lower lobe or composite basilar segments of lower lobe) then a segmentectomy is the procedure of choice. This will provide an excellent oncologic outcome and more readily permit other pulmonary resection than if a lobectomy or greater had been carried out. In all cases a lymph node dissection should be performed and in the case of a sublobar resection it is important to assess, by frozen section, the intersegmental node or nodes between the area being removed and the part of the lobe being left (sump), to be sure no disease remains related to this primary lesion. If the sump node is positive then a lobectomy should be strongly considered. If the lesion is greater than 2 centimeters and for those deep seated more central lesions, a lobectomy is the best operation. If the lesion is about one centimeter and subpleural then a wide wedge resection can be considered though this is an unusual situation for the primary lesion. For the other lesions (non-primary), if they are ipsilateral and easy to identify and resect then they should be removed at the time of the surgery for the primary lesion. If it is possible to resect these lesions with a segment (preferable) or wide wedge this is best. If the non-primary lesions are pure ground glass, relatively small (i.e. less than 2-3 centimeters) and stable then it is reasonable to leave them in place for close follow-up. Once the permanent pathology including molecular analysis is done and the patient has recovered then surgery for the contralateral lesions is considered. Factors that are important in this are residual pulmonary function (repeat pft’s after the first operation), size (both baseline and recent growth) and density of the contralateral lesions. Also, pathology of the resected tumors and whether they represented separate primary tumors or possibly were metastatic tumors, although even with molecular analysis this can be difficult to ascertain, is important in planning. Surgery on the contralateral lesions should be as lung-sparing as possible with segmentectomy being the procedure of choice when possible followed by wide-wedge resections or lobectomy if dictated by size and location. The outcome of patients who had surgery for multiple lung cancers is generally quite good and not statistically different than the outcome for a solitary lung cancer. The patients in these series were highly selected. In most cases the pathology of these lesions is a mix between invasive adenocarcinoma (various subtypes), minimally invasive adenocarcinoma and adenocarcinoma in-situ. Whether mutations are identified is variable and does not seem to influence prognosis. Use of adjuvant therapy depends on the completeness of resection, the nodal status and the molecular analysis of the resected tumors. In general, assuming no nodal involvement and complete resection of the lesions removed, no adjuvant therapy is recommended. In all cases close follow-up is mandatory with visits and frequent ct scans (2-3/yr for 2 years then 1-2/year for 3 years then 1/yr for life). Graph of Survival for patients treated by surgical resection for synchronous primary lung cancers. Figure taken from: Finley et al. Journal of Thoracic Oncology. 2010. (ref 2) Figure 1 References: Shimada et al. Survival of a surgical series of lung cancer patients with synchronousmultiple ground-glass opacities, and the management of the residual lesions. Lung Cancer 2015 Finley et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. Journal of Thoracic Oncology. 2010. Bonanno et al. Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman. Lung Cancer 2016. Fonseca A and Detterbeck FC. How many names for a rose: Inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer 2014. Yasuda M et al. How should synchronous multiple primary adenocarcinomas of the lung be resected? Annals of Thoracic Surgery 2014. Wolf AS et al. Lobectomy versus sublobar resection for small (2 cm or less) non-small cell lung cancers. Annals of Thoracic Surgery 2011. Mohiuddin K et al. Relationship between margin distance and local recurrence among patients undergoing wedge resection for small (<2 cm) non-small cell lung cancer. Journal of Thoracic and Cardiovascular Surgery. 2014. Nakata M et al. Surgical treatments for multiple primary adenocarcinoma of the lung. Annals of Thoracic Surgery. 2004. Battafarano RJ et al. Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival. Annals of Thoracic Surgery. 2002. Gu B et al. A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. Annals of Thoracic Surgery. 2013.

Abstract:
History of standard surgical procedure for lung cancer In 1933, Graham reported the first successful pneumonectomy for a lung cancer patient, who survived for 18 years after surgery. In 1951, Cahan suggested that pneumonectomy with regional lymph node dissection should be a routine procedure for lung cancer in 1951. Then in 1960, Cahan reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.” Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. As for sublobar resection, segmentectomy was initially used for the resection of localized bronchiectasis as reported by Churchill and Belsey (1939). In 1973, Jensik reported their 15-year successful experience of segmentectomy for lung cancer patients. However, the use of sublobar resection as definitive management of NSCLC has been a controversial issue. Lung Cancer Study Group (LCSG) (1995) conducted the only randomized trial comparing sublobar resection with lobectomy for stage IA NSCLC patients. They observed a 75% increase in recurrence and a 50% increase in cancer death in the patients undergoing sublobar resection, compared to those in the patients undergoing lobectomy. This is the reason why lobectomy has remained a standard lung cancer surgery for a half century since Cahn’s successful report in 1960. However, recently, we encounter many patients with the subsolid nodule、and a certain percentage of those patients are multifocal lesion. The significance and role of sublobar resection for subsolid tumor have become importanat so far. Controversies in sublobar resection for patients with small-sized NSCLC Sublobar resection is a lung parenchyma-preserving surgery with limited nodal dissection. However, even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%. Although positron emission tomography (PET) is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis, the assessment of nodal status by PET is not reliable in patients with microscopic nodal metastasis. Riquet (1989) reported that lung cancer metastasizes so easily to the mediastinum that selection of the patients for limited surgery should be discussed carefully. Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20-38% in N2 patients. Therefore, lobectomy with hilar and mediastinal lymph node dissection is considered to be a basic standard procedure for lung cancer. Differences in survival between sublobar resection and lobectomy However, with the recent development of the CT scanner, the number of very early-stage lung cancer showing ground-grass opacity (GGO) on CT is rising as well, and a new therapeutic strategy for nodal dissection has been required. Proposals of sublobar resection for small-size lung cancer less than 2 cm have been undertaken in some previous reports. Many retrospective studies of sublobar resection have already been undertaken for stage IA NSCLC patients. Regarding surgery for compromised stage IA patients, Hoffmann (1980), Landreneau (1997) and Campione (2004) showed no significant survival difference between sublobar resection and lobectomy group. Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20mm or less in diameter. They showed no significant difference in survival between two groups and suggested that sublobar resection was acceptable operation for small-sized lung cancer. Nakamura (2005) reported the results of meta-analysis of 14 comparative studies showing survival difference between lobectomy and sublobar resection. He showed survival after lobectomy was slightly better at 1, 3, and 5 years, but the differences were not significant. Therefore, lobectomy with mediastinal dissection could be an excessive resection for selected patients with early lesion. Lobectomy, however, still remains to be a standard procedure for most patients with lung cancer, simply because there has been no universally accepted guidelines for conducting sublobar resection in the clinical settings. We should wait the final results of clinical trials shown in the following chapter. Clinical trials regarding sublobar resection vs. lobectomy and future perspective Japan Clinical Oncology Group (JCOG) has conducted a cohort study (JCOG0201) evaluating correlation between radiological and pathological findings in stage I adenocarcinomas. With pathologic non-invasive adenocarcinoma defined as those with no lymph node metastasis or vessel invasion, radiological non-invasive lung adenocarcinoma was defined as those with a consolidated maximum tumour diameter to tumour diameter ratio (C/T ratio) of less than 0.5. Currently, a prospective, randomized, multiinstitutional phase III trial for small-sized (<=2 cm) lung cancer patients is being conducted by Cancer and Leukemia Group B (CALGB140503) to determine the effectiveness of an intentional sublobar resection for small-sized peripheral tumors. Similar phase III study is also being conducted by JCOG (JCOG0802). JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multiinstitutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0802, wide wedge resection or segmentectomy for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 50% solid part inside and 2.1-3.0 cm in tumor diameter. Since the clear evidence regarding the survival benefit of sublobar resection for lung cancer patient is lacking so far, lobectomy should be an appropriate therapy for medically operable lung cancer patient at the moment. Abovementioned randomized trials will clearly define the role of sublobar resection in patients with stage I patients. As the number of early-stage peripheral lung cancers is increasing, and a certain number of patients are with multifocal small lesion, the surgical procedure for lung cancer should be tailored to each case by considering CT findings.

Abstract not provided

Abstract:
Advances in Stereotactic Body Radiotherapy Matthias Guckenberger, Switzerland Stereotactic Body Radiotherapy (SBRT) has become the guideline-recommended treatment of choice for patients with early stage NSCLC, who are medically inoperable because of their comorbidities. This reflects that SBRT has transformed from an emerging technology practiced only by few and highly experienced centres to a mature treatment practice broadly in the radiation oncology community setting. Nevertheless, the methodology of SBRT has continuously evolved covering all aspects of patient selection, practice of SBRT planning and delivery and follow-up assessment. Patient selection: In many centres, SBRT has been introduced as a replacement for conventionally fractionated radiotherapy in patients considered fit enough for a six weeks long radical treatment but unfit for surgical resection. Recent data have demonstrated that SBRT is also well tolerated in very old (> 80 years) patients and patients suffering from severe comorbidities [1]. Simultaneously, the patient characteristics of age, performance status and patients comorbidities are not suitable to accurately predict a high risk of early non-cancer death such that these patients could be offered best supportive care and they would not benefit from SBRT as a curative treatment approach [2]. However, several studies have identified interstitial lung disease as a highly significant factor for severe post-SBRT radiation induced pneumonitis; these patients should be treated only with caution [3]. On the other end of the patient spectrum, there is an increasing amount of data comparing SBRT with surgical resection, lobectomy and sublobar resection: despite a growing evidence suggests equivalent outcome, lobectomy remains the standard of care for properly selected patients [4,5]. SBRT planning and delivery: Multiple advanced radiotherapy treatment planning and treatment delivery technologies as well as dedicated SBRT delivery machines have been developed and have become clinically available within the last years. Despite simulations studies showed a benefit for most these technologies, it remains unclear whether small improvements in accuracy and dosimetry will translate into a clinically meaningful improvements of patient outcome. The upcoming ESTRO ACROP practice guideline has therefore only identified few technologies as mandatory components of up-to-date SBRT practice (e.g. type B dose calculation algorithm, image guidance, 4D motion compensation strategy). SBRT dose and fractionation has been one of the most controversially discussed topics in lung SBRT and patterns-of-practice analyses reported a large variability between institutions. Comparison of different fractionation schedules requires radiobiological modelling and several recent studies suggested that the traditional linear-quadratic model (LQ-model) describes the observed outcome with sufficient accuracy [6]. Consequently, biological effective doses (BED) or 2-Gy equivalent doses are used by most studies for dose-effect modelling. Several studies consistently showed that a threshold dose of minimum 100Gy BED (alpha/beta ratio 10Gy) is required for a local tumor control probability of >90%. Furthermore, not only the minimum dose at the PTV edge but also the maximum dose within the GTV was shown as important predictor for local tumor control supporting the traditional SBRT concept of inhomogeneous dose distributions within the PTV. After central tumor location has been called a no-fly-zone for SBRT based on studies with “excessive” toxicity of very high dose SBRT, recent retrospective and prospective data suggest that lower total doses combined with more fractionated SBRT protocols improve the therapeutic ratio. Nevertheless, our understanding of the radiation tolerance of critical central structures is still insufficient and further research is necessary. Follow-up: The development of radiation induced fibrosis in the high dose region is well documented following SBRT. Only recently, algorithms for differentiation between local tumor recurrence and fibrosis have been developed and validated [7,8]: CT features of bulging margin and cranio-caudal growth appear to best differentiate between fibrosis and tumor recurrence. More advanced studies evaluate the value of mathematical image analysis methods, radiomics, but such studies strongly require external validation. 1. Takeda A, Sanuki N, Eriguchi T, et al: Stereotactic ablative body radiation therapy for octogenarians with non-small cell lung cancer. Int J Radiat Oncol Biol Phys 86:257-63, 2013 2. Klement RJ, Belderbos J, Grills I, et al: Prediction of Early Death in Patients with Early-Stage NSCLC-Can We Select Patients without a Potential Benefit of SBRT as a Curative Treatment Approach? J Thorac Oncol, 2016 3. Ueki N, Matsuo Y, Togashi Y, et al: Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol 10:116-25, 2015 4. Chang JY, Senan S, Paul MA, et al: Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 16:630-7, 2015 5. Nagata Y, Hiraoka M, Shibata T, et al: Prospective Trial of Stereotactic Body Radiation Therapy for Both Operable and Inoperable T1N0M0 Non-Small Cell Lung Cancer: Japan Clinical Oncology Group Study JCOG0403. Int J Radiat Oncol Biol Phys 93:989-96, 2015 6. Guckenberger M, Klement RJ, Allgauer M, et al: Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer. Radiother Oncol 109:13-20, 2013 7. Huang K, Dahele M, Senan S, et al: Radiographic changes after lung stereotactic ablative radiotherapy (SABR) - Can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 102:335-42, 2012 8. Peulen H, Mantel F, Guckenberger M, et al: Validation of High-Risk Computed Tomography Features for Detection of Local Recurrence After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 96:134-41, 2016

Abstract:
This session will focus on the use of proton beam radiation therapy for lung cancer. We will review the basic physics of proton beam therapy, why protons are different from photon-based radiation therapy, and the potential advantages of using proton beam therapy to treat lung cancer. We will review the current data about the use of protons, both published and unpublished, and provide updates about ongoing clinical trials testing proton therapy in lung cancer patients.

Abstract:
Introduction Approximately 65 particle therapy facilities are in operation worldwide. Among them, only 10 have carbon-ion therapy (CIRT) facilities (5 in Japan, 2 in Germany, 2 in China, and 1 in Italy), and the remainder have proton therapy facilities. More than 137,000 patients were treated with particle therapy worldwide from 1954 to 2014, including 15,000 in 2014, 86% of which were treated with protons and 14% with carbon ions and other particles. (from the Particle Therapy Co-Operative Group: http://www.ptcog.ch/). The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. Most of the patients who have been cured of cancer worldwide with carbon ions were treated at NIRS (1). From NIRS’s data, the efficacy of CIRT for non-small cell lung cancer (NSCLC) has been suggested. Here those results are reviewed, and the issue of this modern technology is discussed. Characteristics of carbon-ion therapy CIRT has better dose distribution to tumor tissue, while minimizing surrounding normal tissue dose, compared with photon radiotherapy. Moreover, carbon ions have potential advantages over protons. They provide a better physical dose distribution due to lessened lateral scattering. Further, their higher relative biological effectiveness and lower oxygen enhancement ratio are desirable features for targeting radioresistant, hypoxic tumors. The difference between densely ionizing nuclei and sparsely ionising x-rays and protons offers further potential radiobiological advantages, such as reduced repair capacity, decreased cell-cycle dependence, and possibly stronger immunological responses. Carbon-ion therapy of early non-small cell lung cancer Surgical resection with lobectomy has been the standard treatment of choice for early-stage NSCLC. In a 2004 study of a Japanese lung cancer registry comprising 11,663 surgical cases, overall survival (OS) rates at 5 years for stages IA and IB disease are 82.0% and 66.8%, respectively (2). Radiotherapy is an option for patients who are not eligible for surgery or refuse it. Recently, hypofractionated radiotherapy is regarded as an alternative to surgery for localized NSCLC, using x-ray stereotactic body radiotherapy (SBRT) or particle therapy using protons or carbon-ions. With regard to CIRT, for peripheral stage I NSCLC, the number of fractions was reduced in different trials from 18 to 9, then 4, and finally to a single fraction at NIRS (Table 1). The results with CIRT in stage IA NSCLC are similar to the best SBRT results reported worldwide. For stage IB disease, CIRT results appear superior to those reported for photon SBRT in terms of local control and lung toxicity. Despite high local control, disease-specific survival is much lower in stage IB than in stage IA because distant metastatic recurrences are common. A combination of CIRT with systemic therapy is therefore essential to improve survival. CIRT demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, CIRT may be safer for patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. Multi-institutional retrospective study of CIRT for stage I NSCLC was completed and will be presented at ASTRO 2016 by the Japan Carbon-ion Radiation Oncology Study Group (J-CROS). Carbon-ion therapy of locally advanced non-small cell lung cancer There was only one report about CIRT for locally advanced NSCLC. A prospective nonrandomized phase I/II study of CIRT in a favorable subset of locally advanced NSCLC was reported from NIRS (9). They showed that short-course carbon-ion monotherapy (72GyE/16Fr) was associated with manageable toxicity and encouraging local control rates. Among them, cT3-4N0M0 patients were good candidates for CIRT. There is otherwise a lack of evidence currently for CIRT for locally advanced NSCLC, and more study is needed. Moreover, concurrent systemic therapy is essential to improve survival for locally advanced NSCLC. Future directions We organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS). This group is currently conducting trials on several tumor sites which are thought to be most attractive for CIRT, including NSCLC, head and neck disease, locally advanced unresectable pancreatic cancer, hepatocellular carcinoma, locally recurrent rectal cancer, and others. The outcomes of CIRT for stage I NSCLC at all Japanese carbon centers were pooled and retrospectively analyzed. Consequently, CIRT may be considered a low-risk and effective treatment option for patients with stage I NSCLC. J-CROS has now begun a confirmatory multi-institutional prospective study to confirm these results. References: 1. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015; 16: e93-100. 2. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6: 1229-35. 3. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ionradiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2003; 66: 127-140. 4. Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiation Oncol Biol Phys 2007; 67: 750-758. 5. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007; 10: 916-926. 6. Sugane T, Baba M, Imai R, et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer. Lung Cancer 2009; 64: 45-50. 7. Takahashi W, Nakajima M, Yamamoto N, et al. Carbon ion radiotherapy in a hypofractionation regimen for stage I non-small-cell lung cancer. J Radiat Res 2014; 55(suppl 1): i26–i27. 8. Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiation Oncol Biol Phys 2016; 95: 542-548. 9. Takahashi W, Nakajima M, Yamamoto N, and et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015; 121: 1321-7.

Ref.	Pts.	Mean age	T1: T2	Total dose (GyRBE)/ fractions	F/U (months)	5-yr local control	5-yr cause-specific survival	5-yr overall survival	Toxicity grade 3 <
3)	81	72	41: 41	59.4-95.4/ 9-18	52.6	76%	60%	42%	lung 3.7%
4)	50	74.1	30: 21	72/ 9	59.2	94.7%	75.7%	50.0%	skin 2%
5)	79	74.8	42: 37	52.8-60/ 4	38.6	90%	68%	45%	0%
6)	28	82	12: 17	52.8-72/ 4-9	NA	95.8%	NA	30.7%	0%
7)	151	73.9	91: 60	36-50/ 1	45.6	79.2%	NA	55.1%	0%
8)	70	83	39: 31	28-50/ 1	42.7	85.8%	64.9%	39.7%	0%

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Abstract:
Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10~12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig.).Figure 1 The most common (50~60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ~60% and progression free survival of ~11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden.

Abstract:
Figure 1. Sequence of EGFR TKIsFigure 1 Sequencing of EGFR Tyrosine Kinase Inhibitors Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Treatment of EGFR-mutant(EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumour shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ~ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhibit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors(EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. References 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473–481 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor . Cancer Discov 2015;5(7): 713–22 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694–6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR

Abstract:
Somatic mutations clustering in exons 18 to 21 of the EGFR gene characterize distinct lung cancer biologies. Patients with metastatic EGFR-mutated lung cancer are exquisitely sensitive to targeted agents inhibiting the EGFR tyrosine kinase, which have demonstrated superior progress-free survival and, in some instances, overall survival when compared to platinum-based chemotherapy in first-line treatment. Several studies have shown that EGFR mutations can be detected by highly sensitive assay technology in free DNA circulating in the blood from patients with EGFR-mutated lung cancers 1,2,3. Circulating EGFR-mutated DNA may drop below the level of detection in patients responding to EGFR-TKI, and persistence or reoccurrence of circulating EGFR-mutated DNA may associate with primary and acquired resistance 1,3. In addition, clonal evolution of EGFR-mutated lung cancers under EGFR-TKI therapy can be mirrored by the detection of gatekeeper mutations, such as EGFR T790M or the EGFR C797S, in circulating DNA 4,5. Hence, mutation analysis in circulating free DNA has been suggested as a clinically more feasible and less invasive method for detection of predictive genomic biomarkers and treatment monitoring in advanced lung cancer. The development of more sensitive technologies and bioinformatic algorithms enables the study of comprehensive genomic biomarker panels in blood-derived DNA, which cover a broader spectrum of actionable mutations in treatment-naïve patients and those with acquired TKI resistance. Currently, there are still several limitations to overcome. First, the predictive value of a mutation detected in blood-derived DNA cannot be simply extrapolated from validation studies conducted with tumor-derived DNA. In consequence, prospective clinical validation of blood-based biomarkers is mandatory. Secondly, most studies comparing EGFR mutation detection in tumor and “liquid” biopsies side-by-side reveal inferior sensitivity of blood-based assays. Also, there is a considerable degree of discordance between such assays 4,6,7. Thus, “negative” findings in circulating tumor DNA have to be confirmed by a second assay in tumor-derived DNA. Apart from inflating spending on molecular diagnostics, this may result in further treatment delays, which is hard to bear for patients in particular in the first-line setting. While these obstacles may be soon overcome by technological advances and evolving data from validation studies, “liquid biopsies” focusing on DNA and/or RNA will always miss out on the histopathological information that can be derived from a biopsy of a tumor or metastasis. In the era of immunomodulatory antibody therapy information of tumor-infiltrating immune and stromal cells as well as expression of biomarkers by specific cell populations or with spatial variation become increasingly important. Until this information cannot be reproducibly derived by novel assay technologies the detection of genomic biomarkers in blood-derived DNA will become a highly valuable, additive modality for specific scenarios of primary diagnosis and treatment monitoring. References: 1 N Engl J Med. 2008 Jul 24;359(4):366-77. 2 Clin Cancer Res. 2009 Apr 15;15(8):2630-6. 3 PLoS One. 2014 Jan 21;9(1):e85350. 4 Lung Cancer. 2015 Dec;90(3):509-15. 5 Nat Med. 2015 Jun;21(6):560-2. 6 Clin Cancer Res. 2016 Mar 1;22(5):1103-10. 7 J Clin Oncol. 2016 Jun 27. pii: JCO667162.

Abstract not provided

Abstract:
Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’‑deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m² with the fixed dosage of 25 mg/m², respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m² and 36 mg/m², respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m² and S-1 at 30 mg/m² was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage.

Abstract:
The invited talk will firstly talk about the recent advances in novel TKIs overcoming resistance during EGFR-TKI and ALK-TKI treatment. Afterwards, several novel TKIs with CNS penetration that may substantially change the prognosis and treatment strategy of patients with brain metastases will be discussed. Finally, we will take an overview about targeted therapy against rare and novel, potentially druggable oncogenic drivers either in preclinical settings or early-stage clinical trials. As we know, the presence of EGFR activating mutations and ALK chromosomic rearrangements with corresponding tyrosine kinase inhibitors (TKIs) has revolutionized the treatment strategies of patients with non-small cell lung cancer (NSCLC) [1, 2]. Although tremendously initial response and manageable toxicity profiles, however, acquired resistance inevitably develops after approximately 1 year treatment with EGFR-TKIs (erlotinib and gefitinib) and ALK inhibitor (crizotinib). Encouragingly, third-generation EGFR-TKIs including AZD9291, CO1686 and HM61713 have showed striking efficacy overcoming acquired resisitance driven by T790M secondary mutations [3, 4]. In patients who get acquired resistance to first-generation EGFR-TKIs with T790M mutations, the objective response rate (ORR) of AZD9291 was 61% and median progression-free survival (PFS) was 9.7 months [4]. Other novel third-generation EGFR-TKIs such as ASP8274, EGF816, PF-06747775 and avitinib are also being investigated in early-stage clinical trials and the survival and safety data will be released in the near future. Another promising novel EGFR-TKI, namely AZD3759 has showed promising response in patients with brain metastases and leptomeningeal disease, a major case leading to treatment failure. In BLOOM study, 11 out of 21 patients with measurable brain metastases and heavily pre-treated progressed both extracranially and intracranially had tumor shrinkage in the brain at dose ≥50mg BID. Recently, EAI045, an EGFR allosteric inhibitor, in combination with cetuxmab exhibit antitumor activity in mouse models of lung cancer driven by L858R/T790M/C797S, a common resistant mechanism of AZD9291 [5]. Meanwhile, second-generation ALK inhibitors (ceritinib, alectinib and brigatinib) have entered clinical applications for NSCLC patients with ALK rearrangements after failure of crizotinib and third-generation ALK inhibitors (lorlatinib and ASP3026) are also being evaluated in clinical trials overcoming known ALK resistant mutations[6, 7]. In patients who progress on crizotinib, the ORR and PFS of brigatinib at 180mg was 54% and 12.9 months. Lorlatinib, a third-generation ALK inhibitor, also demonstrated robust clinical activity in ALK-rearrangement patients with NSCLC. The ORR was 57% in patients who received 1 prior ALK-TKI and 42% in patients who received ≥2 prior ALK-TKIs. On the other hand, with the development of high-throughput sequencing, called next-generation sequencing (NGS) and genomic technologies, more novel molecular targets such as MET 14 exon skipping splicing mutations[8]have been identified as potential therapeutic targets and simultaneously analyzing hundreds of molecular alterations have turned out reality with limited tumor tissues. In the recent years, the emergence of numbers of oncogenic drivers other than EGFR mutations and ALK rearrangements has divided NSCLC into multiple distinct subtypes amenable to corresponding targeted therapy, including ROS1 rearrangement, RET arrangement, BRAF-V600E mutations, HER2 mutations and MET 14 exon skipping mutations et al. For instance, dabrafenib either as monotherapy or in combination with MEK inhibitor (trametinib) has displayed promising antitumor activity and manageable safety profile in patients with BRAF V600E mutations [9, 10]. In 57 previously treated metastatic NSCLC patients with BRAF-V600E mutations, 63.2% patients (36/57) achieved an overall response [9]. Other novel molecular targets maybe serving as oncogenic drivers including mutations in HER2 (neratinib and pyrotinib) and PI3KCA (BKM120 and GDC0941), ROS1 (entrectinib, foretinib and lorlatinib), RET (XL184) and NTRK (entrectinib) rearrangements and FGFR1 gene amplification (AZD4547, Lenvatinib and FP-1039) are being evaluated either in preclinical settings or early-stage clinical trials. Reference: 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947-957. 2. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371: 2167-2177. 3. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372: 1700-1709. 4. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372: 1689-1699. 5. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016;534: 129-132. 6. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34: 661-668. 7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370: 1189-1197. 8. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5: 842-849. 9. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17: 984-993. 10. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17: 642-650.

Abstract:
Treatment of small-cell lung cancer (SCLC) has not been modified since decades : and consists in a chemotherapy (CT) with platin+etoposide+/-concurrent radiotherapy (RT) and prophylactic cranial irradiation in case of a (near)complete response to therapy. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers and around 50% are metastatic at presentation. Systemic treatment (platin-based doublets) has been implemented for stage IV NSCLC but also for locally advanced and early stages as a (neo)adjuvant therapy to surgery or RT. By the end of the XXth century, a plateau has been reached with CT in stage IV disease with similar results whatever the drug used in conjunction with platin-salt. Since the beginning of the XXIst century there have been tremendous innovations in the systemic treatment of NSCLC. First, adjunction of bevacizumab to CT for stage IV non-squamous cell carcinoma and the use of maintenance therapy have led to an improvement in median survival time (MST) exceeding now one year. Second, targeted therapies proved to be of major interest for patients with EGFR activating mutations leading to a MST>2 years. Other targets of interest have been found such as ALK and ROS1 translocations, V600EBRAF mutations leading to prolonged survival with appropriate treatments. Third, immunotherapy represents now an exciting approach especially for those patients without targetable mutations/translocations. Lung cancer has long been considered as a poor candidate for immunotherapy because of low content of tumor-infiltrating lymphocytes (TIL) compared to other tumors. On the other hand, in case of the presence of TIL the prognosis is better (1). The fact that incidence of lung cancer is especially high in patients who were transplanted (2)or in patients with HIV infection (3)is against the assumption of lung cancer being non immunogenic. There are two types of immunotherapy : the immune checkpoint blockers which aim at enhancing a T-cell response directed against tumoral cells and abrogate the immune tolerance and the therapeutic vaccines designed to induce or amplify an immune response directed against tumor-associated antigens (TAA). The immune checkpoint blockers in current development are anti CTLA4 monoclonal antibodies (ipilimumab), first used in the treatment of melanoma and now investigated in NSCLC and SCLC, anti PD1 (nivolumab, pembrolizumab) or anti PDL1 (avelumab, atezolizumab). All these molecules are now either at an advanced stage of development or already authorized (4). Therapeutic vaccines have already a long story beginning with Coley toxins at the end of the nineteenth century (5). The Coley's toxins, (cultures of streptococci) were infused in patients with bone and soft tissue sarcomas and some impressive regressions were observed. The hypothesis was that the immune reaction provoked by the infusion of the "toxins" present in the infectious material was able to destroy the tumoral cells. However, due to the reluctance of doctors to administer dangerous bacterial culture and the appearance of novel treatments of cancer (CT and RT), the Coley's toxin approach has been abandoned although numerous articles were devoted to this subject (6). Non specific vaccines using for example BCG to stimulate innate immunity have been disappointing as well in SCLC (7-8)and NSCLC (9). Specific immunotherapy aims at the stimulation of adaptive immunity against the vaccine components and thus induces or amplifies an immune response against TAA. These vaccines are either peptides (Tecemotide, MAGE-A3), cellular vaccines (Belagenpumatucel) or vaccines using viral vector (TG4010). Tecemotide and TG4010 are a MUC1 antigen-specific cancer immunotherapy. MUC1 is expressed at the apical surface of mucin-secreting normal epithelial cells of various tissues and can be overexpressed and aberrantly glycosylated in some tumors and thus is an attractive target for immunotherapy. Tecemotide is a liposomal vaccine. In a randomized phase II trial (10), 171 NSCLC patients who were not progressing after induction CT or CT-RT received subcutaneous tecemotide plus best supportive care (BSC) or BSC alone as maintenance therapy . Median survival time (MST) was longer in patients receiving tecemotide (17.2 vs. 13.0 months) but this did not reach statistical significance. As in a post hoc analysis the benefit appeared to be more important for patients with stage IIIB disease, it was decided to perform a phase III study in locally advanced NSCLC (11,12)comparing in non-progressing patients after CT with platin-based doublet and RT, tecemotide versus placebo. MST was 25.8 months with tecemotide versus 22.4 months with placebo (HR 0.89, 95%CI 0.77-1.03, p=0.111). In the concurrent CT-RT subgroup, there was a significant survival benefit in favor of tecemotide whereas in the sequential CT-RT subgroup, survival did not differ between the two arms. A similar study (13)was initiated in Asian people. This trial was prematurely terminated as the sponsor decided to discontinue program with tecemotide in NSCLC MAGE-A3 is an antigen expressed in 76% of melanoma and in 35% of NSCLC. It is absent from normal tissues except for testis and placenta. This vaccine, has been investigated in early stage of NSCLC as an adjuvant treatment. A randomized phase II study(14)compared the MAGE-3A vaccine to a placebo in 182 patients operated of a stage IB or II NSCLC with their tumor expressing MAGE-A3 antigen. The randomization was on a 2 :1 basis. The main objective was to compare the Disease Free Interval (DFI) defined as the time from resection to the date of recurrence (any type) or second primary lung neoplasm. Although there was a trend toward a numerically longer DFI in the MAGE-A3 vaccine group, the main objective was not met. Nevertheless, even if these trends were by far not significant, the results appear promising to the sponsors and a phase III trial was launched (MAGRIT trial) with the same scheme(15). Unfortunately, the biggest trial ever performed with the inclusion of 2312 NSCLC patients is negative regarding as well the primary objective: disease-free survival (DFS) but also the secondary objective, DFS in the group of patients not receiving adjuvant chemotherapy or other subgroups. Belagenpumatucel-L is a vaccine comprising 4 tranforming growth factor-β2-antisense gene-modified irradiated allogeneic NSCLC cell lines. A randomized phase III trial (16)comparing this vaccine to a placebo was performed after platinum-based CT for stage III/IV disease in non progressing patients. This trial was negative with no difference in overall survival and in PFS. However, in a prespecified multivariate analysis, there was an improved survival for patients who were randomized within 12 weeks after CT and for patients who received prior radiation therapy. TG4010 is a suspension of a recombinant modified vaccinia virus strain Ankara coding for the MUC1 TAA and IL2. Feasibility of either upfront combination of TG4010 with cisplatine-vinorelbine or TG4010 alone until progression has been demonstrated in a phase II study(17). Sixty-five patients were randomized. Response rate was 30 % in the combined upfront schedule, MST was 12.7 months and one-year survival rate 53%. Taking into account these results, a phase II randomized study (18)comparing CT with cisplatin and gemcitabine to the same CT + TG4010 was performed. One hundred and forty eight patients with stage IIIB or IV disease were included. The primary endpoint was 6-month PFS with the hypothesis that it will be at least 40% in the combined arm. This objective was met with a 6-months PFS of 43% compared to 35.1% in the CT alone arm. There was a non significant trend toward a higher response rate and a longer time to progression in the combined arm. An exploratory analysis of the subgroups defined by the level of activated NK cells (CD16+CD56+CD69+lymphocytes or TrPAL) shows that a better outcome was observed for those patients with normal level of TrPAL and that the vaccine might be deleterious for those with high level of TrPAL. A phase IIB was then performed to confirm the role of the level of TrPAL(19). 222 patients were randomly allocated to CT+TG4010 or CT+placebo. Median PFS was 5.9 months in the TG4010 group versus 5.1 months in the placebo group (HR 0.74, 95%CI 0.55-0.98, p= 0.019). In patients with TrPAL values less or equal ULN, the HR for PFS was 0.75 (95%CI 0.51-1.03) with a posterior probability of HR being <1 of 98.4% and thus the primary endpoint was met. In patients with high level of TrPAL, there was no deleterious effect but no benefit as the HR for PFS was 0.77 (95%CI 0.42-1.40). As a conclusion, all studies with vaccines have been quite disappointing. To the best of my knowledge, the only vaccine still under investigation remains TG4010, but....phase III trial is not implemented at this time. In each vaccine study some efficacy has been observed in subgroups of NSCLC patients but mostly in post hoc analyses. All vaccine studies have shown that there is no safety problems. The fact that nowadays, considerable interest has been developed toward checkpoint inhibitors, probably explains the disaffection toward vaccines. Hopefully it will be only transient and the already long story of therapeutic vaccines will continue.

Product	Trials conducted	Author (ref)
Tecemotide (Stimuvax*) Merck Serono	Phase IIB maintenance study in stage III/IV NSCLC Phase III maintenance therapy after CT-RT in non resectable stage III disease	Butts(10) Butts(11) Mitchell(12) Wu(13)
MAGE A3 GSK	Adjuvant treatment after surgery Phase II randomized study Phase III study (Magrit trial)	Vansteenkiste(14) Vansteenkiste(15)
Belagenpumatucel Lucanix* NovaRx	Phase III study as maintenance in stage IV disease after 1st line CT	Giaccone(16)
TG4010 Transgene	In combination with first line CT in stage IV disease NSCLC Phase II study Phase IIB randomized study Phase IIB/III randomized study	Ramlau(17) Quoix(18) Quoix(19)

Table 1 Phase II and III vaccine studies in NSCLC References 1. Kawai O, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113:1387–95. 2. Engels EA, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–901. 3. Hleyhel M, et al. Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort. AIDS 2014;28:2109–18. 4. El-Osta H,et al. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. OncoTargets Ther. 2016;9:5101–16. 5. Coley WB. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48. 6. Zacharski LR, Sukhatme VP. Coley’s toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 2005;3:424–7. 7. Maurer LH, et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol 1985;3:969–76. 8. Giaccone G, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer. J Clin Oncol 2005;23:6854–64. 9. Robinson E, et al.. Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy). Cancer Treat Rep. 1985;69:251–8. 10. Butts C, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005;23:6674–81. 11. Butts C, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68. 12. Mitchell P, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015;26:1134–42. 13. Wu Y-L, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011;11:430. 14. Vansteenkiste J, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol 2013;31:2396–403. 15. Vansteenkiste JF, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35. 16. Giaccone G, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015;51:2321–9. 17. Ramlau R, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol 2008;3:735–44. 18. Quoix E, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12:1125–33. 19. Quoix E, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016;17:212–23.

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Background:
Extracellular vesicles are small vesicles released from all cell types which can be used as a form of cell to cell communication. Recently these extracellular vesicles have been shown to play a key role in cancer development, growth, progression and angiogenesis. These extracellular vesicles are loaded with functional mRNAs, miRNAs and proteins which can be transferred from one cell to another. Extracellular vesicles have been known to enter neighboring cells including the surrounding stroma, and even enter biofluids. Our research shows that miRNAs transferred from lung adenocarcinoma cells through extracellular vesicles influence gene expression in endothelial cells and enhance their ability to form new blood vessels.

Methods:
Using 5 lung adenocarcinoma cell lines (H1395, H1437, H2073, H2228 and H2347) we isolated extracellular vesicles using differential ultracentrifugation. RNA was extracted from the extracellular vesicles as well as the cells from which they were derived and profiled for 742 miRNAs using the miRCURY LNA[TM] Universal RT miRNA PCR system (Exiqon) to identify miRNAs that were enriched by at least 4-fold in the extracellular vesicles. Tube formation assays were conducted on a commonly used endothelial cell line HMEC-1.

Results:
We found an enrichment of a select set of miRNAs within lung adenocarcinoma extracellular vesicles. These miRNAs have previously been identified as tumor suppressors: miR-142-3p, miR-143-3p, miR-144-3p, miR-145-5p, miR-150-5p, miR-223-3p, miR-451a, miR-486-5p, miR-605-5p in various cancer types. When extracellular vesicles are isolated from miR-143 and miR-145 over expressing adenocarcinoma lines they contain an increase in their over expressed miRNAs. When these miRNA enriched exosomes were incubated with HMEC-1 cells, we observed an increase in their ability to form new blood vessels and a decrease in the expression of CAMK1D in the endothelial cells. miR-143-3p and miR-145-5p were also found to be enriched in serum samples draining directly from lung adenocarcinoma tumors compared to arterial serum.

Conclusion:
Extracellular vesicles originating from lung adenocarcinoma cells can enter into endothelial cells and increase their ability to form new blood vessels through extracellular vesicle transfer of miR-145/miR-143 suggesting that this form of communication increases angiogenesis within lung adenocarcinoma tumors.

Background:
MicroRNAs are a class of small non-coding RNAs that range in size from 19-25 nucleotides. They have been shown to regulate a number of processes within tumour biology, including metastasis, invasion and angiogenesis. More recently, miRNAs have been linked to chemoresistance in solid tumours, including lung cancer.

Methods:
MicroRNA expression within an isogenic panel of age-matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines was profiled using the 7[th] generation miRCURY LNA arrays (Exiqon). Significantly altered miRNAs within the CisR sublines were manipulated using antagomirs (Exiqon) and Pre-miRs (Ambion) and functional studies were carried out in the presence and absence of cisplatin. To examine the translational relevance of these miRNAs, their expression was examined in a cohort of chemo-naïve patient-matched normal and lung tumour tissue and serum from NSCLC patients of different histologies. To create a xenograft model of cisplatin resistance 1x10[3 ]cells H460 PT or CisR cells were injected into 5-7week old NOD/SCID mice. Tumour volume was measured over time and harvested once the tumour mass measured 500mm[3] and formalin-fixed and paraffin embedded (FFPE). Expression of the 5-miR signature was analysed within FFPE murine tumours and cisplatin resistance was investigated relative to cisplatin sensitive controls.

Results:
Profiling and subsequent validation revealed a 5-miR signature associated with our model of cisplatin resistance (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286). Inhibition of the miR-30 family and miR-34a-5p reduced clonogenic survival of CisR cells when treated cisplatin. Expression of the miRNA signature was significantly altered in both adenocarcinoma (AD) and squamous cell carcinoma (SCC) relative to matched normal lung tissue and between SCC and AD tissue. miR-4286 was significantly up-regulated in SCC sera compared to normal control and AD sera. Similarly to the cell line expression of the miRNAs, the miR-30 family members and miR-34a-5p were up-regulated in the CisR xenograft FFPE tissue relative to PT.

Conclusion:
A novel miRNA signature associated with cisplatin resistance was identified in vitro, genetic manipulation of which altered clonogenic response to cisplatin. The 5-miR signature shows both diagnostic and prognostic biomarker potential across a number of diagnostically relevant biological mediums.

Background:
Fetal and tumour development share striking similarities, such as intense cell proliferation, angiogenesis, increased cell motility, and immune evasion. Molecular regulators, including microRNAs (miRNAs), play important roles in both fetal lung development and in the malignant transformation of adult lung cells. Consequently, investigation of lung tumour biology in the context of lung development may reveal key regulatory mechanisms that tumours hijack from normal development, which potentially play critical roles in the pathology of lung cancer.

Methods:
131 pairs of non-small cell lung cancer (NSCLC) tumour and non-malignant lung tissues and 15 human fetal lung tissue samples were profiled by miRNA-sequencing. Genes controlled by the oncofetal miRNAs identified were first investigated by miRNA-Data-Integration-Portal (mirDIP) prediction, followed by luciferase-reporter assays. Associations between patient survival and mRNA expression of oncofetal miRNA-gene targets were evaluated in independent samples (>1,400 cases) across multiple NSCLC cohorts. Immunohistochemical analysis of oncofetal miRNA targets was performed on 96 lung adenocarcinoma (LUAD) specimens.

Results:
We describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, and identified numerous miRNAs that recapitulate their fetal expression patterns in NSCLC. Nuclear Factor I/B (NFIB), a transcription factor essential for lung development, was identified as being frequently targeted by these oncofetal miRNAs. Overexpression of the oncofetal miRNA miR-92b-3p, significantly reduced NFIB levels in vitro. Concordantly, analysis of NFIB expression in multiple NSCLC cohorts revealed its frequent underexpression in tumours (~40-70%). This is in contrast with its recurrent oncogenic overexpression recently reported in SCLC. Low expression of NFIB was significantly associated with poorer survival in LUAD patients but not in squamous cell carcinoma patients, consistent with the functional role of NFIB in distal lung cell differentiation (i.e., precursor cells of LUAD). Furthermore, an NFIB-related gene signature was identified in LUAD tumours, comprising several well-known lung differentiation markers (e.g., TTF-1, SFTPB, ABCA3). The underexpression of NFIB protein was ultimately validated in LUAD specimens, which also revealed that tumours presenting lower levels of this transcription factor are associated with higher grade, biologically more aggressive LUAD (invasive mucinous, micropapillary and solid subtypes).

Conclusion:
This work has revealed a prominent mechanism for the downregulation of NFIB, a transcription factor essential for lung differentiation, which we found to be associated with aggressive phenotypes of LUAD and consequently, poor patient survival. Restoration of NFIB expression, specifically in LUAD, has the potential to induce lung cell differentiation and thereby reduce tumour aggressiveness.

Abstract not provided

Background:
Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers and adenocarcinoma (ADC) represents the most common histological type with a heterogeneous pattern of growth classified as lepidic, acinar, papillary, solid, and micropapillary. For ADC there are restricted available therapeutic options except for patients that could benefit from target therapy. A valuable therapeutic strategy is represented by angiogenesis inhibitors such as bevacizumab that has been approved for the treatment of NSCLC patients. However, there are concerns about its treatment-related toxicity and the identification of new reliable biomarkers to stratify patients who can really benefit from antiangiogenic drugs is urgently needed. Using miRNA target prediction tools, we selected and investigated the expression level of a panel of miRNAs togheter with their mRNA target involved in the angiogenesis pathway.

Methods:
We designed a custom codeset including probes for six genes (VEGF-A, FLT1, KDR, FLT4, PDGFRa and PDGFRb) and sixteen miRNAs. The expression analysis was performed by the nCounter System® (NanoString Technologies) directly on RNA, enriched of small RNA, purified from the formalin­-fixed and paraffin­-embedded tumor tissues of 80 ADC patients. Of these 25 were predominatly lepidic (31.25%), 24 were predominatly solid (30%), 20 were predominatly acinar (16%), 11 were predominatly papillary (13.75%).

Results:
Comparing the expression levels of mRNAs with the different histological ADC subtypes we found a significant higher expression of VEGF-A in papillary than in other subtypes (p=0.02). In contrast PDGFRa and PDGFRb were upregulated in lepidic and downregulated in papillary subtypes (both p=0.03). Among 16 miRNAs that target the angiogenic mRNA, 6 were significantly downregulated in papillary compared to other groups.

Conclusion:
Our data suggest a distinct angiogenic miRNA-mRNA expression profile among the subtypes of ADC. The higher level of VEGF-A in papillary than in lepidic subtypes could represent a useful biomarker to stratify patients who can effectively treated with bevacizumab, which is directed against VEGF. Moreover, the regulation of angiogenic mRNA factors by miRNAs could provide a novel therapeutic approach based on their expression pattern specific for distinct ADC subtypes. Further studies are nedeed in a larger cohort of patients to confirm our results and to investigate whether different rates of response to treatment are observed among patients stratified according to the proposed biomarkers.

Abstract not provided

Background:
Non-small-cell lung cancer (NSCLC) is one of the most common and high mortality rate carcinoma in China which biomarkers for diagnosis are limited. Therefore, novel biomarkers and methods with increased specificity for diagnosis are explored and required. For now, liquid biopsy for lung cancer oncogenes and next generation sequencing technique are extensive employed in NSCLC. However, increasing evidence illustrates that exosomal microRNAs in circulating fluids provide a promising way as biomarkers for noninvasive cancer diagnosis. Exosomes are 30–150 nm particles which are released from cells into the extracellular environment and stable miRNAs have been identified in plasma exosomes, which play important role in cell communication. Furthermore, exosomal miRNAs present different profiles between patients with cancer and healthy individuals. Whether exosomal miRNAs could benefit NSCLC patient diagnosis remains to be explored.

Methods:
Blood samples were collected from 40 NSCLC patients and 24 healthy volunteers matched with age, gender and blood collection time. Plasma exosomes were accessed by 110,000×g ultracentrifugation and visualized by NS300 equipment. The raw data of exosomal miRNA profiles of NSCLC patients and healthy individuals were generated by NGS around 400× read depth and its expression were measured by Taqman probe quantitive PCR

Results:
In the present study, we revealed that nearly half of exosome RNA was miRNA and NSCLS patients expressed a set of exosomal miRNAs with specificity compared with healthy volunteers. We demonstrated that miR-126-5p and miR-21-3p were down-regulated in NSCLC patients. In addition, we showed that the expression level of miR-124-3p and miR-99a-3p in NSCLC patients was higher than that of healthy individuals. Furthermore, we found miR-99a-3p was clinical stages related in NSCLC patient plasma and miR-375-3p was a potential biomarker for diagnosis and prognosis in NSCLC.

Conclusion:
Exosomal miRNAs in plasma could indicate the progress of NSCLC and a combination of the explored miRNA could serve as a promising biomarker for NSCLS diagnosis and prognosis.

Background:
Lung cancer remains the cause of the most cancer-related deaths each year, with a 5 year survival rate of less than 17%. Targeted therapeutics have been developed against drivers of the lung adenocarcinoma (AC) subtype, but are relevant only to the proportion of patients harbouring these genetic aberrations, emphasizing the need to explore alternative mechanisms of AC development. Natural antisense transcripts (NATs) are long non-coding RNA (lncRNA) products expressed from the opposite strand of coding mRNAs. NATs can function in cis or trans to regulate the transcriptional activity of their cognate gene partner in either a positive or negative fashion. Here we take a novel approach to identify cis- NATs deregulated in lung AC, and explore the function of these genes with regards to their protein coding partner genes.

Methods:
We performed RNA-sequencing on a set of 36 lung AC and matched non-malignant lung tissues. A sign-rank test was used to identify NATs and partner genes with significantly altered expression between tumor and matched normal tissues. These findings were validated in an external dataset of 50 lung AC tumors with matched non-malignant tissue obtained from The Cancer Genome Atlas (TCGA). Survival analysis was performed using a Cox Proportional hazard model, as well as the log-rank method.

Results:
Analysis of Illumina Hi-seq data from TCGA revealed the majority (79%) of deregulated sense-antisense partnerships observed in AC displayed concordant regulation. However, several discordant cis-NAT pairs were identified including an antisense to OPA INTERACTING PROTEIN 5 (OIP5), a gene required for chromatin segregation, as well as an antisense to HIGH MOBILITY GROUP A1 (HMGA1) a gene involved in the metastatic progression of many cancer types. Both the antisense to OIP5 (OIP5-AS1) as well as the antisense to HMGA1, (HMGA1-AS1) were significantly underexpressed in AC, while we find the overlapping protein coding partner genes to be significantly overexpressed, suggesting that these genes may negatively regulate their sense counterparts. In addition both OIP5 and HMGA1 are significantly associated with 5-year survival. Patients with higher expression levels of either of these genes had a significantly shorter overall survival time than patients with low expression levels, highlighting the potential clinical importance of these genes.

Conclusion:
This study characterizes the landscape of antisense expression in AC and highlights novel mechanisms of oncogene regulation through natural antisense transcripts. Characterizing these oncogene regulatory mechanisms could uncover therapeutic intervention points and further our understanding of AC biology.

Background:
The advent of next generation sequencing has lead to the discovery of the functional importance of non-coding RNAs (ncRNAs) in a wide variety of cellular processes, and these genes can be exploited by tumours to drive the hallmarks of cancer. Pseudogenes are DNA sequences that are defunct relatives of their functional parent genes but retain high sequence homology. Long non-coding RNAs (lncRNAs) have been shown to regulate protein-coding genes; however, complex folding patterns make lncRNA function difficult to predict. Several lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans due to sequence complementarity. The biological impact of this mechanism has not been investigated in lung adenocarcinoma (LUAD). We hypothesize that expression changes in lncRNAs expressed from pseudogene loci can affect the expression of corresponding protein-coding parent genes in trans, and that these events provide an alternative mechanism of cancer gene deregulation in LUAD tumourigenesis.

Methods:
We analysed RNA-seq data from 50 LUAD with matched non-malignant tissue obtained from the TCGA for both protein-coding and non-coding gene expression. Significantly differentially expressed lncRNAs located within pseudogene loci were identified by sign-rank test (p<0.001). Mann Whitney U-tests were used to identify lncRNA-parent gene pairs which significantly correlated expression, and survival analysis was performed using a Cox proportional hazard model.

Results:
Our analysis has identified 172 lncRNAs expressed from pseudogene loci that were significantly deregulated in LUAD. Remarkably, many of these lncRNAs were expressed from the loci of pseudogenes related to known cancer genes. One of these lncRNAs, CTD-2583A14.8, was expressed from a pseudogene to ubiquitin-conjugating enzyme E2C (UBE2C), which regulates tumor growth, apoptosis, and angiogenesis through phospho-ERK1/2. We find CTD-2583A14.8 as well as the UBE2C parent gene to be significantly upregulated in LUAD tumours compared to matched normal tissue. Furthermore, tumours with higher levels of CTD-2583A14.8 have significantly higher levels of UBE2C expression than tumours with low levels of CTD-2583A14.8, indicating that CTD-2583A14.8 may positively regulate UBE2C in trans.

Conclusion:
Here we show expression of lncRNAs within pseudogene loci is deregulated in LUAD, and can correlate with the expression of their protein-coding counterparts. Many of these genes associated with this putative lncRNA-pseudogene-protein-coding axis have previously been implicated in cancer. Therefore, this represents an alternative mechanism of cancer gene deregulation, and may represent novel therapeutic intervention points for the treatment of LUAD.

Abstract not provided

Background:
Although lung cancer is the second most-often diagnosed malignancy in both men and women, and the biggest cancer killer of both genders, evidence suggests that the lung cancer experience differs in women compared to men. Lung cancer incidence in men has steadily decreased since the mid-1980s, while in women it has increased. Partly, these patterns reflect sex differences in smoking behavior over the previous two decades. Additional epidemiological evidence suggests that gender impacts most facets of the lung cancer experience, including the incidence, susceptibility, severity, and molecular basis of the disease. However, there is a lack of consensus on both the magnitude and etiology of these gender-based differences. The aim of this currently ongoing systematic literature review is to more precisely define this gender disparity among non-small cell lung cancer (NSCLC) patients worldwide and summarize current opinions about the molecular basis for these observations.

Methods:
A preliminary rapid review was launched to outline gender disparity among NSCLC patients in North America, Europe and South Asia. Independent studies were utilized from Medline; Embase; Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for the period between 1996 and 2016. Based on these results, a systematic literature review was carried out for the period between 1996 and 2016 using Medline and Embase databases worldwide. The main outcome measures are incidence and factors influencing NSCLC between the genders. A validated scoring system was used to appraise eligible studies for methodological quality and level of evidence.

Results:
The preliminary rapid search identified 17 eligible articles for review. Analysis suggests that females are more susceptible to tobacco related carcinogens, have a younger age at diagnosis and higher survival rates. We also observed an increase in the inclusion of female patients in the clinical studies over this period. Based on pre-specified selection criteria, the systematic review generated a total of 367 studies which have been retrieved and considered for further analysis. We will determine gender differences in NSCLC incidence and its molecular aberration utilizing data from independent studies based on rapid analysis of observational studies published globally.

Conclusion:
Our systematic literature review will help validate our preliminary findings that gender disparities in lung cancer do exist. Our findings will provide a platform for policy makers, researchers and clinicians to design clinical trials and interventions that account for these disparities.

Background:
The epidemiologic profile of lung cancer mortality in the U.S. is highly unusual. Mortality in males began to rise rapidly early in the 1920s and continued to increase through the 1990s before leveling off. Mortality in women did not begin to rise until decades later and did not approximate mortality in men until the early years of the twenty first century. This unusual pattern of disease can be explained by review of tobacco industry documents and court records.

Methods:
A search was conducted in the Legacy Tobacco Documents library at the University of California, San Francisco, as well as review of testimony and legal reports from state and federal court decisions.

Results:
The beginning of the epidemic of lung cancer in women in the U.S. can be reliably traced back to Easter Sunday in 1929. On that date, a publicity stunt crafted by Edward Bernays was reported in the New York Times as the "parade of torches" supposedly representing an expression of freedom by American women who would henceforward not be constrained from smoking in public. The public relations effort was supplemented by an advertising campaign orchestrated by Chicago marketing expert Albert Lasker. Female smoking rates began to rise after this date, culminating over the succeeding decades in a sharp increase in lung cancer cases and deaths among women. A second phase of marketing of cigarettes to women and girls in the U.S. began in the 1970s as Philip Morris executive Joseph Cullman collaborated with tennis star Billie Jean King to market a new "slim" cigarette to young women via the Virginia Slims tennis tournament under the slogan "You've come a long way baby." A further contribution to the lung cancer mortality arose out of the efforts of the Council for Tobacco Research (CTR) and the Council for Indoor Air Research (CIAR) to manufacture controversy regarding the danger of smoking as well as involuntary second hand smoking to provide cover for legislators voting against tobacco control legislation. As a direct result, many thousands of non-smoking women have had major involuntary exposure to tobacco carcinogens in the workplace causing lung cancer.

Conclusion:
Lung cancer cases presenting today originated in deliberate campaigns by tobacco executives, marketers and public relations experts to convince women and girls to smoke, despite their clear understanding that the products they were aggressively marketing would inevitably result in hundreds of thousands of deaths.

Background:
Female lung and breast cancers are two distinct disease entities in East Asia. Although studies on second primary cancers following the first breast cancer event have been carried out, no in-depth survey on double primary breast and lung cancers has been done. This study analyzed the association between these two distinct cancer types.

Methods:
In the exploratory cohort study, the data were obtained from the Taiwan National Health Insurance Research Database, which contained information on approximately 24.7 million insured individuals. The Taiwan Population Census and National Cancer Registry Databases were used to identify patients with breast and lung cancers. The cohort included individuals with newly diagnosed primary breast cancer between 2000 and 2011. An age- and sex-matched systematic random-sampling method was used for subject selection in the reference non-breast cancer cohort. Multivariate Cox proportional hazard regression analysis was used to determine the effects of breast cancer on the risk of lung cancer, as shown by hazard ratios (HRs) with 95% CIs. Detailed medical record and pathological reviews were done on the National Taiwan University Hospital (NTUH) patient cohort to validate the national cohort study results. The national lung cancer incidence rate was used as reference incidence rate in the validation cohort.

Results:
A total of 88,439 patients were diagnosed with female breast cancer between 2000-2011 in the national cohort. The HR for subsequent lung cancer was 1.27 (95% CI, 1.09-1.48). When stratified by age, the HR was 5.29 (95% CI, 2.26-12.4) in the patients aged less than 40 years, 1.67 (95% CI, 1.18-2.30) in the group aged 40-49, 1.27 (95% CI, 0.97-1.67) in the group aged 50-59, 1.09 (95% CI, 0.81-1.49) in the group aged 60-69, and 0.70 (95% CI, 0.48-1.02) in the group older than 70 years. A total of 13,517 primary female breast cancer patients were identified in the NTUH electronic medical record system between 2006-2015. The incidence rate ratio for second primary lung cancer was 16.08 in the patients whose primary breast cancer was diagnosed at age younger than 50 years and 1.43 for those diagnosed at age older than 50 years. These results supported the national cohort study findings that early-onset female breast cancer patients bear a relative high risk for second primary lung cancer.

Conclusion:
Our findings suggest a relative high risk for second primary lung cancer among patients whose primary female breast cancer is diagnosed at age less than 50 years.

Abstract not provided

Background:
NLST was the first RPT to demonstrate a significant LC mortality reduction, when comparing CT to CXR-screening. Consequently, CT-screening is now being incorporated into clinical practice. Nonetheless, questions about the value of CT-screening remain given costs of CT and workup of false-positives. A prior cost-effectiveness analysis of CT-screening using NLST data concluded that CT was generally cost-effective (NEJM:371,1793,2014). That analysis was performed under the assumption that CXR-screening only added costs without benefit. In an independent analysis of PLCO comparing CXR to no screening, we found that CXR-screening is associated with a highly significant LC survival advantage. This benefit was unrelated to conventional screening biases, including overdiagnosis. As CXR is less expensive than CT with a lower false-positive rate, its cost-effectiveness relative to CT should be assessed. Data from PLCO and NLST allows comparison of no screening, CXR, and CT.

Methods:
Costs of screening, diagnostic studies, and LC treatment were calculated based on original PLCO and NLST trial data obtained from NCI. These were estimated in 2015 US dollars from the Medicare perspective. Outpatient costs were calculated using the Medicare-2015B fee schedule. Inpatient costs were calculated using a national payment average by assigning a DRG based on procedures performed. Survival data was generated using the Kaplan-Meier method for each study and mean survival was calculated using available data. These estimates were used to calculate incremental cost per life-year gained The NLST-eligible subset of PLCO was also used to facilitate comparison of no screening, CXR, and CT.

Results:
Analysis of PLCO data demonstrate that CXR compared to no screening was associated with a gain of 0.0152 life-years per person at an additional cost of $244 per-person for a cost per-life-year gained of $19,175. In the NLST-eligible subset of PLCO, CXR cost an additional $350 with a gain of 0.0262 life-years per-person for a cost-per-life-year gained of $13,377. In NLST, CT compared to CXR cost an additional $1,181 per-person and with a gain of 0.0157 life-years per-person, or $75,180 per-life-year gained. Using the NLST-eligible subset of PLCO for comparison, the ratio for CT compared to no screening was $36,552.

Conclusion:
CT-screening is both effective and cost-effective and represents the optimal method of screening for LC. However, the survival advantage associated with CXR-screening in comparison to no screening and relatively low cost make CXR a reasonable alternative to CT-screening, particularly in regions of the world where cost and availability limit access to CT-screening.

Background:
The National Lung Screening trial (NLST) showed that screening with low-dose computed tomography (CT) compared with chest radiography reduced lung-cancer mortality. There is very few data's on subjects with occupational abestos exposure. We examined the cost-effectiveness of CT lung cancer screening in a french cohort of abestos post professional exposure subjets (APEXS cohort).

Methods:
We estimated mean lif-years, costs and incremental cost-effectiveness ration (ICER) for screening with low-dose CT compare to no screening in this population of abestose exposed subjects. Estimations of life-years gained were based on the efficacy of NLST trial aplpied to APEXS cohort, adjusted to sex and age. Costs were limited to directs costs, from the payer perspective. We also performed sensitiviy analysis based on several assumptions of screening program efficacy.

Results:
Compared with no screening, screening with low-dose CT, over a period of 2 years, will cost, for 1000 subjects of APEXS cohort 312 645 €, will provide 9.4 additional life-years. The corresponding ICER was 33 102 € per life-gained. Sensitiviyt analysis showed that this result is sensitive to screening program efficacy (number, stage, and survival diagnosed by the program).

Conclusion:
ICER of low-dose CT lung cancer program in a cohort of abestos post occupational exposure population appears as acceptable from the French health system.

Abstract not provided

Background:
Cancer-related mortality can be measured by two disparate methods: relative survival (RSR, observed survival of cancer patients versus expected survival of a matched population), and cause-specific survival (CSS, based on lung-cancer-specific mortality among cancer patients). Both are vulnerable to biases: RSR depends on a comparable reference population, while CSS relies on accurate cause-of-death coding. Regardless, RSR is more common in population-based studies as the cause of death is uninvolved. We apply both methods to the same dataset to assess their implications among early-stage NSCLC.

Methods:
Outcomes of patients diagnosed with stage I/II NSCLC (2000-2013) were obtained from the SEER registry. Five-year cumulative incidence of death (CID) is estimated by competing risk approach. Population-level mortality was extracted from the National Center for Health Statistics. The actuarial survival were summarized as RSR (Ederer II) and CSS, stratified by age at diagnosis and stage. In addition, the sensitivity of the methods is assessed by including patients with unknown cause of death in CSS (CSS-2).

Results:
Analyses included 15792 age <60 and 70789 age 60+ patients, with stage I (81%) or II NSCLC. Death with unknown cause was 5% of all deaths; 5-year CID for lung-cancer, other-known and other-unknown deaths were 43%, 14% and 2%. Lung-cancer 5-year CID increased with age, from 22% (age <44) to 47% (age 75+) among stage I, and 44% to 68% among stage II. CSS were greater than RSR in all cases. Although the bias was negligible for 1-year follow-up, the deviation increases with increasing age and years of follow-up. The estimated CSS-2s were always between RSR and CSS, suggesting that RSR underestimates the true lung-cancer-survival.

Conclusion:
In practice, RSR is appropriate for short follow-up and aggregate summaries, while caution is advised when reporting RSR by age groups for longer follow-up. Accurate assessment of the causes of death may alleviate such biases.Figure 1

Background:
United States Preventive Services Task Force (USPSTF) and Centers for Medicare & Medicaid Services (CMS) recommendations for annual screening for lung cancer with low dose CT (LDCT) scans rely on age and smoking history to identify those at high risk for lung cancer. The Tammemagi et al. six year lung cancer risk prediction model, PLCOm2012, developed and validated in large lung cancer screening clinical trials, demonstrated good predictive performance in study participants. A 1.51% PLCOm2012 risk threshold has been reported to outperform CMS/USPSTF entry criteria. This is the first time the model predictive performance has been evaluated in clinical practice.

Methods:
Predictive performance of a reparameterized (no education predictor variable) six year lung cancer risk prediction model, PLCOm2012noEd, was retrospectively assessed in 2297 consecutive individuals that underwent clinical CT lung screening between January 1, 2012 and November 30, 2015. All patients met the National Comprehensive Cancer Network (NCCN) Lung Cancer Screening Guidelines Group 1 or Group 2 high-risk criteria.

Results:
79 cancers were detected in the 2297 screened individuals with a mean follow-up of 2.12 years (75.9% (60/79) – NCCN Group 1). The model six year mean risk for lung cancer was higher for participants with lung cancer, 4.71%, as compared to those without lung cancer, 3.54% (p=0.008). Area under the curve (AUC) of the receiver operator characteristics (ROC) was 0.635 (95% CI 0.577 – 0.693). At the 1.51% predicted risk recommended screening threshold overall sensitivity = 86.1%, specificity = 29.8%, and PPV = 4.2%. For NCCN Group 1 (similar to CMS/USPSTF entry criteria), sensitivity = 91.7%, specificity = 20.7% and PPV = 4.04%. For NCCN Group 2 (younger, lighter smoking history, no limit on time quit with one additional risk factor) mean predicted risk for participants with lung cancer was 2.35% as compared to 1.83% for those without lung cancer but the difference was not statistically significant; p=0.2374. As the incidence of lung cancer was the same in NCCN Group 2 and NCCN Group 1 (3.24% vs 3.51%; p=0.8566) the sensitivity of the model for NCCN Group 2 at the recommended 1.51% screening threshold was reduced to 68.4% with a specificity of 56.3%.

Conclusion:
Lung cancer risk prediction model, PLCOm2012noEd demonstrated reduced sensitivity in individuals meeting NCCN Group 2 high-risk criteria undergoing clinical CT lung screening and may not be appropriate to adequately assess risk of lung cancer in this population.

Background:
Evidence from a variety of settings indicates the presence of socioeconomic differences not only in the risk of developing cancer, but also in management and outcomes. We examined the influence of educational level on stage at presentation, management and mortality in patients with non-small cell lung cancer (NSCLC) in Sweden, a country with a National Health System aiming to provide medical care on equal terms to all residents.

Methods:
We identified 24,385 patients with a NSCLC diagnosis 2002-2011 in Lung Cancer Data Base Sweden, a research database generated by record linkage between the Swedish National Lung Cancer Register and several other population-based registers. In analyses adjusted for comorbidity and other prognostic factors, ORs and HRs were estimated to examine associations between patients´ educational level and aspects of management and mortality.

Results:
Diagnostic intensity CT Thorax, CT upper abdomen and transthoracal biopsy were more commonly performed in patients with high education. In multivariable analysis, the likelihood to undergo PET scan and EGFR testing was significantly higher in patients with high compared to low education OR 1.39 (95% CI 1.23-1.57) and 1.28 (95% CI 1.05-1.55), respectively. No social gradients in EGFR testing was observed in an analysis restricted to non-smoking patients with adenocarcinoma. Stage and histopathology Stage at diagnosis did not differ between educational groups. Adenocarcinomas were proportionally more common in patients with high compared to low education, both in all patients (61.9% vs 53.9%) and among non-smokers (50.7% vs 46.7%). Waiting times There were no differences in waiting times between dates of referral and diagnosis, or between dates of diagnosis and start of treatment. Multidisciplinary conference and treatment intensity The odds for treatment decisions being made in a multidisciplinary setting was higher for patients with high compared to low education (OR 1.26; 95% CI 1.04-1.51). In stage IA-IIB disease, the likelihood to undergo surgery was non-significantly elevated in patients with high education (OR 1.26; 95% CI 0.98-1.63). Mortality In early stage disease, high education was associated with lower all-cause (HR 0.79; 95% CI 0.70-0.89) and cause-specific mortality (HR 0.76; 95% CI 0.66-0.88) after adjustment for treatment, sex, age, region, year, comorbidity, smoking, stage, histology and performance status.

Conclusion:
We found evidence of social gradients in diagnostic and treatment intensity in patients with NSCLC. While there were no difference in stage at diagnosis between educational groups, a lower mortality in early stage NSCLC was observed in patients with high education.

Abstract not provided

Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present updated safety and efficacy data, including survival, for patients with ED SCLC enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.

Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and overall survival (OS).

Results:
24 patients with ED SCLC and tumor PD-L1 positivity were enrolled and received ≥1 dose of pembrolizumab. At the data cutoff date (June 9, 2016), median follow-up duration was 9.8 months (range, 0.5-24.0 months); 3 patients (12.5%) remain on treatment. The ORR was 37.5% (95% CI, 18.8%-59.4%), including 1 complete and 8 partial responses in 24 evaluable patients. Median duration of response was 9.0 months (range, 1.9-19.9+ months). Median PFS was 1.9 months (95% CI, 1.7-5.9 months); the 6- and 12-month PFS rates were 29.8% and 24.8%, respectively. Median OS was 9.7 months (95% CI, 4.1 months-not reached); the 6- and 12-month OS rates were 66.0% and 35.7%, respectively. No new safety concerns were noted. Sixteen of 24 (66.7%) patients experienced treatment-related AEs. Two patients experienced grade 3-5 treatment-related AEs: 1 patient had blood bilirubin increased (grade 3) and 1 patient experienced grade 3 asthenia and grade 5 colitis.

Conclusion:
Pembrolizumab demonstrated promising antitumor activity in this pretreated, PD-L1–positive ED SCLC population. The responses were found to be durable and may have led to an OS benefit for the subset of patients who achieved objective responses with pembrolizumab.

Background:
While the majority of small cell lung cancer (SCLC) patients succumb to their disease within a few months, there is a small group of patients who survive for many years after their diagnosis. Factors contributing to the SCLC long-term survivorship remain largely unknown. Herein, we compared tumors from exceptional survivors (EXS) and patients with the expected outcome (EOP) to determine genomic and immunological determinant of SCLC survivorship.

Methods:
In the Mayo Clinic tissue registry, we identified surgical blocks from 12 EXS who survived > 4 years after surgery and 14 EOP who died < 2 years of surgery. These cohorts were created to have no statistical differences in clinical TNM stage, curative versus non-curative intent surgery, age, gender, and smoking status between EXS and EOP. Tumor areas were macro-dissected for gene expression profiling by the Human Transcriptome Array (Affymetrix). Also, tissue sections were stained for key immunological markers, including CD8, CD4, CD3, CD279, FoxP3, CD138, CD20, CD21, CD14, CD68, and also LYZ. Concentrations of immune cells in intra-tumor areas (IE), stroma (ST), and tumor/non-tumor interface (IF) were assessed by an image processing program (Aperio). Staining patterns in each of the three zones in EXS and EOP tumors were compared.

Results:
More than 90% of differentially expressed genes were over-expressed in EXS compared with EOP. Furthermore, over 75% of the known over-expressed genes were either immunoglobulin or MHC related and a majority of the remaining genes were immune function related such as cytokines. We then performed IHC for key immunological markers and found significantly higher concentration of immune cells including CD8 and PD-1 positive cells in the tumor microenvironment, especially at the tumor stromal interface in EXS compared with EOP (p < 0.005 for both markers). Furthermore, the total number of infiltrating immune cells (T-cells, B-cells, Plasma cells, monocytes and macrophages was significantly higher in EXS in the interface region (p < 0.0005).

Conclusion:
Gene expression profiling revealed that anti-tumor immunity is an important factor for SCLC survival. Further studies by IHC suggested the presence of immune cells especially cytotoxic T-cells in the tumor microenvironment and particularly at the tumor-stromal interface to be major contributors to long term survivorship in SCLC. These findings suggest that immunotherapeutic strategies may be effective for patients with SCLC.

Background:
SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.

Methods:
Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.

Results:
Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop

Conclusion:
Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.

Abstract not provided

Background:
Alisertib, an investigational selective Aurora A kinase inhibitor, showed single-agent antitumor activity in preclinical in vivo SCLC models and was synergistic with paclitaxel in this setting. We report the efficacy, quality of life (QoL), and safety from this study.

Methods:
Patients ≥18 years with SCLC relapsed <180 days after standard first-line platinum-based chemotherapy were randomized 1:1 to alisertib 40 mg orally twice-daily on days 1–3, 8–10, 15–17 + paclitaxel 60 mg/m[2] IV on days 1, 8, 15 (Arm A) or matched placebo + paclitaxel 80 mg/m[2] (Arm B) in 28-day cycles. Patients were stratified using an interactive voice response system (IVRS) by type of relapse post-frontline platinum (sensitive vs resistant/refractory) and presence/absence of brain metastases at baseline. Protocol Amendment 2 corrected the definition for relapse per standard guidance; stratification factors were corrected accordingly. Primary endpoint was progression-free survival (PFS) per stratified log-rank test. QoL outcomes were assessed per EORTC QLQ-C30 and -LC13.

Results:
178 patients were randomized, 89/89 to Arm A/B (median age 62/62 years). Survival, response, QoL, and safety results are presented in the Table. The analysis of PFS using IVRS stratification favored Arm A, as did the analysis per corrected stratification factors. Mean EORTC QLQ-C30 QoL scores were similar between arms, as were mean change-from-baseline values at end of treatment (-5.7 in Arm A vs -4 in Arm B). Figure 1



Conclusion:
Alisertib + paclitaxel shows favorable PFS over placebo + paclitaxel with both initial and updated IVRS stratification. A similar favorable trend was also observed for OS and ORR although not statistically significant. Comparable changes in QoL scores were observed from baseline in both arms. The alisertib + paclitaxel arm showed higher rates of AEs and discontinuation due to AEs. Updated survival analyses are pending.

Background:
A significant proportion of limited-stage small cell lung cancer are elderly. However, there is paucity of data on the efficacy and safety of concurrent chemo-radiotherapy in the elderly to guide treatment decision-making.

Methods:
Data from the CONVERT trial was retrospectively analysed to compare the outcome of patients 70 years or older to patients younger than 70 years. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks or 66Gy in 33 once-daily fractions over 6.5 weeks starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by Prophylactic Cranial Irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy.

Results:
Of 547 patients randomised between April 2008 and November 2013, 57 patients were excluded for the purposes of this analysis as they did not receive concurrent chemo-radiotherapy. Of the 490 included patients, 67 (13.7%) were age 70 years or older with median age of 73 years (70-82). Patients’ characteristics were well balanced apart from more male in the elderly group (p=0.02). There was no significant difference in the number of chemotherapy cycles administered in the two groups (p=0.24). A higher proportion of patients received 30 or 33 fractions of radiotherapy as per protocol in the younger group (85% vs. 73%; p=0.03). Neutropenia grade 3/4 occurred more frequently in the elderly group (84% vs. 70%; p=0.02) but there was no statistically significant difference in neutropenic sepsis (4% vs. 7%; p=0.07) and non-haematological acute/late toxicities. There were two vs. six treatment-related deaths in the elderly and younger group respectively (p=0.67). At median follow up of 46 months for those alive; two-year survival was 53% (95% CI 41-64) vs. 57% (95% CI 52-61), median survival was 29 months vs. 30 months in the elderly vs. younger group respectively. Hazard ratios for overall survival and progression free survival were 1.15 (95% CI 0.84-1.59; log-rank p=0.38) and 1.04 (95% CI 0.76-1.41; log-rank p=0.81) respectively. In the elderly group median survival was not significantly different in patients who received once vs. twice daily radiotherapy (p=0.91).

Conclusion:
Radiotherapy treatment delivery was higher in the younger group but toxicity and survival rates were similar in elderly compared to younger patients. Concurrent chemo-radiotherapy with modern radiotherapy techniques is a treatment option for elderly patients with good performance status.

Background:
Circulating tumour cells (CTCs) are prevalent in patients with small cell lung cancer (SCLC) (Hou et al. JCO 2012) but their clinical utility is not known for patients with limited disease (LD) who receive concurrent chemoradiation. Here we report on a patient subgroup who underwent CTC analysis and treatment on the Concurrent ONce-daily (OD) VErsus Twice-daily (BD) RadioTherapy (CONVERT) trial (Faivre-Finn Proc. ASCO 2016) that demonstrated a non-significant difference in the primary endpoint of two-year survival for the OD (51%) and BD (56%) arms.

Methods:
Blood samples (7.5mls) were collected at baseline, prior to any treatment from patients who were enrolled to the CONVERT trial at The Christie Hospital site, Manchester, UK. CTCs were enumerated prospectively using the Cellsearch platform. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks (Arm 1) or 66Gy in 33 once-daily fractions over 6.5 weeks (Arm 2) starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by prophylactic cranial irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy. Staging by Positron Emission Tomography (PET) was permitted. Standard statistical methods were used to examine associations between CTC number (CTC#), clinical factors and outcomes.

Results:
Of 547 patients randomised between April 2008 and November 2013, 79 patients (41 in Arm1 and 38 in Arm 2) underwent CTC enumeration (CTC subgroup). The clinical demographics and median overall survival (OS) of the CTC subgroup did not differ significantly from the overall study population. The median number (range) of CTCs per 7.5mls blood for all 79 patients was 1 (0-3750) and for arm 1 and arm 2 patients respectively, 12 (0-164) and 158 (0-3750) (p=0.495). There was a trend for association of CTC# with higher TNM stage. CTC# was significant for survival in univariate and multivariate analysis. The median (95% CI) OS for ≥15 CTCs (n=18) was 6.01 (4.2-11.5) months compared to 30.77 (19.7-39.3) months for < 15 CTCs (n=61), p <0.001. The positive predictive value of CTC# ≥15 for survival ≤ 2 years is 100%, and ≤ 1 year is 72%. CTC# also predicted for worse outcome in patients who had undergone PET staging.

Conclusion:
CTC# is highly prognostic for poor survival in patients with LD-SCLC, treated with concurrent chemoradiotherapy, and could aid treatment decision making for this disease.

Abstract not provided