Virtual Library

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    ES02 - Quality Care in Lung Cancer (ID 770)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Nursing and Allied Professionals
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 206 BD
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      ES02.01 - Expanding PROs in Daily Practice (Now Available) (ID 11356)

      10:30 - 10:45  |  Presenting Author(s): Kahren White

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer remains the leading cause of cancer deaths internationally (1). There have been recent improvements in the early diagnosis of lung cancer, with the implementation of lung cancer screening programs in a number of countries and the addition of targeted therapies, which may improve progression free survival for some patients. However, mortality remains high and people living with a lung cancer diagnosis have some of the highest symptom burden experienced across all cancer diagnoses (1,2).

      Patient reported outcome measures (PROs) can be defined as “any report on the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else” (3). PROs have been systematically embedded into clinical trials to track side effects and to measure the health related quality of life (HRQOL) of participants. Internationally we are seeing the use of PROs moving into daily clinical practice (4, 5). What are the benefits of using PROs in clinical practice and can they be introduced and embedded into daily practice?

      PROs can allow patients to highlight to their health care team their current physical and psychosocial issues. In a short clinic appointment with a health care provider the patient may not feel there is time to discuss the most important issues that are affecting them. The health care professional may not ask to right questions to understand the key issues for that person at that time in the context of a short clinic appointment. What is an issue for the patient may not be what the health professional perceives is an issue, leading to barriers in providing truly patient centred care and ensuring shared decision making (6). The utilisation of PROs prior to a clinic appointment can facilitate the therapeutic conversation to ensure the main issues for the patient are addressed at that time.

      The use of PROs recorded directly into the electronic health record can facilitate communication with the health care team through the receipt of notifications about patient symptoms and function. This can facilitate the management of patient’s symptoms in real time, also allowing for the review longitudinal data about a patients PROs over time (7). An RCT into systematic electronic collection of PROs during chemotherapy treatment with automated health care professional e-alerts found the intervention group had better HRQOL, fewer emergency visits and hospitalisations, as well as improved quality-adjusted survival (8).

      The European Organisation for Research and the Treatment of Cancer (EORTC) QLQ-C30 and the Functional Assessment of Cancer Therapy (FACT-G) are two of the most commonly used general PROs. Both of these PROs have lung cancer subscales, with questions developed and validated for the lung cancer population. In New South Wales, Australia the Edmonton Symptom Assessment Scale (ESAS) and the Hospital Anxiety and Depression Scale (HADS) are being piloted for collection electronically into oncology medical information systems across the state as part of the state-wide collection of PROs in a number of chronic health conditions. Information from these scales will be available for health professionals at the point of care and will also be linked to the NSW Cancer Registry to allow for longitudinal analysis of PROs with specific cancer treatment protocols. The International Consortium for Health Outcomes Measurement (ICHOM) have also developed a lung cancer standard set, using the EORTC QLQ-C30 and EORTC QLQ-LC13 as measures of the degree of health for people with a lung cancer diagnosis (9).

      With the increasing use of technology, linked e-health records and the understanding of the benefit of the use of PROs in clinical practice cancer centres should be implementing PROs as standard practice in clinical care. This will ensure health care professionals are able to identify and address physical and psychosocial issues for people living with lung cancer at the point of care.

      References:

      1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer. 2015;136(5):E359-86.

      2. Mohan A, Singh P, Singh S, Goyal A, Pathak A, Mohan C, et al. Quality of life in lung cancer patients: impact of baseline clinical profile and respiratory status. Eur J Cancer Care (Engl). 2007;16(3):268-76.

      3. U.S. Department of Health and Human Services. Guidance for industry patient-reported outcome measures: Use in medical product development to support labeling claims. Silver Spring, MD: Food and Drug Administration; 2009.

      4. Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013;13:211.

      5. Girgis A, Durcinoska I, Levesque JV, Gerges M, Sandell T, Arnold A, et al. eHealth System for Collecting and Utilizing Patient Reported Outcome Measures for Personalized Treatment and Care (PROMPT-Care) Among Cancer Patients: Mixed Methods Approach to Evaluate Feasibility and Acceptability. Journal of Medical Internet Research. 2017;19(10):e330.

      6. Büttner M, Zebralla V, Dietz A, Singer S. Quality of Life Measurements: Any Value for Clinical Practice? Current Treatment Options in Oncology. 2017;18(5):30.

      7. Basch E. Patient-reported outcomes - Harnessing patients' voices to improve clinical care. New England Journal of Medicine. 2017;372(2):105-8.

      8. Basch E, Deal AM, Kris MG, Scher HI, Hudis CA, Sabbatini P, et al. Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(6):557-65.

      9. International Consortium for Health Outcomes Measurement. Lung cancer data collection reference guide. International Consortium for Health Outcomes Measurement; 2017.

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      ES02.02 - PRO: To Medicate: Managing Breathlessness (Now Available) (ID 11357)

      10:45 - 11:00  |  Presenting Author(s): Alexandre Chan

      • Abstract
      • Presentation
      • Slides

      Abstract

      Breathlessness is a severe symptom that is associated with suffering at end of life. Moderate to severe breathlessness is observed in 20-80% advanced cancer patients, and this symptom is considered as a poor prognostic factor. Currently, opioids (such as morphine) are widely used as first line treatment for reducing the severity of breathlessness in advanced cancer patients. In this session, I will discuss the clinical evidence, involving both efficacy and safety aspects, supporting the routine use of opioids for managing breathlessness.

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      ES02.03 - CON: Not to Medicate: Managing Breathlessness (Now Available) (ID 11358)

      11:00 - 11:15  |  Presenting Author(s): Catherine L Granger

      • Abstract
      • Presentation
      • Slides

      Abstract

      This presentation will discuss dyspnoea in lung cancer with a focus on non-pharmacological management strategies. Lung cancer is associated with high disease burden and physical hardship. People with lung cancer experience complex symptoms, which can include dyspnoea, fatigue, cough and pain. In lung cancer, multimorbidity is also common, particularly chronic obstructive pulmonary disease (COPD) which is seen in 40-70% of patients, and itself is also associated with chronic dyspnoea.

      Dyspnoea is the “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity and vary in their unpleasantness and in their emotional and behavioral significance” [1, 2]. It is common in lung cancer, affecting up to 60% of patients. It varies in intensity and is associated with significant unpleasantness [3]. A recent systematic review found that the distress associated with dyspnoea in lung cancer is variable, and there does not appear to be a relationship to disease stage [3]. There are a wide variety of instruments available to measure dyspnoea. It is recommended that assessment includes intensity and sensory quality, distress or unpleasantness, and impact on health-related quality of life [1].

      Dyspnoea results in an emotional response and functional consequences [4], including distress and interference with daily activities [5]. Avoidance of triggers, including avoiding physical activity, promotes a vicious cycle of inactivity and functional decline [6]. Whilst the initial focus of managing dyspnoea is to optimise medical and pharmacological management of the underlying lung cancer and comorbid conditions, if dyspnoea persists, there are a range of non-pharmacological strategies that can be considered.

      There is high level evidence that pulmonary rehabilitation reduces dyspnoea in chronic respiratory diseases, particularly COPD and interstitial lung disease [7]. Similarly, in chronic heart failure, cardiac rehabilitation is also effective at reducing dyspnoea [7]. These outpatient-based exercise rehabilitation programs usually run for 6 to 12 weeks in duration, and include aerobic and resistance exercise training, education and behaviour change. They are associated with reduced self-reported dyspnoea, reduced exertional dyspnoea during exercise, and improved exercise tolerance [1]. The mechanisms in which exercise is thought to reduce dyspnoea in these settings is through system efficiency, reduced dynamic hyperinflation and reduced sensitivity to dyspnoea.

      There are a range of other strategies for dyspnoea which have been used in a variety of conditions. For short term relief, there is high level evidence for the use of chest wall vibration or walking aids (such as walking frames) [8]. Other strategies, with lower-level or unclear evidence, include breathing exercises (such as pursed lip breathing, breathing control and inspiratory muscle training), music, hand-held fans and acupuncture [8].

      Specifically in lung cancer there is less research regarding non-pharmacological interventions for dyspnoea. In lung cancer, there is growing evidence supporting the role of pulmonary rehabilitation to improve a number of patient outcomes including exercise capacity, muscle strength and fatigue [9]. Studies consistently demonstrate that pulmonary rehabilitation can be applied safely and effectively at all stages of disease [9]. In terms of improving dyspnoea, pulmonary rehabilitation and exercise programs have been shown to be effective, however the impact on dyspnoea has only been studied in a small number of studies to date [10].

      Complex interventions for dyspnoea in lung cancer have been successfully tested in a small number of randomised controlled trials. These interventions use a combination of techniques such as patient and carer education, breathing control, activity pacing, relaxation techniques, hand-held fans, psychosocial support and multi-disciplinary input, and are run through nursing or breathlessness clinics.

      Despite promising evidence regarding the use of non-pharmacological interventions for dyspnoea in lung cancer, these have not been sufficiently implemented into practice [4]. A number of barriers exist including lack of funding for services, the current structure of the multi-disciplinary team, and the need for adequate staff training [4]. Further work is needed to look at how such services can be embedded into lung cancer care.

      References

      1. Parshall, M., et al., An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med, 2012. 185(4): p. 435-52.

      2. Banzett, R., et al., Multidimensional Dyspnea Profile: an instrument for clinical and laboratory research. Eur Respir J, 2015. 45(6): p. 1681-91.

      3. Kathiresan, G. et al., Dyspnea in lung cancer patients: a systematic review. Lung Cancer, 2010. 1: p. 141-150.

      4. Johnson, M. and D. Currow, Treating breathlessness in lung cancer patients: the potential of breathing training. Expert Review of Respiratory Medicine 2016. 10(3): p. 241-243.

      5. Cheville, A., et al., The value of a symptom cluster of fatigue, dyspnea, and cough in predicting clinical outcomes in lung cancer survivors. Journal of Pain and Symptom Management, 2011. 42(2): p. 213-221.

      6. Granger, C., et al., Low physical activity levels and functional decline in individuals with lung cancer. Lung Cancer, 2014. 83(2): p. 292-299.

      7. Man, W., et al., Building consensus for provision of breathlessness rehabilitation for patients with chronic obstructive pulmonary disease and chronic heart failure. Chronic Respiratory Disease, 2016. 13(3): p. 229-239.

      8. Bausewein, C., et al., Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane Database Syst Rev, 2008(2): p. Cd005623.

      9. Granger, C., Physiotherapy management of lung cancer. Journal of Physiotherapy, 2016. 62(2): p. 60-67.

      10. Bade, B., et al., Increasing physical activity and exercise in lung cancer: reviewing safety, benefits, and application. J Thorac Oncol, 2015. 10(6): p. 861-71.

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      ES02.04 - Molecular Testing 101 for Nurses (Now Available) (ID 11359)

      11:15 - 11:30  |  Presenting Author(s): Beth Eaby-Sandy

      • Abstract
      • Presentation
      • Slides

      Abstract

      Molecular testing in NSCLC is now a standard of care for newly diagnosed non-squamous NSCLC. There are guidelines detailing the appropriate population to test and which tests should be preformed. However, several barriers exist to testing including both medical as well as administrative, making testing rates less than optimal. Several testing platforms exist, and vary internationally.

      Other challenges for nurses include interpretting the testing results and relaying appropriate information to patients. Also, counseling patients on the value of waiting for results of testing prior to starting therapy can be difficult, and is often performed by the oncology nurse. Utilization of a clinical tissue navigator can make this process more seamless and ensure testing is performed.

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      ES02.05 - Structured Approach For Developing and Implementing and Advanced Practice Nursing Role in Lung Cancer (Now Available) (ID 11360)

      11:30 - 11:45  |  Presenting Author(s): Andrea Serena  |  Author(s): Solange Peters, Manuela Eicher

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background: Lung cancer patients experience significant physical symptoms, psychological distress and have many supportive care needs impacting their quality of life. In recognition of the complex health needs of patients with lung cancer and the European Partnership for Action Against Cancer recommendations, the University Hospital of Lausanne (CHUV) (Switzerland) aimed to integrate an Advanced Practice Nurse in Lung Cancer (APNLC) within the specialized Multidisciplinary Team (MDT) of the Thoracic Cancer Center. To date, there are limited data on the effectiveness of APNLC interventions for improving lung cancer patient outcomes. Introducing a new Advanced Practice Nursing (APN) role is a complex process and the full integration of this role depends both on successful role development and implementation. International recommendations for developing APN roles recommend pilot testing to assess the feasibility and acceptability of novel APN roles prior to formally assessing the effectiveness of the these roles for patients, providers and organizations. This study aimed to 1) develop and implement an APNLC role within the context of the CHUV Thoracic Cancer Center, 2) explore the acceptability of the new APNLC role from the perspective of a MDT and patients cared for by the APNLC, 3) assess the feasibility of the APNLC consultations and the ability to collect patient-reported outcome measures (PROMs) during first-line treatment, 4) describe changes in self-efficacy for managing lung cancer-related symptoms, symptom intensity/burden and unmet supportive care needs of APNLC patients during first-line treatment.

      Methods: To develop and implement the APNLC role we employed the first 7 phases of the “The Participatory, Evidence-based, Patient-focused process for APN role development, implementation, and evaluation” (PEPPA framework). Focus groups were conducted with nurses (n=5 nurses) and physicians (n=6 physicians) to explore the acceptability of the APNLC role. Additionally, semi-structured interviews were conducted with lung cancer patients (n=4) and the APNLC. The others aims were addressed using a convenience sample of newly diagnosed lung cancer patients receiving systemic therapy with/without radiotherapy. In order to assess the feasibility of the APNLC consultations and the ability to collect PROMs, an exact single-stage phase II design was applied. The study was considered as feasible if at least 55% of patients received all the scheduled APNLC-led consultations and completed PROMs assessments at the three time-points [Baseline, T1 (between day 4-50) and T2 (between day 71-95)]. Descriptive statistics were used to summarize the data and mixed effect models was applied to explore changes in perceived self-efficacy for managing lung cancer-related symptoms, symptom intensity/burden and unmet supportive care needs during first-line treatment.

      Results: Following the first seven phases of the PEPPA framework, the APNLC role was designed based on consensus of key stakeholders within the MDT. The APNLC role focused on providing psychological support, enhancing symptom self-management as well as providing therapeutic education and information about disease/treatments to patients and families. The APNLC role is also tasked with facilitating communication and information exchange within the MDT to improve collaboration and promote continuity of care. The designed APNLC-led intervention included four systematic, alternate face-to-face/telephone consultations with lung cancer patients during first-line treatment. Three main themes emerged describing the acceptability of the APNLC role: “role identification”, “role-specific contributions” and “providing flexible service”. Physicians and patients alike clearly recognized the APNLC role and emphasized the contribution to continuity of care, providing psycho-social support and enabling symptom self-management. Oncology nurses within the MDT perceived the APNLC role as overlapping with their own role and they expressed concern about losing part of their traditional role. Flexibility in providing care was seen as strength of the APNLC role yet this also posed organizational challenges related to work-load. Among the 46 patients enrolled in the feasibility study, 35 met the feasibility criteria receiving the four APNLC consultations (76%, 95% CI: 0.61-0.87) and 26 completed PROMs assessments at the three timepoints (56%, 95% CI: 0.41-0.71). These initial findings were promising for the feasibility of APNLC consultations and the ability to collect PROMs during first-line treatment. Longitudinal analysis of patient outcomes showed a trend towards improved patient self-efficacy for managing symptoms between baseline and T1, which remained stable at T2. Notably, the intensity of predominant symptoms increased over time yet unmet information needs decreased significantly between baseline and T2 (OR= 0.15 [95% CI: 0.03-0.68] p<0.01).

      Discussion/Conclusions: For the first time in Switzerland, we describe the development process of an APNLC role within a multidisciplinary thoracic cancer team. Findings highlight the applicability and the utility of the PEPPA framework as a structured approach for developing and implementing new APNLC roles - particularly in the context of the Swiss health care system where APN roles are yet in early stages of development. Barriers identified during the implementation of the APNLC role were primarily related to intra-professional rather than inter-professional factors. In light of these observations of intra-professional tension, study results underscore the importance of developing a national definition of APN role and regulations guiding APN roles to support their expansion in the country and enhance acceptability of these roles. Initial results were promising in terms of feasibility suggesting that APNLC-led consultations were appropriate and perceived as beneficial for many patients. Indeed, implementation of the APNLC role in the MDT seems to contribute to the improvement and maintenance of patient’s perceived self-efficacy for managing symptoms and decreased unmet supportive care needs. However, to better support lung cancer patients in their symptoms self-management and decrease their symptom burden, findings of this research point to adjustments that could be made to improve the effectiveness of the APNLC role. First, we propose to adjust the dose of APNLC intervention by increasing the frequency and intensity of consultations. Second, we propose to develop an interdisciplinary approach involving joint APNLC-physicians consultations for managing complex lung cancer patients.

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    JTO - Meet the JTO Editor (ID 868)

    • Event: WCLC 2018
    • Type: Meet the JTO Editor
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 12:00 - 13:30, Room 206 BD
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      JTO.01 - Meet the JTO Editor (ID 12622)

      12:00 - 13:30  |  Presenting Author(s): Alex Adjei

      • Abstract
      • Slides

      Abstract not provided

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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.01 - PARP Inhibitor Radiosensitization of Small Cell Lung Cancer Differs by PARP Trapping Potency (Now Available) (ID 13358)

      15:15 - 15:20  |  Presenting Author(s): Benjamin H Lok  |  Author(s): James H Laird, Jennifer Ma, Elisa De Stanchina, John Poirier, Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.

      Method

      Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in six SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. The dose modification factor (DMF), defined as the ratio of RT dose needed to achieve an equivalent level of survival with RT alone compared to that for RT plus drug, was calculated at 37% survival. Phosphorylated gH2AX sub-nuclear foci were assessed by immunofluorescence to quantify double-stranded DNA breaks (DSBs). Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.

      Result

      Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays with a talazoparib dose of 20 nM demonstrating a DMF ranging from 1.61 – 2.88 in 4 cell lines with 0.2 nM demonstrating a DMF of 1.56 in 1 additional cell line. We confirmed radiosensitization in 3 of 3 cell lines by CSAs with DMF ranging from 1.40 – 2.20. To determine effects of PARP trapping on radiosensitization, we identified that concentrations of 200 nM talazoparib and 1600 nM veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization (DMF 3.3 with talazoparib vs DMF 1.0 with veliparib). This observation further correlated with an increased number of DSBs induced by talazoparib as compared to veliparib, where we found that talazoparib produced more residual DSBs than veliparib and DMSO with IR (gH2AX foci mean per cell: talazoparib 53.5, veliparib 33.5, DMSO 25.5) and without IR (40.0, 19.6, 14.6). Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.

      Conclusion

      PARP inhibition effectively sensitizes SCLC cell lines and PDXs to RT, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of RT in SCLC.

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      MA22.02 - Activation of MAPK Suppresses Neuroendocrine Transcription Factors and Causes Transdifferentiation of Small Cell Lung Cancer (Now Available) (ID 14051)

      15:20 - 15:25  |  Presenting Author(s): Yusuke Inoue  |  Author(s): William Lockwood

      • Abstract
      • Presentation
      • Slides

      Background

      Gene alterations involved in activating signaling through receptor tyrosine kinases/RAS/RAF/MEK/ERK pathway are extremely rare in small cell lung cancer (SCLC). In addition, EGFR expression is lost during the histological reprogramming of EGFR mutation-positive lung adenocarcinoma (LUAD) to SCLC, despite the cancer retaining the original EGFR mutation. These observations imply that signaling through mitogen-activated protein kinases (MAPKs) - critically important in non-small cell lung cancer - might be detrimental in SCLC biology. Here we investigated the impact of induction of two mutated oncogenic proteins, EGFRL858R and KRASG12V, the most common drivers of LUAD, on the phenotype and signaling profiles of SCLC.

      Method

      EGFRL858R or KRASG12V were aberrantly expressed in an inducible manner in three SCLC cell lines (H2107, H82, and H524). The effects of induction of these oncogenes were determined through cell viability analysis and Western blotting analysis particularly focusing on the regulation of master neuroendocrine transcription factors such as insulinoma-associated protein 1 (INSM1), POU class 3 homeobox 2 (BRN2), achaete-scute hologue 1 (ASCL1), and neurogenic differentiation factor 1 (NEUROD1). Genome-wide expression profiles were assessed in a longitudinal manner after oncogene induction and specific gene sets driven by MAPK activation in each SCLC cell line were defined.

      Result

      INSM1 and BRN2 were expressed in all the SCLC cell lines assessed. ASCL1 was expressed only in H2107 (classic type). Alternatively, NEUROD1 was expressed in the variant type SCLC cell lines, H82 and H524. Induction of mutant-EGFR or -KRAS resulted in different cell viability according to cell lines: H82 cells showed higher proliferation rate and the others showed lower proliferative ability. Furthermore, induction of these oncogenes caused transition from suspension to adherent phenotype in all the three cell lines. Importantly, EGFR/KRAS induction downregulated neuroendocrine transcription factors and these effects were more strongly observed after KRAS induction than after EGFR induction, which was concordant with the difference in degrees of phospho-ERK1/2 upregulation after induction of these mutant-oncogenes. Notably, treatment with SCH772984, an ERK1/2 inhibitor, rescued the repression of neuroendocrine factors by KRAS induction. Gene expression profiling is currently underway to reveal specific factors mediating ERK induced suppression of neuroendocrine programs.

      Conclusion

      Activation of the RAS/RAF/MEK/ERK pathway causes phenotypic transition in SCLC growing in suspension to the adherent phenotype and suppresses neuroendocrine differentiation. Thus, ERK signaling has an fundamental role in repression of neuroendocrine differentiation programs and may be important in regulating histological transversion of SCLC to and from NSCLC with implications to drug resistance.

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      MA22.03 - SCLC Circulating Tumour Cell Derived Explants: The Clinical Characteristics of Patients Whose Samples Generate CDX (Now Available) (ID 12969)

      15:25 - 15:30  |  Presenting Author(s): Alexander John Vickers  |  Author(s): Louise Carter, Melanie Galvin, Mathew Carter, Lynsey Franklin, Karen Morris, Jacqueline Pierce, Kristopher Frese, Fiona Blackhall, Caroline Dive

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) prognosis is dismal, with minimal improvement in recent years. Work with SCLC cell lines and targeted therapies have been disappointing when translated into clinical practice. Circulating tumour cells (CTCs) represent a readily accessible liquid biopsy, which can be used to generate CTC derived explants (CDXs) for the study of SCLC biology and the investigation of biomarkers and therapeutics. These clinically relevant models appear to mirror patient response to therapeutics. Our aim was to assess if the patients whose samples generated a CDX represent the SCLC population, and determine if the clinical features of these patients offer insight into CTC biology.

      Method

      This was a single centre, retrospective analysis of 147 SCLC patients who had participated in The CHEMORES Study in which SCLC patients were asked to donate blood samples for the discovery and validation of novel biomarkers. Paired patient blood samples were taken for CTC enumeration using CellSearch Technology and for attempted CDX model generation. We obtained demographic and clinical information on these patients, and analysed the data for differences between patients whose blood samples generated a CDX and those whose did not.

      Result

      231 paired blood samples were taken from 147 patients, with 45 CDXs successfully generated from 34 patients. CTC number was significantly higher in samples which generated a CDX than those which didn’t, p=0.001. Successful progression samples had a significantly lower CTC number than successful baseline samples, p=0.026. There was no significant difference in age, gender, pack year history, performance status, stage, chemosensitivity or the presence of liver or brain metastases between patients whose samples did and did not generate a CDX. Metastatic burden was significantly higher in patients whose samples generated a CDX, p=<0.001. Progression free (PFS) and overall survival were significantly shorter in patients whose samples generated a CDX, p=<0.001

      Conclusion

      CTC number correlates with CDX success, although a specific CTC phenotype may be more important. CTCs at progression may have a more aggressive phenotype than those at baseline. CDXs appeared to represent the SCLC population which is important when translating knowledge gained by studying CDXs into clinical practice. CTCs may play a role in the widespread metastatic dissemination of SCLC and thus survival of patients. Shortened PFS in the absence of difference in chemosensitivity may be due to outliers with particularly long PFS in the unsuccessful group. Further genomic and phenotypic analysis of subpopulations of CTCs may provide further insight.

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      MA22.04 - Discussant - MA 22.01, MA 22.02, MA 22.03 (Now Available) (ID 14617)

      15:30 - 15:45  |  Presenting Author(s): Céline Mascaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA22.05 - Impact of Tumor Spread Through Air Spaces (STAS) in Lung Neuroendocrine Tumors (NETs) (Now Available) (ID 14221)

      15:45 - 15:50  |  Presenting Author(s): Katsura Emoto  |  Author(s): Rania Gaber Aly, Takashi Eguchi, Kyuichi Kadota, Natasha Rekhtman, Kay See Tan, Prasad S. Adusumilli, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously reported the prognostic significance of STAS in lung adenocarcinoma and squamous cell carcinoma. The aim of this study was to investigate the incidence and prognostic impact of STAS in lung NETs.

      Method

      We evaluated all tumor slides (range 2-7, median 3) for presence of STAS from patients with p-Stage I-III primary lung NETs [n=628, typical carcinoid (TC, n=305), atypical carcinoid (AC, n=38), large cell neuroendocrine carcinoma (LCNEC, n=93) and small cell lung carcinoma (SCLC, n=57)]. Patients with combined NETs were excluded from this analysis (n=19). Cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were analyzed by competing risks approach.

      Result

      STAS was identified in 25% of NETs (15% in TC, 37% in AC, 43% in LCNEC, and 46% in SCLC). Prognostic analysis in TC cohort was not conducted due to the small number of events (<5 events). Patients with STAS positive tumors were associated with higher CIR than STAS negative tumors in the total (AC-LCNEC-SCLC) cohort as well as individual AC, LCNEC and SCLC cohorts (Figure 1, A-D). STAS was also associated with higher LC-CID in all cohorts except for AC (Figure 1, E-H). In multivariable analysis, STAS was a significant risk factor for recurrence and lung cancer specific-death, independent of stage and histologic subtype. Stratified by stage, STAS was an independent predictor of recurrence (subhazard ratio [SHR] 2.39, 95% CI 1.26-4.54, p= 0.007) and lung cancer-specific death (SHR 2.42, 95% CI 1.21- 4.84, p= 0.012) in LCNEC. In SCLC, STAS was also an independent risk factor of lung cancer-specific death (SHR 4.06, 95% CI 1.33- 12.35, p= 0.014).

      stas net figure abstract iaslc 2018 isa.jpg

      Conclusion

      STAS is a significant prognosticator in individual NET subtypes; AC, LCNEC, and SCLC. STAS is an independent poor prognostic factor in LCNEC and SCLC for lung cancer-specific death.

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      MA22.06 - Preinvasive Multifocal Neuroendocrine Lesions with Primary Typical Carcinoid Lung Tumors: A Negative Prognostic Factor? (Now Available) (ID 12432)

      15:50 - 15:55  |  Presenting Author(s): Niccolo Daddi  |  Author(s): Valentina Tassi, Elisa Scarnecchia, Frances Allison, Jacopo Vannucci, Rosanna Capozzi, Valeria Liparulo, Kazuhiro Yasufuku, Marc De Perrot, Andrew Pierre, Özgür Mete, Renato Colella, Stefano Ascani, Piero Ferolla, Gail Elizabeth Darling, Shaf Keshavjee, Francesco Puma, Thomas Kenneth Waddell

      • Abstract
      • Presentation
      • Slides

      Background

      Impact on survival in patients with surgically resected multifocal neuroendocrine lesions (MNET), such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) or tumorlets, along with primary typical lung carcinoid (TC) is unclear. Aim of this study is to analyze whether synchronous preinvasive multifocal neuroendocrine lesions of the lung with primary TC tumors (MTNET+TC) may represent a negative prognostic factor.

      Method

      A retrospective study, prospectively collected, for TC from two institutional databases was evaluated with a lifelong follow-up from surgery. Patients who did not receive surgery, underwent bronchial resection or lung transplant were excluded. Pathology specimens were all reclassified according the 2015 WHO and the eight AJCC Staging system. Kaplan-Meier(KM) method and Log-rank test reports significance between TC and were MTNET+TC were used. Hence a 1:1 propensity score matching analyses was done by adjusting the imbalance and comparing the overall survival and progression free rate between matched groups with a Cox proportional hazards regression model. A p value of 0.05 or less was considered significant.

      Result

      From January 1983 to December 2013 a total of 234 patients was outlined from the databases (TABLE). A total of 41 patients (17.5%) with MNET+TC were identified. Overall KM progression free survival achieved at 5 and 10 years respectively MNET+TC 93.2% and 83.8% compare to TC 98.4% and 96.1% (p =0.00039). Thirty-six MNET+TC were matched pairs vs. TC alone. Univariate Cox proportional hazards model for matched patients MNET+TC compared to TC was 2.78 (95% CI=0.84-9.3, p=0.095). Difference in progression free rate between matched groups was p<0.001.

      table_net_daddi.jpg

      Conclusion

      Synchronous multifocal neuroendocrine preinvasive lesions (MNET) with primary typical carcinoid (TC) lung tumors can be a negative prognostic factor. Careful search of MNET should be always performed in clinical and pathological staging of a suspected primary TC. The increased risk of progression of MNET+TC warrants an accurate and lifelong follow-up.

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      MA22.07 - Prognostic Value of Distant Organ-Specific Metastases in Newly Diagnosed Lung Neuroendocrine Tumors: A Population-Based Study (Now Available) (ID 12684)

      15:55 - 16:00  |  Presenting Author(s): Min Fan  |  Author(s): Junmiao Wen, Jiayan Chen, Di Liu, Xinyan Xu, Junhua Zhang, Yu Gu, Lv Huang

      • Abstract
      • Presentation
      • Slides

      Background

      Lung neuroendocrine tumors (Lung NETs) are rare neoplasms with inferior outcomes for patients with distant metastases. AJCC cancer staging system for the classification of NETs was first introduced in 2010. However, the prognostic impact of metastatic sites for lung NETs are poorly explored. We aimed to fill this gap of our knowledge using the SEER database.

      Method

      Clinical-pathological characteristics, specific metastatic sites and outcomes of stage IV lung NETs (according to AJCC 7th edition) were extracted from the SEER database from 2010-2014. Overall survival (OS) and Lung cancer-specific survival (LCSS) were estimated by the Kaplan-Meier method and comparisons conducted using log-rank tests and Cox regression models.

      Result

      A total of 2337 stage IV lung NETs patients were identified. The 5-year OS and LCSS were 10.7% and 18.3%, respectively. Among them, 2159 patients had specific organ metastases (liver, lung, bone or brain) at diagnosis. Liver was the most common metastatic site (1183, 50.6%), followed by bone (801,34.3%), lung (701,29.9%) and brain (616,26.4%). Patients with isolated lung metastases (1-, 5-year OS: 63.2%, 43.2%; 1-, 5-year LCSS: 74.0%, 62.9%,) had significantly better outcomes comparing to other patterns of metastases. The outcomes of patients with any brain metastases was most unfavorable (1-, 5-year OS: 20.3%, 2.1%, p<0.001; 1-, 5-year LCSS: 26.8%, 7.7%, p<0.001). Multivariate Cox regression analysis on OS and LCSS revealed that age > 60 years (p<0.001), male gender (p<0.001), poorer differentiation (p<0.001) and brain metastases (p<0.001) were independently poor prognostic factors for stage IV lung NETs patients.

      Conclusion

      The prognostic impact of metastatic site was unambiguous in stage IV patients with lung NETs. Comparing other metastatic patterns, brain metastases was associated with significant worse survival outcomes. Nearly twenty-fold difference in 5-year survival was revealed between isolated lung and brain metastases. For advanced lung NETs patients, brain metastases might be considered as a distinct category of dismal outcomes.

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      MA22.08 - Discussant - MA 22.05, MA 22.06, MA 22.07 (Now Available) (ID 14618)

      16:00 - 16:15  |  Presenting Author(s): Giuseppe Pelosi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA22.09 - Should Stereotactic Radiosurgery be Considered for Salvage of Intracranial Recurrence in Small Cell Lung Cancer? (Now Available) (ID 14092)

      16:15 - 16:20  |  Presenting Author(s): Brooklyn Mazure  |  Author(s): Neil Guest, Ariel Letcher, Sunita Ghosh, Zsolt Gabos, Karen P Chu, Brock Debenham, Tirath Nijjar, Diane Severin, Rufus Scrimger, Wilson Roa, Don Yee, Alysa Fairchild

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) remains a standard of care for small cell lung cancer (SCLC) to improve overall survival (OS) and prevent recurrence in limited (LS) and extensive stage (ES) disease. Intracranial recurrence (IC) after PCI affects 12-33%. Limited published data describe outcomes of salvage reirradiation (ReRT). Our purpose was to review outcomes after IC post-PCI or therapeutic whole brain radiotherapy (WBRT).

      Method

      Consecutive patients with pathologically-confirmed SCLC assessed (01/2013-12/2015) at a tertiary cancer centre (catchment 1.5M) were retrospectively reviewed. Demographics, treatment and outcomes were abstracted and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed.

      Result

      Median age was 66.1yrs, 53% female, and 80% ECOG 0-2 (N =372). Median survival (MS) was 24 months (95%CI 18.3-29.7 mos) for 103 LS, and 7 months (95%CI 6.1-7.9 mos) for 269 ES patients. 72/103 LS received PCI (69.9%), 84.7% of whom had radical thoracic radiotherapy (RT). 54/269 ES patients presented with brain metastases (BM); 98/215 of the remaining received PCI, and 72 of those thoracic RT (84.7% 25-30Gy/10). PCI dose was 25Gy/10 in 95.9%. PCI patients had better performance status (PS), and were more likely to receive chemotherapy (CT) and thoracic RT (all p<0.013). 18.8% (32/170) recurred post-PCI (13 LS; 19 ES) at a median of 11.5 mos. 45/54 presenting with BM received WBRT (83.3% 20Gy/5), 14 of whom recurred. MS after PCI was 28 mos vs 12 mos for LS and ES, respectively. For LS patients with IC post-PCI, MS was 20 mos vs 38 mos without IC (p=0.03). On MVA, interval between brain RT predicted OS after PCI (HR 0.87; p<0.001), while stage (HR 3.56; p=0.008) and cranial RT dose predicted IC (HR 0.65; p=0.047). At IC, 56.5% (26/46) had <5 BM, median 1.7cm (range 0.5-5cm), 39.1% had no extracranial disease, 6 were asymptomatic, and 50% had ECOG 0-2. 30/46 had ReRT: 27 WBRT and 3 stereotactic radiosurgery (SRS). In retrospect, 17/46 would have been candidates for salvage SRS: 5 LS post-PCI; 8 ES post-PCI; and 4 ES post-WBRT.

      Conclusion

      This cohort seems to challenge the belief that in-brain progression is always: diffuse; associated with clinical deterioration; and synchronous with systemic failure. With potential for OS >6 months, repeat WBRT risks meaningful neurocognitive toxicity. Further data are required; however, approximately 1 in 3 SCLC patients who recur after PCI or WBRT appear clinically appropriate for salvage SRS.

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      MA22.10 - Prevalence and Risk Factors of Brain Metastases in Limited Stage Small Cell Lung Cancer Immediately Before Prophylactic Cranial Irradiation (Now Available) (ID 13185)

      16:20 - 16:25  |  Presenting Author(s): Zhengfei Zhu  |  Author(s): Xiao Chu, Xi Yang

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastasis (BM) and improves overall survival (OS) in limited-stage Small Cell Lung Cancer (LS-SCLC) patients with complete or partial remission after receiving chemoradiotherapy. However, cranial magnetic resonance imaging (CMRI) before scheduled PCI is not mandatory, and its necessity remains controversial. Therefore, we conducted this study to evaluate LS-SCLC patients’ BM rate revealed by CMRI immediately before PCI.

      Method

      283 consecutive LS-SCLC patients diagnosed at our center between 2014 and 2017 were evaluated, all have negative base-line CMRI. Patients received platinum-based chemotherapy plus concurrent or sequential thoracic radiation. 119 complete or partial responders were identified. All received another CMRI immediately before PCI and constituted the cohort of interest. Logistic regression was employed to assess the relationship between pre-PCI BM risk and the following variables: age, gender, smoking history, lymph node stage or time from treatment initiation to pre-PCI MRI (TTPCI). Cox regression was employed to evaluate relations between these risk factors and OS. Two-sided P value <0.05 was considered statistical significant.

      Result

      25 out of 119 (21%) LS-SCLC patients developed pre-PCI BMs, TTPCI (2.83 to 13.03 months) was revealed as an independent risk factor for pre-PCI BM (risk ratio: 1.653, 95% CI: 1.312 – 2.084, P < 0.001, Table 1). Patients with pre-PCI BM have significantly shorter OS (hazard ratio: 1.653, 95% CI: 1.312 – 2.084, P < 0.001, Table 1).

      table 1.jpg

      Conclusion

      A considerable portion of LS-SCLC patients developed BM after definitive chemoradiotherapy and immediately before PCI. We recommend mandatory CMRI before PCI in these patients. Earlier scheduled PCI may reduce BM rate in selected LS-SCLC patients, further studies are warranted to determine the optimal PCI timing for LS-SCLC patients.

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      MA22.11 - Risk of Hippocampal Metastases in Small Cell Lung Cancer: Implications for Hippocampal Sparing Cranial Irradiation (Now Available) (ID 12791)

      16:25 - 16:30  |  Presenting Author(s): Rachel Effeney  |  Author(s): Lekshmi Nair, Michelle Murphy, Craig Hukins, Margot Lehman, G Tao Mai

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) decreases the incidence of brain metastases (BMs) and can improve overall survival. However whole brain radiation therapy is associated with a decline in neurocognitive function. Hippocampal-sparing whole brain radiation therapy (HS-WBRT) aims to minimise damage to neural progenitor cells (NPCs) within the hippocampus and reduce the toxicity of PCI, although there may be an increased risk of treatment failure in the hippocampal region. The incidence of hippocampal metastases was investigated in patients with BMs from SCLC to evaluate the feasibility of HS-WBRT in this population.

      Method

      Patients with SCLC presenting between 2000 and 2016 with BMs at presentation or during their disease course without previous cranial irradiation were identified from a prospectively maintained database. Hippocampal metastases (HMs) were defined as metastases within the hippocampus and a 5-mm radial expansion (hippocampus avoidance zone, according to the Radiation Therapy Oncology Group 0933 atlas). The rate of hippocampal metastases and associated clinical features were analysed.

      Result

      One hundred and twenty eligible patients with a total of 754 brain metastases were identified. In 67 (55.8%) patients BMs were detected at diagnosis of SCLC and in 53 (44.2%) patients BMs developed later without previous PCI. The median number of metastases was 3, and 27 (22.5%) patients had a single BM. There were 22 (18.3%) patients with hippocampal metastases. A total of 23 (3.1%) metastases involved the hippocampal avoidance area. On logistic regression analysis, the number of brain metastases was an independent risk factor for HMs.

      Conclusion

      The overall incidence of hippocampal metastases in our cohort of SCLC patients is high. As HS-WBRT may increase the risk of treatment failure in the spared region, prospective randomised trials are encouraged.

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      MA22.12 - Discussant - MA 22.09, MA 22.10, MA 22.11 (Now Available) (ID 14622)

      16:30 - 16:45  |  Presenting Author(s): Houda Bahig

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.01 - Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids (Now Available) (ID 12144)

      13:30 - 13:35  |  Presenting Author(s): Sebastiao Martins-Filho  |  Author(s): Michael Cabanero, Nhu-An Pham, Erin L Stewart, Deepti Ravi, Devalben Patel, Judy McConnell, Alexandria Grindlay, Frances Allison, Ming Li, Frances A Shepherd, Ming Sound Tsao, Kazuhiro Yasufuku, Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance.

      Method

      From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models.

      Result

      Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+).

      Conclusion

      Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

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      MA27.02 - Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Non-Small Cell Lung Cancer Xenografts Through p-STAT3/HIF-1 Alpha Pathway (Now Available) (ID 14322)

      13:35 - 13:40  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Xiong Chun Jin, Fan Tong, Chunhua Wei, Hui Lu

      • Abstract
      • Presentation
      • Slides

      Background

      Our study aimed to investigate specific biological effect of hypofractionated radiotherapy (HFRT) on tumor angiogenesis, when compared with conventional radiotherapy (CRT).

      Method

      Firstly, models of nude mice as well as dorsal skinfold window chamber (DSWC) bearing H460 and HCC827 (NSCLC cell lines) were established. Tumors suffered irradiation with doses of 0 Gy (control group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). After irradiation, xenograft volumes were recorded every other day. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; α-SMA and CD34 immune-histochemical staining was employed to detect the micro-vessel density (MVD) and coverage rates of pericyte on tumor vessels; pimonidazole hydrochloride was used to detect hypoxia; western blotting and RT-PCR were used to detect the expression levels of p-STAT3, HIF-1α, SDF-1 and VEGFA. Then, S3I-201, the STAT3 inhibitor, was used to further verify the mechanism of the effect of HFRT on vascular normalization.

      Result

      Compared to CRT groups, the growth suppression effect of HFRT on tumor tissue was enhanced, accompanied by stronger effect on decrease in MVD, vascular normalization and improvement of tumor hypoxia. RT-PCR and western blotting exhibited that HFRT promoted the vascular normalization by activating STAT3/ HIF-1α signaling pathway.

      Conclusion

      Compared to CRT, the pathway of p-STAT3/HIF-1α and its downstream angiogenic factors (VEGFA and SDF-1) might play important roles in forming of a window-period of vascular normalization in NSCLC, which contributed to the specific biological effect of HFRT on tumor vasculature.

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      MA27.03 - Multi-Omic Characterization of TKI-Treated Drug-Tolerant Cell Population in an EGFR-Mutated NSCLC Primary-Derived Xenograft (Now Available) (ID 13370)

      13:40 - 13:45  |  Presenting Author(s): Erin L Stewart  |  Author(s): Michael Cabanero, Vibha Raghavan, Jeffrey Bruce, Paul Guilhamon, Rajat Singhania, Nhu-An Pham, Shu Yi Shen, Tiantian Li, Ming Li, Natasha B Leighl, Frances A Shepherd, Trevor J. Pugh, Daniel De Carvalho, Mathieu Lupien, Geoffrey Liu, Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Sixty to eighty percent of advanced stage lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutated tumors respond to first generation EGFR tyrosine kinase inhibitors (TKIs). However, cure is not yet achievable with any EGFR TKI monotherapy, as patients eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be important for tumor cells surviving TKI. We hypothesize that molecularly characterizing DTCs in vivo and comparing them to the untreated tumor in a patient-derived xenograft (PDX) model may delineate mechanisms of tolerance that closely mimic those occurring in patients.

      Method

      DTCs were produced via chronic exposure to erlotinib in a lung adenocarcinoma PDX harbouring an exon 19 deletion. Histological, genomic, transcriptomic (including single-cell RNA-seq), and epigenetic characterizations were performed on DTCs and compared to untreated baseline (BL) tumors.

      Result

      Compared to BL, DTCs exhibit decreased levels of proliferation (Ki67 by immunohistochemistry (IHC) and increased expression of senescence/quiescence (p21) and anti-apoptosis (BCL-XL) immunohistochemistry (IHC) markers, while maintaining EGFR pathway signaling (pEGFR, pAKT, pERK, pS6 IHC). Whole exome-sequencing provides evidence that DTCs likely do not represent mutationally distinct subclones from the bulk tumor. Instead, DTCs exhibit a number of differentially expressed genes compared to BL tumors that are involved in cell cycle arrest, senescence/quiescence, differentiation, vesicles, and inflammation. Genes with epigenetic differences (chromatin openness and/or promoter methylation) are involved in similar cellular processes. A minor (<2%) subpopulation of transcriptomically-defined DTC-like cells in the BL tumors are very similar to the DTCs, supporting the hypothesis that DTCs may exist prior to treatment. A number of transcription regulators are found to have differential gene expression and epigenetic regulation as well as DNA-binding motifs found in regions of chromatin uniquely open in DTCs or baseline tumors. These transcription regulators are involved in cell maintenance, proliferation, and differentiation, and may play key roles in promoting DTC phenotype.

      Conclusion

      In this specific EGFR mutant PDX model sensitive to first generation TKIs, DTC-like cells are found in the BL untreated tumors, and its resultant phenotype after exposure to TKI appears to be involved in cell cycle, differentiation, senescence/quiescence, proliferation and maintenance. PDX models may provide insights into therapeutic strategies to target DTCs, and further improve the survival of EGFR-mutated NSCLC patients.

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      MA27.04 - Discussant - MA 27.01, MA 27.02, MA 27.03 (Now Available) (ID 14583)

      13:45 - 14:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA27.05 - Drug Loaded Mesenchymal Stem Cells for Targeted Lung Cancer Treatment in Mice (ID 11827)

      14:00 - 14:05  |  Presenting Author(s): YAOJIONG Wu  |  Author(s): Xusheng Wang

      • Abstract

      Background

      Mesenchymal stem cells (MSCs) are cells residing in many tissues of our body. Due to their low immunogenicity, allogeneic MSCs have been used extensively for immune regulation and many other conditions. Over 90% of culture expanded MSCs are entrapped in the lungs after intravenous infusion. Taking this advantage, in this study, we utilized MSCs as a vehicle for targeted delivery of drugs to the lungs to treat lung cancer.

      Method

      For enhanced cellular uptake, docetaxel (DTX) was loaded in PLGA-PEG nanoparticles (NPs). Lung cancer was induced in KrasG12D mice, who expressed a form of constitutively activated Kras protein in lung cells upon local administration of cre-advenovirus (AdCre) solution. The size of lung cancer was assessed by PET-CT and tissue analysis.

      Result

      The amount of DTX uptake by MSCs at 1, 3, 7, 12, and 24 hours was measured by LC-MS, and the result showed that DTX intake reached peak at 12 hours with ~36 μg in 106 MSCs, compared to 15 μg DTX in equal number of fibroblasts, indicating that MSCs had higher NPs-DTX uptake capacity than fibroblasts. To visualize MSCs in vivo, MSCs were labeled with luciferase (Luci). 106 MSCs-Luci loaded with NPs-DTX were injected intravenously in mice. In vivo imaging system (IVIS) analysis showed a predominant accumulation of the cells (drug) in the lungs at 24 hours after injection. The effect of MSCs/NPs/DTX in inhibiting lung cancer development was evaluated in KrasG12D mice. Five days after lung cancer induction, the mice received an intravenous injection of 106 MSCs loaded with NPs-DTX (~25 μg), NPs-DTX (~200 μg) alone, or PBS every 5 days. 30 days after tumor induction, PET-CT analysis detected large masses in the lungs in PBS treated mice, compared to much smaller masses in MSCs/NPs/DTX-treated or NPs-DTX-treated mice. In consistence, the tumor weight was significantly lower in MSCs/NPs/DTX-treated or NPs-DTX-treated animals than PBS-treated mice, and similar reductions in tumor weight were found in MSCs/NPs/DTX-treated or NPs-DTX-treated mice.

      Conclusion

      Thus our data indicate that MSC loaded with DTX can provide targeted therapy for lung cancer to achieve equal cancer inhibition with much lower doses of DTX thus reducing side effects of the drug. As allogeneic MSCs do not cause obvious immune rejection, our study suggests a novel approach for targeted lung cancer therapy.

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      MA27.06 - Therapeutic Silencing of Oncogenic KRAS With a Mutant-Specific Short Interfering RNA (Now Available) (ID 12227)

      14:05 - 14:10  |  Presenting Author(s): Chad Victor Pecot  |  Author(s): Amanda Van Swearingen, Bjoern Papke

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic mutations in RASgenes are well established drivers of cancer. In particular, lung, pancreatic and colorectal cancers carry high rates of oncogenic mutations in KRAS. Promising preclinical strategies with RNA interference (RNAi) have been developed to target oncogenic RAS function, yet a clinically effective anti-RAS therapy remains to be achieved. While genetic knock-down of mutant KRASwith RNAi is one promising approach, current methods are not selective and also decrease normal RAS, raising concerns about potential normal tissue toxicity.

      Method

      We took a novel in silico approach to develop a library of siRNAs that are theoretically capble of silencing mutant KRAS sequences yet spare the wild-type sequence. We utilized a 3T3 model system to test our library of siRNAS against various human KRAS G12 and G13 mutations compared with the wild-type sequence. Dose titrations were performed to assess the unique affinity of our lead candidate for mutant v. WT. Using a KRAS mutant orthotopic lung model, we assessed in vivo silencing and therapeutic effects following delivery of our lead candidate when packaged into a nanoliposome.

      Result

      Here we describe a custom designed short interfering RNA (siRNA) oligonucleotide (KRAS-m) that displays a higher affinity for the most frequent subsets of oncogenic KRASmRNAs than for wild-type KRASmRNA. Using 3T3 cells stably expressing wild-type or various KRAS mutations, we observed that KRAS-m preferentially suppressed expression of G12C, G12D, G12V and G13D missense mutations compared to wild-type KRAS. Additionally, KRAS-m impaired proliferation of lung cancer cells in 2D as well as 3D spheroids embedded in extracellular matrix. In order to optimize in vivo stability and minimize toxicity, a 2’O-methylation strategy was utilized and several equipotent modifications were found. To overcome future clinical limitations of delivering siRNA to tumors, we evaluated a lipid nanoparticle platform (LNP) clinically-proved to be safe and highly efficient at delivering systemic RNAi. Biodistribution studies in a syngeneic, orthotopic metastasis model of KRAS (G12D) lung adenocarcinoma revealed substantial uptake of LNP-siRNAs in lung tumors and metastasis. Time-kinetic studies in this model revealed a single delivery of LNP-KRAS-m siRNA significantly silenced KRAS protein expression in tumors for at least 3 days. Compared with LNP-control siRNAs, following two deliveries of LNP-KRAS-m siRNAs model led to significant reductions in disease burden.

      Conclusion

      Taken together, our data indicate a novel strategy to target oncogenic KRAS-driven lung tumors using a mutant-specific siRNA capable of targeting many of the most common KRAS mutations.

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      MA27.07 - Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors (Now Available) (ID 12771)

      14:10 - 14:15  |  Presenting Author(s): Hirotsugu Notsuda  |  Author(s): Nhu-An Pham, Ming Li, Ni Liu, Vibha Raghavan, Zhenhao Fang, Christopher B Marshall, Nadeem Moghal, Mitsuhiko Ikura, Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      BRAF mutations occur in 2-5% of non-small cell lung cancers with ~50% being non-V600E. Previous studies reported that two BRAF G469 mutations, G469V and G469A increase kinase activity and MAPK activation, thus are likely oncogenic. Patients with non-V600E mutations are mostly not sensitive to approved BRAF inhibitors vemurafenib or dabrafenib. We established a lung adenocarcinoma (LUAD) patient derived xenograft (PDX) that is epidermal growth factor receptor (EGFR) wild type and non-amplified, but harbors BRAF G469V mutation, yet is sensitive to gefitinib. We performed functional studies to characterize the oncogenicity and sensitivity of BRAF G469 mutations to EGFR tyrosine kinase inhibitors (TKIs).

      Method

      PDX12 was established in NOD-SCID mice from a resected stage IIIA LUAD. The XDC12 cell line was established from PDX12. NCI-H1395 and -H1755 LUAD cell lines with BRAF G469A mutation were obtained from ATCC. BRAF mutant driver activity was characterized by shRNA knockdown of BRAF in LUAD cell lines and the ability of the mutants to promote IL3-independent growth when expressed in Ba/F3 cells. PDX12 responsiveness to TKIs was evaluated by tumor volume shrinkage while cell line sensitivity was quantified using the MTS assay. Drug effects on signaling were assessed by phospho-immunoblotting. Computational modeling was used to predict how the mutations promote BRAF activation and sensitivity to EGFR-TKIs, while purified BRAF proteins were used to validate predictions.

      Result

      Knockdown of BRAF by shRNA inhibited growth of all BRAF mutant cell lines, while ectopic BRAF G469V and G469A expression in Ba/F3 cells promoted IL3-independent MAPK activation and growth, supporting both mutations being oncogenic drivers. The XDC12 cell line was sensitive to EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib), but resistant to the BRAF inhibitor dabrafenib, which correlated with inhibition of MAPK phosphorylation. By contrast, H1395 and H1755 cell lines with BRAF G469A mutations were resistant to both the EGFR-TKIs and the BRAF inhibitor. Similarly, only Ba/F3 cells expressing BRAF G469V, but not G469A, were sensitive to EGFR-TKIs. Consistent with the in vitro data and our initial PDX findings with gefitinib, multiple EGFR-TKIs induced tumor shrinkage in PDX12 in vivo.

      Conclusion

      BRAF G469V/A mutations are oncogenic drivers but are insensitive to BRAF inhibitors. However, only BRAF G469V, but not G469A mutation, is sensitive to EGFR-TKIs. Thus, two different driver alterations affecting the same BRAF codon can lead to distinct drug sensitivities.

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      MA27.08 - Discussant - MA 27.05, MA 27.06, MA 27.07 (Now Available) (ID 14581)

      14:15 - 14:30  |  Presenting Author(s): Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA27.09 - Dual Inhibition of BCL-XL and MCL-1 is Required to Induce Tumour Regression in Lung Squamous Cell Carcinomas Sensitive to FGFR Inhibition (Now Available) (ID 12645)

      14:30 - 14:35  |  Presenting Author(s): Marie-Liesse Asselin-Labat  |  Author(s): Clare E Weeden, Casey Ah-Cann, Aliaksei Holik, Delphine Merino, Guillaume Lessene

      • Abstract
      • Presentation
      • Slides

      Background

      Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been described in 20% of lung squamous cell carcinoma (SqCC), suggesting that FGFR tyrosine kinase inhibitors may constitute a new therapeutic approach for patients carrying this genetic alteration. However, a recently completed clinical trial reported low response rates to FGFR therapy, indicating the need for refined biomarkers. We have recently described that high levels of FGFR1 RNA expression better predicts response to FGFR inhibitors, yet the treatment results in tumour cell stasis as opposed to cell death. BH3-mimetics are a class of anticancer agents that block the BCL-2 family of pro-survival proteins to induce cell death and were recently approved for clinical use in blood cancers. We therefore hypothesized that combining BH3-mimetics with FGFR-targeted therapy may enhance the killing of SqCC cells.

      Method

      We developed patient-derived xenograft models of lung squamous cell carcinoma and evaluated the activity of specific inhibitors of BCL-XL (A1331852), BCL-2 (ABT-199), MCL-1 (S63845) or FGFR (BGJ398) as single agents or in combination in vitro and in vivo. Genetic knockout of BCL-XL was also performed using CRISPR/Cas9. We evaluated compounds synergy in vitro using BLISS assay and in vivo efficacy using mRECIST.

      Result

      Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We identified a greater reliance of lung SqCC cells on BCL-XL compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitor alone gives a survival benefit in combination FGFR therapy in vivo. In contrast, triple BCL-XL, MCL-1 and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC.

      Conclusion

      Our work therefore provides a rationale for the simultaneous inhibition of MCL-1, BCL-XL and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

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      MA27.10 - EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies (Now Available) (ID 11863)

      14:35 - 14:40  |  Presenting Author(s): Yijun Jia  |  Author(s): Tao Jiang, Xuefei Li, Chao Zhao, Caicun Zhou, Sha Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immuneapproach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy.

      Method

      We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry.

      Result

      Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment.

      Conclusion

      Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.

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      MA27.11 - Genomic Sequencing and Editing Revealed the GRM8 Signaling Pathway as Potential Therapeutic Targets of Squamous Cell Lung Cancer (ID 12246)

      14:40 - 14:45  |  Presenting Author(s): Panpan Zhang  |  Author(s): Shaolei Li, Yue Yang

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of cancer death worldwide. Squamous cell carcinoma (LUSC) is one subtype of non-small-cell lung cancer (NSCLC), and ranks at the second of lung cancer incidence. Although targeting receptor tyrosine kinases (RTKs) had already brought better clinical outcomes to NSCLC patients carrying corresponding mutations, very few mutated targets had been identified in LUSC subtype, probably because of the lack of mutation hotspot and functional validation of mutated candidate.

      Method

      The whole exome (WES) and whole genome (WGS) sequencing and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from 11 groups of LUSC primary tumors and corresponding patient-derived xenografts (PDXs).

      Result

      The WES data revealed high homologies on the mutation types and signatures among primary tumor and different passages of PDX tumor samples. Nine significant genes carrying single nucleotide variations (SNVs) and three carrying copy number variations (CNVs) were identified as targeting candidates from WES and WGS data based on the mutation frequency and driver gene analysis. The oncogenic or tumor suppressor functions of those 12 candidates were validated through CRISPR-Cas9 loss-of-function system in tumor cells derived from PDX tissues carrying corresponding mutations and in normal bronchial epithelial cell-line. Furthermore, using CRISPRa transcriptionally activating system, one novel candidate, Metabotropic glutamate receptor 8 (GRM8) was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway.

      Conclusion

      The components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer.

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      MA27.12 - Discussant - MA 27.09, MA 27.10, MA 27.11 (Now Available) (ID 14582)

      14:45 - 15:00  |  Presenting Author(s): Dave Barbie

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS04 - Joint GLCC/IASLC Session: Exploring Hot Topics for Advocates (ID 783)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Advocacy
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 BD
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      MS04.01 - Collecting Data in the Real World - How Can Patient Groups Work with Researchers in Defining and Collecting Real-World Evidence? (Now Available) (ID 11415)

      10:30 - 10:45  |  Presenting Author(s): Taofeek Owonikoko

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS04.02 - How Is Lung Cancer Screening Evolving to Be More Efficient and Effective? (Now Available) (ID 11416)

      10:45 - 11:00  |  Presenting Author(s): David Raymond Baldwin

      • Abstract
      • Presentation
      • Slides

      Abstract

      At the time of writing this summary, only the US and Canada had approved national screening with low radiation dose computed tomography (LDCT) and this was based primarily on the US National Lung Screening trial (NLST).[1]Since this landmark study, there has been much debate and further research work to clarify the best way to undertake a screening programme. Initially, uncertainty about the detail of an optimal programme that ensures that benefits outweigh harms in a cost-effective manner, was a reason to delay initiation of programmes in other countries.[2] However, many now believe that there is sufficient evidence to design a programme that will deliver a substantial reduction in mortality well within the commonly quoted willingness to pay thresholds in developed countries.[3]What is making policy makers cautious is the fact that the results of the only other randomised trial powered to detect a lung cancer mortality difference, the Dutch-Belgian NELSON trial, are still awaited.

      Figure 1 shows some of the factors that may be crucial in producing a favourable balance between benefits and harms and these are summarised below.

      Selecting people at high risk of lung cancer, who are more likely to benefit than those at low risk makes the intervention more cost effective. The use of multivariable risk prediction models increases the cost effectiveness over simple age and smoking criteria used in NLST. It is important that people who are at too low risk, some being the 10-15% of people who develop lung cancer but have never smoked, understand why they should not be screened. There is also an intermediate risk group where cost is the main consideration.

      Modelling has shown that annual scanning is more cost effective than biennial. However, where a previous CT is negative (no significant pulmonary nodules) the risk of cancer a year later is low, allowing a 2-year interval and cost savings. Imaging and reporting standards are well-developed.

      Indeterminate findings need to be managed according to guidelines that employ initial interval LDCT, recognising that the risk of malignancy is low, avoiding overdiagnosis, higher radiation dose imaging and false positive diagnostic tests[4, 5]. The false positive rate is 1-3% where this patient-centred definition is applied.

      Clinical work-up and treatment should also follow modern pulmonary nodule management and other clinical guidelines[4, 5]to reduce overdiagnosis and harms from biopsies and surgery by reducing intervention where the risk of malignancy is low or when cancers are indolent and unlikely to cause harm. Applying this “intelligent” approach yields a benign resection rate of around 10% and the in most recent UK pilot it was 2%. [6-8]

      Smoking cessation support should be integral as the overall quit rates are greater than in the general population and further increased by intermediate findings.

      Some issues are unresolved and could further improve cost-effectiveness. Participation in screening has been disappointing in the US and active research into ways to increase this is needed to ensure an impact at population level. The value of add-on health interventions and addressing incidental findings needs to be carefully evaluated using the same principle of benefit outweighing harm. Information to support people to make an informed decision about whether screening is right for themis an area of continuing research and relies heavily on the input of patients and the public. An undoubted challenge to implementation in some countries is the demand on human and physical resources.

      Screening for lung cancer makes logical sense and has a strong evidence base but delivering an optimum programme is dependent on attention to detail. It is important that country-specific pilot programmes now underway adhere to best practice so we see detection of early stage disease and high curative treatment rates with low rates of intervention for benign disease. This will help clinicians and opinion leaders, in partnership with advocates, to convince policy makers and governments of the need for investment.

      References

      1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening.New England Journal of Medicine 2011, 365:395-409.

      2. Field JK, Aberle DR, Altorki N, Baldwin DR, et al: The International Association Study Lung Cancer (IASLC) Strategic Screening Advisory Committee (SSAC) Response to the USPSTF Recommendations.J Thorac Oncol 2014, 9:141-143.

      3. Matthijs Oudkerk AD, Rozemarijn Vliegenthart, Thomas Henzler, et al: European position statement on lung cancer screening.Lancet Oncology 2017, 18:e754–e766.

      4. Callister ME, Baldwin DR, Akram AR, et al: British Thoracic Society guidelines for the investigation and management of pulmonary nodules.Thorax 2015, 70 Suppl 2:ii1-ii54.

      5. MacMahon H, Naidich DP, Goo JM, et al: Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017.Radiology 2017,284:228-243.

      6. Field JK, Duffy SW, Baldwin DR, et al: UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.Thorax 2016, 71:161-170.

      7. Flores R, Bauer T, Aye R, et al: Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer.J Thorac Cardiovasc Surg 2014, 147:1619-1626.

      8. Crosbie PA, Balata H, Evison M, et al: Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.Thorax 2018.doi: 10.1136/thoraxjnl-2017-211377.

      slide1.jpg

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      MS04.03 - Exploring Smoking Stigma, Negativity and Lung Cancer - What Can Be Done? (Now Available) (ID 11417)

      11:00 - 11:15  |  Presenting Author(s): Stefania Vallone

      • Abstract
      • Presentation
      • Slides

      Abstract

      Misinformation or false myths about cancer generate fear and a negative perception of a person affected by this disease. Lung cancer patients experience a higher level of cancer-related stigma than other cancer patients, because the general negative attitude about smoking, recognized as one of the main risk factors, contributes to the stigmatization of people who live with this condition. Although the relation between tobacco use and lung cancer is established, worldwide lung cancer patients are affected by a noteworthy and unjustified stigma and considered responsible of their disease in a different way from other cancer patients. For it, they are often reluctant to disclose the disease, because of fear to be discriminated, and patients' stories show that stigma could be harmful and detrimental to them and their loved ones and may cause limitations in working toward a cure. The lack of public empathy and support adds an emotional burden to an already frustrating situation that can affect quality of life and may contribute to depression, anxiety, poor self-esteem, guilt, shame, blame, negatively impacting psychological adjustments and interpersonal communication. Low public support for lung cancer is not restricted to popular perceptions and attitudes, but can also be seen in research funding. Lung cancer remains an underfunded disease and despite the higher mortality, it received less funding compared to other common cancers, such as breast cancer.

      What can be done?

      Stigma impacts all spheres of a person’s life and patients, caregivers, advocates and healthcare professionals have started years ago actively working in this area developing programs and campaigns that can help to change this situation, partly persisting because smoking is still considered more as a bad habit rather than a serious addiction. It’s important to motivate and encourage smokers to quit rather than blaming them, and even when the lung cancer has already been diagnosed, smoking cessation is important for a better quality of life. Providing smoke-free policies and tailored and effective campaigns is essential for improving the people awareness about the issue that smoking contributes to a number of diseases and cancers even if most people associate it exclusively with lung cancer. But, lung cancer is not just a smoker's disease, there are additional factors to consider and the education of patients, the general public and the health care personnel on these topics plays a valuable role. To help dispel stigma it is crucial the dissemination of correct and up-to-date information, the commitment of celebrities, patient families and friends, doctors in campaigning and advocating on their behalf, sharing the stories of lung cancer patient’s in order to increase the visibility of this disease and to generate a movement able to create a support network more sympathetic with these people, because they need and deserve care and support, not an evaluation of the possible causes of the disease. Raising the awareness is one of the main goals of any Lung Cancer Advocate worldwide and in conjunction with Lung Cancer Awareness Month, observed annually in November, many advocacy groups improve their efforts independently or in cooperation for promoting public campaigns about prevention, screening, new treatments and other issues. With the purpose of harmonizing the action, some years ago the International Association for the Study of Lung Cancer (IASLC) proposed and lead a unified effort among a consortium of non-profit lung cancer patient organizations and individuals to produce a coordinated public awareness campaign for Lung Cancer Awareness Month (LCAM) in November in order to reach the maximum amount of impact on media coverage, policy makers and public support.

      Reducing stigma is also one of pillar of the global action of GLCC (Global Lung Cancer Coalition) that in 2010, commissioned a research carried out by Ipsos MORI, which surveyed over 16,000 people in 16 countries, and found some evidence that sympathy levels were influenced by rates of smoking in each country. Between 10% and 29% of people admitted to feeling less sympathetic towards lung cancer sufferers because of its association with smoking.

      In 2017, GLCC commissioned a new multi-national study to Populus agency to undertake an online survey of adults across 25 countries for understanding attitudes towards lung cancer among the public. The results confirmed that 21% of people, out of least 1,000 adults per country still agree that they have less sympathy for people with lung cancer than other forms of cancer.

      In conclusion, in lung cancer there is a strong need to overcome many challenges to ensure that all of the patients may have the same hope and equal chances to fight against this disease. Lung cancer patients and caregivers still face a number of significant challenges and more has to be done to increase public awareness, to provide diagnostic tools and access to safe and effective treatments, to support efficient research and to combat the stigma. We’ve come a long way, and we certainly have a long way to go. We should work all together to effectively diminish the stigma that surrounds lung cancer and move forward in a positive way.

      References:

      1) Lung cancer stigma, depression, and quality of life among ever and never smokers Janine K. Cataldo, Thierry M. Jahan, and Voranan L. Pongquan

      2) Public attitudes about lung cancer: stigma, support, and predictors of support Jared Weiss,1Briana J Stephenson, Lloyd J Edwards, Maureen Rigney, and Amy Copeland

      3) Lung cancer in never smokers: clinical epidemiology and environmental risk factors Jonathan M. Samet, Erika Avila-Tang, Paolo Boffetta, Lindsay M. Hannan, Susan Olivo-Marston, Michael J. Thun and Charles M. Rudin

      4) Global Perception of Lung Cancer: An Ipsos MORI report for the Global Lung Cancer Coalition

      5) Based on WHO data (2005) on prevalence of tobacco used by country (full data and further information can be found at http://www.who.int/mediacentre/factsheets/fs297/en/index.html

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      MS04.04 - E-Cigarettes - What Do Lung Cancer Advocates Need to Know? (Now Available) (ID 11418)

      11:15 - 11:30  |  Presenting Author(s): Carolyn Dresler

      • Abstract
      • Presentation
      • Slides

      Abstract

      Since the release of the IASLC Statement on e-cigarettes in 2014(1), opinion in relation to their role has become more not less polarised. E-cigarettes are not going away as an issue and advocates should be aware of the state of knowledge generally and of reputable information to which they can refer. Lung cancer advocates and patient supporters should have enough knowledge to assist individual patients to make an informed decision, to educate if that is their role and to advocate for the best care environment for those who have lung cancer or are at elevated risk for the development of lung cancer in the future. Some scenarios are worthy of consideration.

      The smoker who needs surgical resection.

      Smoking cessation is standard-of-care before thoracic surgery. Cessation reduces respiratory and cardiac morbidity and improves wound healing. Almost all smokers in this situation quit easily. Limited studies suggest an adverse effect of e-cigarettes on wound healing that is similar to smoking. More disturbingly, a bronchoscopy study found severe bronchial inflammation(2). There is sufficient, reasonable concern about impaired healing of the bronchial stump and compromised sputum clearance to explicitly recommend against the use of e-cigarettes before surgery even if smoking cessation is achieved.

      Patients with advanced lung cancer

      Advanced lung cancer is no longer rapidly and uniformly fatal. In the previous era, before recent treatment advances, with targeted small molecules and immunotherapy, it was difficult to show a survival advantage but continued smoking was associated with impaired quality of life and longer periods in hospital stay in cancer patients. There are no similar data for the complete substitution of smoking for e-cigarettes. Cessation should still be the aim. There are also practical problems with few health-care providers permitting e-cigarette use in enclosed spaces. NRT in contrast can be used in any location.

      Current smokers involved in lung cancer screening programs or with incidental nodules

      This is unquestionably a high value group for effective smoking cessation intervention. The considerations are those for the availability and recommendation for e-cigarettes in the community generally.

      What is the benefit of e-cigarettes in promoting cessation

      In its report, NASEM concluded that there is limited evidence that e-cigarettes are effective aids to promote smoking cessation, moderate evidence from randomized controlled trials that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine and that There is insufficient evidence from randomized controlled trials about the effectiveness of e-cigarettes as cessation aids compared with no treatment or FDA–approved smoking cessation treatments(3). Since that report was released, the largest RCT of e-cigarettes vs other treatment options published in NEJM found no benefit for e-cigarettes(4).

      What are the harms especially long-term when long term use is encouraged

      There are probably few harms of a short-course (6 weeks or less) of e-cigarette use but a statistically significant decline in lung function is detected at 3 months. Airway inflammation is also seen rapidly. Some Much attention has been focussed on the claim that e-cigarettes are 95% safer than smoking. This claim is supported by no evidence. It is true that tobacco smoke contains putative cancer-causing chemicals that are at low levels in e-cigarette vapour but the real situation is more complex. In the bronchoscopy study looking at airway protein levels, there was a cluster of adverse changes seen only with smoking, another seen with smoking and e-cigarette use and a third seen only with e-cigarette vapour(2). Whether these are from the base chemicals, nicotine or flavourings is uncertain. Long-term studies are few. Use of e-cigarettes for two years in a study sponsored by a tobacco-company subsidiary detected very rapid (5%/year) loss of lung function(6). There are no meaningful long-term studies for CV risk and smoking-related cancers.

      What are the wider harms in promoting smoking in youths and young adults?

      The NASEM report concludes that there is “substantial evidence that e-cigarette use increases risk of ever using combustible tobacco cigarettes among youth and young adults”. Based on a meta-analysis, after adjustment for all reasonable confounders the risk is about 3-fold. It is inevitable that promotion amongst children and young adults will occur generating concerns as now seen with the JUUL product.

      Where is the role of e-cigarettes at the present time as a smoking cessation aid?

      E-cigarettes represent an intuitive solution for some smokers and there is a wealth of non-evidence-based information accessible on the internet. It is challenging for health advocates to accede to the use of a treatment that appears to be ineffective yet having this evidence-based approach is seen by many wedded to harm reduction as negative. Subject to the regulatory environment in each country, it may be reasonable to tolerate, under supervision, e-cigarette use where an individual will only attempt smoking cessation with e-cigarette use. This should be time-limited to perhaps 6-8 weeks with cessation of e-cigarettes if smoking continues; leading to a consideration of other options. If cessation is achieved, e-cigarette use should be withdrawn. There should be no compromise on the question of concurrent smoking/e-cigarette use that offers no health benefit and is unstable with many patients reverting to smoking.

      References:

      1. Cummings KM, Dresler CM, Field JK et al. E-cigarettes and cancer patients. J Thorac Oncol. 2014; 9: 438-41

      2. Ghosh A, Coakley RC, Mascenik T et al. Chronic E-Cigarette Exposure Alters the Human Bronchial Epithelial Proteome. Am Rev Resp Crit Care Med 2018; 198: 67-76.

      3. National Academies of Sciences and Engineering and Medicine. Public health consequences of e-cigarettes. Washington. DC: The National Academies Press, 2018.

      4. Halpern SD, Harhay MO, Saulsgiver K, et al. A Pragmatic Trial of E-Cigarettes, Incentives, and Drugs for Smoking Cessation. N Engl J Med 2018; 378:2302-2310

      5. McNeill A, Brose LS, Calder R et al. Evidence review of e-cigarettes and heated tobacco products 2018. A report commissioned by Public Health England. London: Public Health England.

      6. Walele T, Bush J, Koch A et al. Evaluation of the safety profile of an electronic vapour product used for two years by smokers in a real-life setting. Regulatory Toxicology and Pharmacology 2018; 92:226–238.

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    MS06 - Practical Issues in the Management of Oligometastatic NSCLC (ID 785)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 BD
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      MS06.01 - The Role of Radiation in Treating the Mets (Now Available) (ID 11423)

      13:30 - 13:45  |  Presenting Author(s): Hak Choy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS06.02 - The Role of Interventional Pulmonology and Radiology (Now Available) (ID 11424)

      13:45 - 14:00  |  Presenting Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Role of Pulmonology and Interventional Radiology in the Management of Oligometastatic NSCLC

      Oligometastatic disease is a difficult management issue when encountered in NSCLC. Often defined as low metastatic burden and limited organ involvement disease, with clinical impact perceived as between truly localised potentially curable disease and a extensive incurable metastatic tumour, therefore with major implication for the patient in terms of treatment, with the potential to pivot the decision making from palliative to curative intent.

      In addition the site(s) of oligometastatic disease is heterogenous with potential to affect any site in the body, both intra and extra- thoracic, thus requiring a truly multidisciplinary approach to its management.

      It is essential to make an accurate diagnosis, to consider synchronous cancers and to rule out more extensive metastatic disease given the differing management strategies required.

      For the Pulmonologist and Interventional Radiologist, for intrathoracic oligometastatic disease, the issues are the diagnostic challenges and potential therapeutics. The use of image guided trans thoracic needle biopsy has long been used effectively by Interventional Radiology for the pathological diagnosis of suspected lesions. With modern endobronchial ultrasound, Pulmonologists are able to contribute more by accessing central and peripheral lung lesions by navigation and guided bronchoscopy e.g. ultrasound guided, electromagnetic navigation and transparenchymal approaches. With the increasing use of molecular techniques to distinguish cancers even of the same morphological appearance, such diagnostic approaches are of increasing clinical utility.

      For intrathoracic therapeutics, local Interventional Radiology ablative techniques such as radiofrequency ablation has long been used, with microwave ablation increasingly popular. In parallel with diagnostics, emerging Pulmonology techniques are also researching the potential application of these techniques applied endobronchially in addition to new modalities such as steam ablation.

      Interventional Radiologists also have a useful role to play in the management of extra-thoracic oligometastatic disease, as techniques such as radiofrequency and microwave ablation can be used such as for liver lesions.

      This session will review the emerging data for the key role of Pulmonology and Interventional Radiology in the Management of Oligometastatic NSCLC.

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      MS06.03 - The Role of Surgical Resection (Now Available) (ID 11425)

      14:00 - 14:15  |  Presenting Author(s): Boris Sepesi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is an aggressive malignancy with low (< 10%) 5-year survival rates when metastases appear. Historically, surgical resection in metastatic setting has not been beneficial in term of survival; this was especially true when options for effective systemic therapy were limited. It is now recognized that up 50% of patients who presents with metastatic NSCLC have a limited (up to 5) number of metastases. Common sites of metastases include brain, lungs, adrenal glands, bones, or liver.

      In appropriately selected patients, surgical resection in metastatic lung cancer may be considered for the control of primary tumor, regional nodal disease, and metastases present within the same surgical field (example: metastases in ipsilateral ribs, or another lobe in the same lung as primary tumor). Surgical resection of selected extra-thoracic metastases is also possible; however, radiation is more commonly employed in those circumstances.

      The main goal of surgery in oligometastatic setting is to achieve complete disease control. Careful patient selection must account for the extent and the location of primary tumor and nodal disease, physiologic status and reserve of the patient, tumor histology, biomarkers, synchronous or meta-chronous presence of metastases and number of metastases, previous therapies and planned post-surgical systemic or other local therapies.

      Invasive mediastinal staging with either mediastinoscopy or endobronchial ultrasound is of utmost importance prior to proceeding with surgery. Long-term outcomes with positive ipsilateral mediastinal N2 or contralateral N3 lymph nodes are poor as compared to N0 or N1 nodal status; N2 and N3 disease should be considered contraindication for surgical therapy outside of a clinical trial. Lobectomy with mediastinal node dissection is a preferred procedure for primary tumor in oligometastatic circumstances. Pneumonectomy, especially on the right side should be avoided, and its need should be regarded as a relative contra-indication. If brain metastases are present, they should be treated first; other metastatic sites maybe addressed based on symptoms. Commonly, systemic platinum-based chemotherapy has been administered as the 1st line therapy for 3-4 cycles to sort out the cancer biology and response to chemotherapy. Stable or improved disease following chemotherapy makes proceeding with surgical resection of primary tumor and control of oligometastases reasonable. However, this paradigm continues to evolve in the era of immunotherapy and targeted therapy.

      There are a number of advantages to surgical resection of lung cancer in oligometastatic setting, as compared to other local modalities. Complete resection provides the best chance for prolonged local and regional disease control. It hypothetically removes all or at least the majority of cancer clones, it allows for detailed pathological analysis of the tumor and lymph nodes, and it provides adequate tissue for translational studies or personalized experimental treatment approaches. With current minimally invasive approaches such as video assisted or robotic assisted thoracic surgery recovery from surgical treatment of lung cancer can be expeditious. With the use of enhanced recovery pathways, even recovery after thoracotomy mimics recovery after minimally invasive thoracic surgery. Potential disadvantage of surgical therapy in oligometastatic lung cancer is the risk of post-operative cardiac or pulmonary complications, resolution of which may require time and may delay other necessary therapy. This again highlights the importance of patient selection for surgical therapy.

      Surgical Resection of Oligometastatic Lung Cancer in the Era of Targeted Therapy and Immunotherapy.

      Within the last year, immunotherapy has become the frontline treatment modality for metastatic lung cancer. Response rates, durability of responses, and toxicity profiles with immunotherapy are all better than with chemotherapy. Although imperfect, PD-L1 expression and tumor mutation burden serve as predictive biomarkers for immunotherapy. Many studies of combined chemo-immune regimens, or combination immune regimens are underway. These results are encouraging, however, as we improve systemic disease control, loco-regional lung cancer control will become even more important. The role and timing of local treatments following immunotherapy or targeted therapy in oligometastatic setting are currently under study. While there are reports of radiation therapy potentiating immunotherapy, evidence is not conclusive and biomarkers are still under investigation. Surgical therapy and radiation therapy should be considered complementary modalities in oligometastatic lung cancer. If lobectomy is possible for primary disease control in an acceptable-risk surgical candidate, it should not be discarded as an option over radiation. Considering current operative experience following prolonged immunotherapy, it is hypothesized that salvage surgical resections for local recurrence following immune-radio therapy may be difficult and may convert possible routine early lobectomy to an eventual salvage pneumonectomy.

      As the therapeutic options for oligometastastic lung cancer continue to evolve with much improved systemic options, effective local and regional therapy will become more important. Novel surgical techniques and enhanced recovery pathways have decreased the morbidity and sped up patients’ surgical recovery. Surgical resection should therefore continue to play a role in the multi-modality setting for oligometastatic lung cancer in appropriately selected patients.

      References:

      Gomez DR, Blumenschein GR Jr, Lee JJ, Hernandez M, Ye R, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Gibbons DL, Karam JA, Kavanagh BD, Tang C, Komaki R, Louie AV, Palma DA, Tsao AS, Sepesi B, William WN, Zhang J, Shi Q, Wang XS, Swisher SG, Heymach JV. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682. doi: 10.1016/S1470-2045(16)30532-0. Epub 2016 Oct 24.

      Patrini D, Panagiotopoulos N, Bedetti B, Mitsos S, Crisci R, Solli P, Bertolaccini L, Scarci M. Surgical approach in oligometastatic non-small cell lung cancer. Ann Transl Med. 2018 Mar;6(5):93. doi: 10.21037/atm.2018.02.16. Review.

      Stephens SJ, Moravan MJ, Salama JK. Managing Patients With Oligometastatic Non-Small-Cell Lung Cancer. J Oncol Pract. 2018 Jan;14(1):23-31.

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      MS06.04 - Systemic Therapy for Oligomets: Before, During, or After Local Therapies? (Now Available) (ID 11426)

      14:15 - 14:30  |  Presenting Author(s): Ross Camidge

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastatic disease reflecting the concept of limited metastatic spread may be discussed in the setting of the sites of disease at diagnosis of stage IV disease. However, an analogous situation may also occur at progression on a therapy controlling all other sites of disease – so called oligoprogressive disease. Both may be considered for local ablative therapies (usually radiation or surgery, but also some other techniques such as radiofrequency ablation). When considering systemic therapy this may be before the local therapy as induction treatment for initial oligometastatic disease; as part of the radical local therapy (for example, combination chemoradiation therapy); or as maintenance therapy after the local therapy. The latter could reflect continuation of a tyrosine kinase inhibitor, pemetrexed or bevacizumab and could also apply to the oligoprogressive scenario.

      The issues to address are the adequacy of assessing oligometastatic disease at the time local therapy is considered; the details that appropriately define oligometastatic or oligoprogressive disease suitable for local therapy; and the potential for a direct interaction with the local therapy.

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      MS06.05 - The Special Case of Brain Metastases: Systemic Therapy, Radiation or Both? (Now Available) (ID 11427)

      14:30 - 14:45  |  Presenting Author(s): Laurie Gaspar

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS09 - Tumour Board - Tissue Acquisition and Staging (ID 788)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 BD
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    MS18 - Management of SCLC Patients Not Represented in Clinical Trials (ID 797)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 206 BD
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      MS18.01 - Treatment of Patients with Poor Performance Status (ECOG 3-4) (Now Available) (ID 11477)

      13:30 - 13:50  |  Presenting Author(s): Luiz H. Araujo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Performance status (PS) is a strong prognostic factor in most solid tumors, often impacting on oncologists’ approach.1 In small cell lung cancer (SCLC), treatment decision in patients with poor PS is a challenging and complex one. To fully contemplate this matter, one must take into account the specificities of this disease, the current knowledge on the field and possible alternatives in order to take the most ethical and supported decision.2

      Let’s start by imagining a case of a 60 year-old male with a history of heavy smoking, that was admitted due to extensive-stage SCLC presenting with shortness of breath, superior vena cava syndrome (SVCS), and significant weight loss. The ECOG PS was 3. His serum LDH was 600 U/l, and sodium was 120 mEq/L. A PET-CT showed an infiltrative mediastinal mass causing compression of the superior vena cava, in addition to several liver metastases (TNM stage IVB). No brain metastasis was detected on a brain MRI.

      This case may seem quite familiar to many attending clinicians that routinely care of lung cancer patients. For instance, this case highlights the early metastatization of SCLC, which presents with extensive stage in around two-thirds of patients. It is also known that approximately 10% of SCLC patients present with SVCS; constitutional symptoms such as weight loss may indicate extrathoracic spread; and hyponatremia may be related to paraneoplastic syndrome of inappropriate antidiuretic hormone (SIADH).3

      The correct frequency of SCLC patients presenting with a poor PS is not fully described, however the literature points that approximately 30-40% of lung cancer patients may present with PS 2-4. In SCLC, it has been described that up to 30% of patients may have a PS of 3 or 4,1 which is in line with its rapid growth and spread. Given this aggressive nature and the high response rate to systemic therapy, it is recommended that SCLC patients be managed promptly, avoiding delays to diagnose and stage. Most experts recommend initiating specific therapy within 1-2 weeks of diagnosis in order to avoid significant worsening in symptoms and PS.3

      When appreciating a SCLC patient with a poor PS, one can realize the clear lack of evidence to guide therapy decision in this setting.2 In fact, most clinical trials will only enroll PS 0-1, limiting the representativeness and generalization of their findings. Patients with PS 2 generally derive lower benefit from chemotherapy (CT) in clinical trials, presenting worse response rate and shorter progression-free survival.2 In regards to PS 3 or 4, these are never represented in clinical trials. The clinical approach is therefore guided based on expert consensus. Guidelines recommend consideration of combination CT when poor PS is due to disease symptoms.4 In our case, the PS 3 seems to be a constitutional manifestation of advanced SCLC, which could be reversed with CT. Dyspnea caused by SVCS could also be alleviated with CT.

      SCLC is one of the rare exceptions where oncologists may be willing to offer palliative CT even in poor PS patients. A common routine is to try a couple of CT cycles, hoping that patients will experience an improvement in symptoms and PS.2 Nevertheless, one should also take into account several other factors that may limit the willingness to start systemic therapy, including the poor prognosis, CT toxicity, and patient/family expectations.5 In reality, data show that only a limited subset of cases will experience longer survival. In a review of 40 SCLC patients presenting with poor PS, median overall survival was 64 and 7 days in PS 3 and 4, respectively.6 Thirty-five percent of patients received only one CT cycle, and 30% died prematurely after the first cycle - mostly PS 4.6 In these situations, palliative measures may be utilized, instead of CT, and help improve quality of life. In general, second-line CT is limited to patients with favorable PS (0-2) since response rate tends to be low. Prophylactic cranial irradiation is not recommended for patients with poor PS.4

      Adding up to this complex therapy decision, one should review the extreme of patients that require admission to an intensive care unit (ICU). A hospital mortality of 72% has been described among 25 consecutive SCLC cases, independently of therapy.7 In particular, all SCLC patients requiring mechanical ventilation died within 3 months of ICU admission, mostly during the ICU stay.7 This kind of outcomes may be strongly considered when discussing therapy decisions with patients and families.

      Novel therapies have revolutionized NSCLC therapy, including small targeted inhibitors and immunotherapy. In SCLC, PD1/PDL-1 inhibitors have shown activity in a subset of cases, especially in combination with CTLA4 inhibitors or CT.8 Nevertheless, combination immunotherapy may cause significant toxicity that limits its indication in patients with poor PS. Unfortunately, this matter will not be addressed in ongoing clinical trials, leaving oncologists with the difficult task of deciding if immunotherapy – alone or in combination – is appropriate in these settings. One possible approach to be evaluated in clinical trials is to start combination immunotherapy after the best response to induction CT, hence selecting for responding patients that may present a more favorable prognosis. This study concept illustrates the importance of designing specific trials for “real world” patients that often present with limited PS.

      In summary, SCLC patients may often present with poor PS. These cases should be approached by a multidisciplinary team with expertise to conduct both aggressive and palliative measures with the primary goal of providing symptom relief and, whenever feasible, extend survival. At the end of the day, the Hippocrates quote is more up to date than ever: "To cure sometimes, to relieve often, to comfort always".

      References

      1. Lilenbaum RC, et al: J Thorac Oncol 3:125-9, 2008

      2. Gajra A, et al: J Natl Compr Canc Netw 12:1015-25, 2014

      3. Pietanza MC et al: In: DeVita 2015

      4. NCCN Guidelines 2018

      5. Koedoot CG, et al: J Clin Oncol 20:3658-64, 2002

      6. Baldotto CS, et al: Support Care Cancer 20:2721-7, 2012

      7. Soares M, et al: Chest 131:840-846, 2007

      8. Antonia SJ, t al: Lancet Oncol 17:883-895, 2016

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      MS18.02 - Treatment of Elderly Patients with SCLC (Now Available) (ID 11478)

      13:50 - 14:10  |  Presenting Author(s): Karen Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer accounts for approximately 30,450 (13%) new cases of lung cancer each year in the United States. The worldwide incidence is unknown. SCLC frequently occurs in elderly patients as defined by >70 years of age. A recent analysis of the surveillance, epidemiology and end results (SEER) database showed the incidence of elderly patients diagnosed with SCLC increased from 23% in 1975 to 40% in 2010 with a quarter of patients age 80 or greater (1). Due to comorbidities associated with the aging process resulting in frailty and organ dysfunction, elderly patients (especially patients over the age of 80) may not be offered treatment and are underrepresented in clinical trials. This presentation will review the available retrospective and prospective data.

      Limited Stage SCLC (LS-SCLC)

      Concurrent chemoradiation is the standard of care for patients with limited stage disease. Three age-specific retrospective analyses of randomized, North American cooperative group studies evaluating cisplatin-based regimens did not demonstrate significant differences in overall survival or other efficacy endpoints by age (2). However, two of the studies reported significantly increased treatment related toxicity and mortality in the elderly population. To address the toxicity issue, phase II trials evaluated modified chemotherapy and radiotherapy regimens. These studies showed modified regimens were active and less toxic but no definitive trials have been performed. Alternatively, carboplatin is frequently substituted for the more toxic cisplatin in the concurrent regimen. Another approach is to omit the radiation and administer chemotherapy alone. However, a retrospective analysis of elderly LS-SCLC patients from the National Cancer Data Base from 2003 -2011 demonstrated the use of modern chemoradiation was superior to chemotherapy alone on univariate and multivariate analysis with a 3-year OS of 22% vs 6.3% respectively, P<.001. This effect was seen in patients 80+ years and in patients with comorbidities (3). A subset analysis also showed concurrent treatment significantly improved survival over sequential treatment. Similar findings were observed by the Dutch (4).

      Extensive Stage SCLC (ES-SCLC)

      Etoposide and a platinum agent (cisplatin or carboplatin) is the standard of care for upfront treatment of ES-SCLC. Despite the acceptance of etoposide plus carboplatin as a tolerable and equivalent regimen, elderly patients may not receive treatment. A review of the Alberta Cancer Registry revealed that 32% of patients age 75+ did not receive chemotherapy (5). Of the patients who received chemotherapy, 52% completed all cycles and 66% did not require a dose reduction. Patients who completed all cycles with a dose reduction had a decreased risk of death 1.02 (95% CI: 0.57-1.82) compared to a risk of death of 2.72 (95% CI: 1.52-4.87) for patients who did not complete therapy. Four phase II studies evaluating dose modifications of carboplatin and etoposide in the elderly found similar survival outcomes to standard doses (5). In a recent phase II study from China 34 elderly patients or patients with a PS of 2 who received carboplatin and etoposide had a median PFS of 5.8 months and an OS of 14 months (6). Toxicity was acceptable with Grade 3 or greater neutropenia and febrile neutropenia occurring in 40% and 7% of patients, respectively.

      Prophylactic Cranial Irradiation

      The role for prophylactic cranial irradiation (PCI) in the elderly population is controversial. Retrospective population based and trial specific analyses have shown that PCI improves survival compared to no PCI but concern over increased neurocognitive dysfunction has resulted in limited uptake of PCI (7-9). Indeed, a comparison of tested and self-reported cognition in two RTOG trials evaluating PCI in patients with LS-SCLC demonstrated higher rates of cognitive decline with advanced age (10). Modern radiation techniques, hippocampal sparing and memantine may reduce the rate of cognitive decline. Recent data also suggests that MRI surveillance may be an option for patients with ES-SCLC (11).

      Geriatric Assessment Tools

      Geriatric oncology is addressing the optimal approach to the care of these patients through the development of geriatric assessment tools to better define risks and benefits. Investigators are encouraged to incorporate these tools into their clinical trials. Treating physicians should also consider using validated geriatric assessment tools in their routine practice such as the new ASCO 2018 guideline (12).

      Overall, elderly patients should be offered standard treatment but they may require dose modifications. Participation in clinical trials and trials that address the unique needs of the elderly are strongly encouraged.

      REFERENCES

      Abdel-Rahman O. Changing epidemiology of elderly small cell lung cancer patients over the last 40 years; a SEER database analysis. Clin Respir J. 12:1093-9, 2018.

      Palis AG, et al. Treatment of small-cell lung cancer in elderly patients. Cancer. 116:1192-200, 2010.

      Corso CD, et al. Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer. J Clin Oncol. 33:4240-6, 2015.

      Janssen-Heijnen ML, et al. Tolerance and benefits of treatment for elderly patients with limited small-cell lung cancer. J Geriatr Oncol. 5:71-7, 2014.

      Fisher S, et al. Uptake and tolerance of chemotherapy in elderly patients with small cell lung cancer and impact on survival. J Cancer Epidemiol. 2012:708936, 2012.

      Igawa S, et al. Comparison of carboplatin plus etoposide with amrubicin monotherapy for extensive-disease small cell lung cancer in the elderly and patients with poor performance status. Thorac Cancer. 2018, Jun 5 [Epub ahead of print].

      Eaton BR, et al. Effect of prophylactic cranial irradiation on survival in elderly patients with limited-stage small cell lung cancer. Cancer. 119:3753-60, 2013.

      Rule WG, et al. Prophylactic cranial irradiation in elderly patients with small cell lung cancer: findings from a North Central Cancer Treatment Group pooled analysis. J Geriatr Oncol. 6:119-26, 2015.

      Damhuis RAM, et al. Usage of Prophylactic Cranial Irradiation in Elderly Patients With Small-cell Lung Cancer. Clin Lung Cancer. 19:e263-7, 2018.

      Gondi V, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 86:656-64, 2013.

      Takahashi T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 18:663-71, 2017.

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      MS18.03 - Treatment of SCLC transformed from EGFR Mutant Adenocarcinoma (Now Available) (ID 11479)

      14:10 - 14:30  |  Presenting Author(s): Nicolas Marcoux

      • Abstract
      • Presentation
      • Slides

      Abstract

      While most molecular findings at time of resistance to EGFR tyrosine kinase inhibitors (TKIs) involve point mutations in the EGFR gene or the development of specific signaling bypass tracts, more fundamental changes in cell functioning can occasionally be seen. Indeed, neuroendocrine transformation, specifically to small-cell lung cancer (SCLC), is a relatively rare but recurrent finding at the time of acquired resistance to EGFR TKIs, developing in 3-10% of cases[1],[2],[3]. De novo, EGFR-mutant SCLC has also been reported and represents a subset of the very rare cases of SCLC seen in never-smokers[4]. In both instances, biopsies are histologically indistinguishable from the more frequent, smoking-associated SCLC.

      Although the transformed tumors maintain the same founder EGFR mutation as the initial adenocarcinoma at the DNA level, dependence on EGFR signaling is typically lost through reduced expression of the EGFR protein[5]. Patients with alterations of both TP53 and RB1 at the time of initial diagnosis of adenocarcinoma seem to be at significantly higher risk of transformation[6]. Although this finding was initially described with immunohistochemistry (IHC) assays, it is likely applicable to mutations found by next-generation sequencing (NGS) genotyping panels increasingly used in routine clinical care. Importantly, the percentage of patients with these anomalies that will eventually go on to transform is unknown. The threshold for obtaining tissue biopsy at progression should be lower in patients who are incidentally found to have mutations in TP53 and RB1 at initial diagnosis, but no intervention is currently known to decrease transformation risk. Mainly for that reason, specifically obtaining TP53/RB1 IHC or mutational status at diagnosis should be considered investigational.

      Rather than a linear evolution from NSCLC to SCLC, many experts believe that small-cell transformation occurs in the context of multiple clonal subpopulations evolving dynamically. The cell population that eventually becomes clinically apparent as SCLC has been shown to branch out early from the main adenocarcinoma subpopulation[6], sometimes even prior to initial clinical diagnosis of lung cancer. Clinically, small-cell transformations are usually seen after months to years of TKI therapy (as discussed next), which leads to the hypothesis that the small-cell-prone clonal subpopulation can remain dormant for long periods of time. Although APOBEC-induced hypermutation has been shown to occur in these cells, the specific mechanisms at play during this apparent prolonged period of cell dormancy remain largely unknown. Another proof of the polyclonal nature of these cancers can be seen in the occasional reversal to NSCLC histology at progression after administration of a SCLC-directed therapy such as platinum-etoposide[7].

      Due to the rarity of SCLC transformation, published clinical data related to patients’ evolution is retrospective and almost exclusively in the form of case reports. However, a retrospective series of 67 EGFR-mutant patients with SCLC transformation treated in 11 high-volume North American centers was recently presented[8]. Demographic characteristics, including age, race and smoking status, were concordant with the general EGFR population and median time between initial diagnosis of metastatic NSCLC and SCLC transformation was 18 months. Almost all patients were actively receiving TKI therapy at time of transformation. Median overall survival from initial diagnosis was 32 months, similar to what is seen in standard EGFR-mutant NSCLC. However, once SCLC was identified (including in 9 patients with de novo EGFR-mutant SCLC), median survival was 11 months, more in line with what is seen in smoking-associated SCLC. While high clinical response rates to platinum etoposide (54%) and taxanes (50%) were noted, these responses were mostly transient, with median progression-free survivals of 3.4 and 2.7 months respectively. Importantly, considering the interest surrounding these therapies, no responses were seen in 17 patients who received checkpoint inhibitors, including the ipilimumab-nivolumab combination. Cytotoxic chemotherapy, especially the classic regimen of platinum-etoposide, thus appears to be the favored initial approach to SCLC-transformation. Potential for reversal to NSCLC, performance status and toxicity profiles must be taken into account for later lines of therapy. Although CNS involvement is frequent, prophylactic cranial irradiation is not recommended.

      Despite these recent improvements in our understanding of EGFR-mutant small-cell transformation, its rarity makes it challenging to prospectively evaluate novel therapeutic strategies. Prospective identification of patients at high risk of transformation and multicentric collaborative efforts will likely be needed to improve outcomes for this entity.

      [1]Piotrowska Z, Stirling K, Heist R, et al. OA 07.05 Serial Biopsies in Patients with EGFR-Mutant NSCLC Highlight the Spatial and Temporal Heterogeneity of Resistance Mechanisms. Journal of Thoracic Oncology. 2017 Nov 1;12(11):S1762.

      [2]Sullivan I, Planchard D. Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience. Therapeutic advances in respiratory disease. 2016 Dec;10(6):549-65.

      [3]Yu H, Arcila ME, Rekhtman N, et al. Analysis of Mechanisms of Acquired Resistance to EGFR TKI therapy in 155 patients with EGFR-mutant Lung Cancers. Clinical cancer research. 2013 Mar 7:clincanres-2246.

      [4]Varghese AM, Zakowski MF, Helena AY, et al. Small-cell lung cancers in patients who never smoked cigarettes. Journal of Thoracic Oncology. 2014 Jun 1;9(6):892-6.

      [5]Niederst MJ, Sequist LV, Poirier JT, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nature communications. 2015 Mar 11;6:6377.

      [6]Lee JK, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. Journal of Clinical Oncology. 2017 May 12;35(26):3065-74.

      [7]Mooradian MJ, Piotrowska Z, Drapkin BJ, et al. Clonal Evolution and the Role of Serial Liquid Biopsies in a Case of Small-Cell Lung Cancer–Transformed EGFR Mutant Non–Small-Cell Lung Cancer. JCO Precision Oncology. 2017 Nov 7;1:1-7.

      [8]Marcoux N, Gettinger SN, O'Kane GM, et al. Outcomes of EGFR-mutant lung adenocarcinomas (AC) that transform to small cell lung cancer (SCLC).J Clin Oncol 36, 2018 (suppl; abstr 8573).

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      MS18.04 - Retreatment with Platinum and Etoposide and Treatment Beyond Second Line (Now Available) (ID 11480)

      14:30 - 14:50  |  Presenting Author(s): Charles Butts

      • Abstract
      • Presentation
      • Slides

      Abstract

      Extensive stage small cell lung cancer (SCLC) is characterized by an initial response to chemotherapy followed by progression usually within 6 months. The clinical approach to second line therapy and beyond depends on patient wishes, performance status (PS), and duration of response to initial therapy or progression free interval (PFI). While some have challenged the importance of PFI in selection of subsequent therapy (1), guidelines by the European Society of Medical Oncologists (ESMO) (2) and the American College of Chest Physicians (ACCP)(3), recommend treatment options based on PFI. This presentation will focus on retreatment with platinum-based chemotherapy and treatment beyond second line.

      The ACCP guidelines, which have been endorsed by the American Society of Medical Oncology (ASCO) recommend re-challenge with the first line regimen in patients with a PFI of at least 6 months. The ESMO guidelines define sensitive relapse as a PFI of more than 3 months and suggest these patients may derive benefit from re-challenge with the original, usually platinum based, regimen.

      Genestreti (4) evaluated the benefit of re-challenge with platinum-etoposide in a retrospective, multi-institutional review. In 112 patients who progressed more than 90 days after initial chemotherapy, re-challenge with platinum-etoposide resulted in a response rate (RR) of 45% and a median overall survival (mOS) from re-challenge of 7.9 months. There was no difference in survival using PFI of 90, 120, or 150 days. A second European multicenter study (5) reported outcomes of 161 patients receiving second line therapy. Platinum sensitive patients (PFI 3 months) who were re-challenged had a higher RR and longer mOS. Response to first line therapy and PS were independent predictors of survival.

      Single institutional series have also supported the importance of sensitivity to first line therapy in determining second line treatment. Nagy-Mignotte (6) defined sensitive disease as PFI of at least 3 months. Of the 300 patients who received first line platinum-etoposide therapy, 48% had sensitive disease and the majority of these (72%) were re-challenged. The RR to re-challenge was 65% (21% complete response) and mOS from second line was 9.3 months. Patients with resistant or refractory disease were primarily treated with taxanes or topotecan. The RR in these patients was 21% with mOS of 5.2 months and 3.8 months. Kim et al (7) found response to initial therapy and PS to be significantly associated with survival after second line therapy in 232 patients from a single institution in Japan.

      Treatment Beyond Second Line

      There are currently no approved third line therapies for SCLC and the evidence for benefit from any therapy consists of retrospective reports and phase II trials.

      In the largest series reported from Japan (8) only 30% of SCLC patients receiving first line therapy went on to receive third line treatment. The majority of patients received single agent therapy in third line with amrubicin being most common (47%). Independent prognostic factors were time to treatment failure of at least 5 months and PS at time of third line therapy. A Dutch study found only 18% of their SCLC patients received at least 3 lines of therapy. The RR to third line was 25% with mOS of 5 months (9).

      An international multi-center retrospective analysis (10) found that the majority of patients were re-challenged with a regimen previously received in first or second line, with 6% of patients receiving platinum-based chemotherapy in all 3 lines. The RR was modest at 18% with mOS from third line of 4.7 months. Response to second line therapy was predictive of response to third line but only baseline LDH was prognostic for survival.

      It is clear that few patients with SCLC go on to receive treatment beyond second line. However, carefully selected patients with good PS may derive benefit. There is a need for new, active therapies. The most promising new options for treatment beyond second line include targeted therapy to DLL3 (rovalpituzumab-T) and immunotherapy. Updated results with these agents will be discussed.

      References

      Lara P et al Journal of Thoracic Oncology 2015; 10(1):110-115

      Fruh M et al Annals of Oncology 2013; 24 (Suppl 6): vi99-vi 105

      Jett J et al Chest 2013; 143 (5) (Supp): e4005-e4019

      Genestreti G et al Clinical Lung Cancer 2015; 6: 223-8)

      Garassino MC et al Lung Cancer 2011; 72: 378-83

      Nagy-Mignotte H Clinical Lung Cancer 2012; 78: 112-120

      Kim YH et al Cancer 2008; 113: 2518-23

      Saruwatari K et al Clinical Lung Cancer 2016; 17:581-87

      DeJong WK et al, Lung Cancer 2006; 52: 339-42

      Simos D et al Clinical Lung Cancer 2014; 15: 110-118

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    MS24 - Global Perspectives on Tobacco Control (ID 802)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 BD
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      MS24.01 - Tobacco Control Impacting the Effectiveness and Cost of Cancer Care (Now Available) (ID 11501)

      10:30 - 10:45  |  Presenting Author(s): Graham Warren

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS24.02 - Legal Action Against the Tobacco Industry in Europe (Now Available) (ID 11502)

      10:45 - 11:00  |  Author(s): Wanda De Kanter

      • Abstract
      • Presentation
      • Slides

      Abstract

      A growing coalition of individual patients and anti-tobacco and health organizations in the Netherlands has pressed charges against four tobacco companies active in the Netherlands: Philip Morris International, British American Tobacco, Japan Tobacco International and Imperial Tobacco Benelux.

      The tobacco manufacturers are accused of attempted murder and manslaughter and/or premeditated attempts to cause grievous bodily harm and/or premeditated attempts to cause damage to health. Another accusation concerns the falsification of documents. Currently, a court of appeal is considering whether it will order the Public Prosecution Service to bring this case to court after the Service earlier had decided it could not do so.

      If the case eventually is brought to court it would be the first criminal case against the tobacco industry in the world.

      Deliberate addiction

      In September 2016 criminal lawyer Bénédicte Ficq (Ficq & Partners) filed a criminal complaint against the tobacco industry on behalf of two lung patients and the Youth Smoking Prevention Foundation[1].

      The complaint documentation[2] filed argues that the tobacco industry deliberately makes cigarettes more addictive by adding hundreds of additives, which makes new smokers addicted quickly and makes existing smokers more addicted.

      Furthermore, the accusation focusses on the fact that cigarette companies make tiny holes in the filters of cigarettes in order to sabotage the official measurements of harmful substances. The holes in the filters, almost invisible to the naked eye, draw extra air into the measurement machines. As a result, those machines measure lower values than those actually inhaled by smokers, who block the holes with their lips and fingers as they smoke. Because of this, smokers inhale 2 to 3 times the recorded and maximum allowed levels of harmful substances.

      Additives

      Lawyer Bénédicte Ficq commented: ‘When I began to study all the additives that cause, enhance and maintain addiction, I nearly fell off my chair in shock at all the manipulated additives in cigarettes. The industry just one goal, and that is to get people addicted. People do not realize just how manipulated a cigarette is today. We want to make that clear to the Public Prosecutors Office, and we are convinced that when, like us, it understands what tobacco manufacturers put on the market, it too will conclude that it amounts to “causing grievous bodily harm”.’

      No free will

      The case submitted demonstrates the various ways the tobacco industry can be held legally responsible for the health damage caused to smokers. By knowingly and intentionally getting smokers addicted, the tobacco industry denies them their free will to smoke or not. The fact that cigarettes are a legal product according to the Tobacco Act does not relieve the tobacco industry of its obligation to respect other laws. According to the submission made, the tobacco industry fails to comply with a number of criminal law provisions. It therefore has a case to answer before a criminal court.

      Growing coalition

      In the months that followed the initial complaint, more and more organizations joined, including the Dutch Cancer Society (DCS), the Dutch Journal of Medicine (NTvG), the Federation of Cancer Patients, the Netherlands Cancer Institute (NKI-AVL), the combined Academic Medical Centers in the Netherlands, and most of the professional organizations of medical specialists and health care workers. Together these organizations represent the better part of the medical profession in the Netherlands as well as many thousands of patients.

      Appeal after rejection

      Last February, the Dutch Public Prosecution Service concluded ‘that it is not possible to bring a successful prosecution against the tobacco industry under the current legal and regulatory frameworks’.[3] Lawyer Bénédicte Ficq has an entirely different view and in May on behalf of her clients made use of the possibility to appeal the decision with the court of appeal. The court currently assesses whether a prosecution would be feasible and whether this prosecution is expedient. If the court judges that both criteria have been met, it will order the prosecution.

      Press coverage

      The case against the tobacco companies from the start has got a lot of attention in both national and international media. All major moments in the case caused extensive press coverage with peaks when the case was first announced, when the Dutch Cancer Institute decided to join the case, and when the Public Prosecution Service announced not bring the case to court.

      Internationally the case was covered by leading media including The Guardian, The Independent, The Washington Post, Japan Times, ABC, NBC, Fox, and Channel New Asia. Der Spiegel[4] published an extensive double interview with Bénédicte Ficq and Wanda de Kanter.

      All the press coverage added to the public awareness of the addictive nature of tobacco and the manipulative nature of the tobacco manufacturers. A publicity campaign of the same size would be worth millions.

      International followers

      The Dutch team met in Geneva with lawyers and anti-smoking organizations from different countries to give them backgrounds to the Dutch case and share their research findings and legal approach. Many consider to follow the Dutch example. In France the National Committee to Counter Tobacco use already pressed charges against tobacco companies operating in France[5] generally on the same accusations as in the Netherlands.

      It is due to two brave lung patients that the criminal case is on the agenda in the Netherlands and internationally, opening the eyes of the public for the despicable practices of the tobacco industry. It is time that these practices are considered where they belong: in criminal court.

      Drs. Wanda de Kanter is lung physician in the Dutch Cancer Institute (NKI-AVL), chair of the Dutch Youth Smoking Prevention Foundation and member of the IASLC Tobacco and Prevention Team. She was awarded twice (in 2014 and 2015) the Woman in the Media Award for women who are most visible in media.

      [1] www.stichtingrookpreventiejeugd.nl

      [2] https://sickofsmoking.nl/wp-content/uploads/2017/03/Complaint-Tobacco-Industry.pdf

      [3] https://www.om.nl/algemeen/english/@102217/no-further/

      [4] http://www.spiegel.de/spiegel/tabak-und-sucht-was-sie-noch-nicht-ueber-zigaretten-wissen-a-1195389.html

      [5] http://www.cnct.fr/communiques-de-presse-44/le-scandale-du-filtergate-177.html

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      MS24.03 - The Importance of Physician Involvement in Tobacco Control (Now Available) (ID 11503)

      11:00 - 11:15  |  Presenting Author(s): Jacek Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco remains the most important preventable cause of premature mortality in the world. WHO, based on Framework Convention on Tobacco Control (WHO-FCTC), recommends the implementation of comprehensive tobacco control measures, including tobacco price policies, bans on tobacco advertising, promotion and sponsorship, health education, access to tobacco dependence treatment, strict regulation of tobacco products and other interventions.

      Physicians remain among the most respected and trusted community voices on health matters and should play a key role in all tobacco control measures. Their activities may be accomplished at both individual, institutional, community and society levels.

      In the everyday health-care setting physicians should counsel patients and their families against smoking and exposure to second-hand smoke and assist them to overcome tobacco addiction (1). Successful intervention begins with identifying users and appropriate interventions based upon the patient's willingness to quit. To motivate patients to quit they should be informed about the health, economic and social benefits of quitting (2). The activities that can help patients ready to quit are summarized in the "5 A's” model developed by The United States Department of Health and Human Services (3). This minimal intervention that may be accomplished within 3-5 minutes, includes asking about tobacco use, advising users all users to quit, assessing willingness to quit, advising quitting, and further referring and arranging for cessation services.

      To perform properly these roles, all physicians should be provided a basic training on brief interventions for smoking cessation and on evidence-based tobacco cessation measures. An indispensable condition for the effective physicians’ cessation counseling are their own behaviors and practices. Physicians should serve as role models in not smoking or quitting smoking for the general public. Compared to smokers, physicians who do not smoke are far more likely to engage in cessation advice and counselling (4, 5). Indeed, greater tobacco control progress has been shown in countries with lower smoking rates among physicians (6)

      Tobacco control activities at the community level, apart from those described above, may include speaking out publicly and lobbying for comprehensive public policies to control tobacco use, visiting schools to promote tobacco-free lifestyles and cultures, organizing campaigns to extend tobacco-free public places or disseminating evidence-based information and materials about tobacco related problems through local media.

      Professionals that have leadership positions should engage in the policy-making process at the community and national level. This may include promoting WHO-FCTC, developing tobacco-control strategies, participation in legislation processes and supporting comprehensive tobacco control measures, such as increased taxation and prices of tobacco products or lobbying for funding of tobacco control programs. An example of a bottom-up initiative undertaken by health professionals was the development of policy recommendations of a tobacco control bill and the legislation that banned smoking in public places in Poland (7). A similar initiative was undertaken by the British Medical Association that prompted the development of the legislation to smoking ban in enclosed public places in the United Kingdom (8).

      Medical societies should encourage their members to become engaged in tobacco control advocacy, organize plenary sessions and panel discussions at society conferences and workshops, adopt resolutions and issue ethical opinions on members, advocate for health care systems to reimburse for cessation counseling and treatment, issue press releases, hold press or organize direct lobbying by medical society leaders (9).

      In conclusion, the professional responsibility of physicians extends beyond the treatment of tobacco-related disease to include prevention, cessation counseling and policy advocacy, in the fight to eradicate tobacco use as an international public health pandemic.

      References

      1. Richmond R. Physicians can make a difference with smokers: Evidence-based clinical approaches. Int J Tubercul Lung Dis 1999; 3: 100–12.

      2. A guide for tobacco users to quit. World Health Organization 2014. http://apps.who.int/iris/bitstream/handle/10665/112833/9789241506939_eng.pdf;jsessionid=8FE92AF3B90AA67BDE48927455DD9210?sequence=1

      3. Toolkit for delivering the 5A’s and 5R’s brief tobacco interventions in primary care. World Health Organization 2014.

      4. Azuri J, Nashef S. Primary care physicians' characteristics and attitudes on smoking cessation. Am J Health Behav 2016; 40: 578-84.

      5. Meshefedjian GA, Gervais A, Tremblay M, et al. Physician smoking status may influence cessation counseling practices. Can J Public Health 2010; 101: 290-293..

      6. Smith DR, Leggat PA: The historical decline of tobacco smoking among Australian physicians 1964–1997. Tob Induc Dis 2008, 4:13. doi:10.1186/1617-9625-4-13.].

      7. Jassem J, Przewoźniak K, Zatoński W. Tobacco control in Poland-successes and challenges. Transl Lung Cancer Res 2014; 3:280-285.

      8. The human cost of tobacco. Passive smoking: doctors speak out on behalf of patients. British Medical Association, July 2004.

      9. Engaging doctors in tobacco control. American Cancer Society 2003.

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      MS24.04 - Challenges of Tobacco Control in China (Now Available) (ID 11504)

      11:15 - 11:30  |  Presenting Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco use remains a serious threat to global health and has killed almost 100 million individuals during the 20th century, and if current trends continue, approximately 1 billion people will die from tobacco use during the 21st century1. The rates of smoking prevalence are still increasing in many low- and middle-income countries, although decreasing in most high-income countries, thus, the number of tobacco-related deaths will continue to increase in the future years. China, the largest populous country in the world with a population of more than 1.3 billion individuals, is also facing this rigorous public health challenge. Owning to the large population base, China remains the largest tobacco producer and consumer in the world2, 3. According to the report of World Health Organization (WHO) in the year of 2009, China consumed more than 2.2 trillion cigarettes, which account for 38% of the world’s cigarettes and more than the other top four tobacco-consuming countries combined2. Each year, more than 1.2 million people have been killed as a result of tobacco use in China and by the year 2030, the number of tobacco-related deaths will go up approximately 300%, resulting 3.0 million tobacco-related deaths annually1. Even to this day, the situation of tobacco control in China is still increasing serious, accompanying with high smoking prevalence, low and affordable price of cigarettes, poor knowledge of tobacco harms, and heavy economic burden of tobacco-related diseases etc.

      The WHO Framework Convention on Tobacco Control (FCTC), which covers 87.4% of the world’s population and consists of more than 170 countries as signatories, is the first ever international treaty devoted to tobacco control in the world. Despite ratifying the FCTC in the year of 2005, the pace of tobacco control in China has lagged behind of most of the eligible signatories, which rank in the bottom 20% in WHO’s ranking of the success of countries in tobacco control and FCTC compliance4, 5. With an effort to assist eligible signatories to reduce tobacco use, the WHO FCTC introduced the MPOWER measures (Monitoring tobacco use and prevention policies; Protecting people from the harms of tobacco smoke; Offering help to quit tobacco use; Warning about the dangers of tobacco; Enforce bans on tobacco advertising, promotion and sponsorship; Raising taxes on tobacco)6. However, the implement of MPOWER measures needs to be largely improved in China at present.

      The health professionals also play a critical role in smoking cessation and even brief smoking cessation interventions are effective. However, the awareness of adverse health effects of smoking in health professionals is relatively poor in China7, 8. Cigarette gifting culture is another concern. Rarely seen in other cultures, the practices of gifting and sharing cigarettes are well accepted and pervasive across China. In Chinese culture, cigarette sharing or gifting is a bridge for establishing and maintaining interpersonal relationships, as well as a gesture to show respect and welcome guests. As a result, cigarette sharing or gifting is not only a contributor to individuals initiating smoking process, but also a major barrier to smoking cessation, especially in rural China9. In addition, it is worth noting that China’s State Tobacco Monopoly Administration is not only a governmental agency responsible for all aspects of tobacco industry, including tobacco growing, processing, product manufacturing and distribution and also material and machinery supplies, it is also in charge of tobacco control affairs in China, which presents a serious conflict of interest and is another significant obstacle for tobacco control in China10.

      In summary, several impediments for tobacco control in China need be overcome, including poor awareness of harm of tobacco use and high smoking prevalence among physicians, cigarettes gifting and sharing culture, and conflict of interest in government agency. Therefore, it is very important to improve the awareness of the harms of tobacco use, decrease the smoking prevalence among physicians, and training standard anti-tobacco skills for health professionals. Furthermore, additional cultural-specific measures also should be taken to discourage sharing or gifting cigarettes to reduce tobacco use through sharing or gifting, especially in rural China. More importantly, to separate the functions of the government from the tobacco industry may be the most critical step to eliminate the contradictions in China’s tobacco policies and to fulfill the WHO FCTC goals in China.

      Reference

      1. World Health Organization. WHO Global Report: Mortality Attributable to Tobacco. Geneva: World Health Organization. http://www.who.int/tobacco/publications/surveillance/rep_mortality_attibutable/en/index.html. .

      2. World Health Organization. 2008–2013 action plan for the global strategy for the prevention and control of noncommunicable diseases. http://whqlibdoc.who.int/publications/2009/9789241597418_eng.pdf.

      3. China Health Statistics Yearbook. . http://wsb.moh.gov.cn/htmlfiles/zwgkzt/ptjnj/year2011/index2011.html.

      4. World Health Organization. Parties to the WHO Framework Convention on Tobacco Control. 2011. Available from: http://www.who.int/fctc/signatories_parties/en/index.html.

      5. Yang GH, Li Q, Wang CX, et al: Findings from 2010 Global Adult Tobacco Survey: implementation of MPOWER policy in China. Biomed Environ Sci 23:422-9, 2010.

      6. World Health Organization. WHO report on the global tobacco epidemic, 2008: The MPOWER package.

      7. Yang Y, Wang JJ, Wang CX, et al: Awareness of tobacco-related health hazards among adults in China. Biomed Environ Sci 23:437-44, 2010

      8. Xu Y, Xu S, Wu Q, et al: Tobacco knowledge among adults in Zhejiang Province, China. PLoS One 8:e59172, 2013.

      9. Rich ZC, Hu M, Xiao S: Gifting and sharing cigarettes in a rural Chinese village: a cross-sectional study. Tob Control 23:496-500, 2014

      10. He P, Takeuchi T, Yano E: An overview of the China National Tobacco Corporation and State Tobacco Monopoly Administration. Environ Health Prev Med 18:85-90, 2013.

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    MTE06 - Symptom Management in Mesothelioma (Ticketed Session) (ID 816)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Mesothelioma
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 206 BD
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      MTE06.01 - Role of Pleurectomy in Palliation of Symptoms (Now Available) (ID 11556)

      07:00 - 07:30  |  Presenting Author(s): John G Edwards

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MTE06.02 - How to Register Toxicity and Guide Patients (Now Available) (ID 11557)

      07:30 - 08:00  |  Presenting Author(s): Liz Darlison

      • Abstract
      • Presentation
      • Slides

      Abstract

      There are 125 million people exposed to asbestos in the workplace and it causes over 100,000 deaths annually (IOSH 2018). The UK has the highest incidence of Malignant Mesothelioma in the world with 2697 cases in 2015 (CRUK 2018).

      Approved treatment in the UK has not changed for over a decade with Pemetrexed and Cisplatin being the only standard treatment widely available. However the last 2 years has seen an increase in clinical trial opportunities using both targeted and immunotherapy drugs. To help promote equitable access, Mesothelioma UK publishes a regular clinical trials update listing all trials that are open to recruitment (Mesothelioma UK 2018).

      These new treatment options have brought with them new challenges in terms of patient expectation, accessing treatment and side effects.McCambridge et al (2018) describe 2017 as a year characterised by several important advances in the field although only a minority are considered practice changing. This results in patients feeling anxious about the ongoing limited treatment options and frustrated by difficulties experienced in trying to access new treatment modalities.

      This presentation will briefly review current treatment options in the UK and how patients and health care professionals are kept informed about treatment and trial opportunities. Approaches to managing treatment expectation are explored and finally how health care professionals and patients are educated about side effects from new treatment modalities in and out of clinical trials.

      References

      IOSH 2018 (Institute of Occupational Safety and Health) No Time to Lose Campaign https://www.iosh.co.uk/VP/Home/Toolkit/IOSH-No-Time-to-Lose-Campaign.aspx (Last viewed June 18th 2018)

      CRUK 2018 (Cancer Research UK) Mesothelioma Incidence Statistics https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/mesothelioma/incidence (Last viewed June 28th 2018)

      Mesothelioma UK 2018 Clinical Trials http://www.mesothelioma.uk.com/information-support/information/clinical-trials/ (Last viewed July 4th 2018)

      McCambridge AJ, Napolitano A, Mansfield AS, Fennell DA, Sekido Y, Nowak AK, Reungwetwattana T, Mao W, Pass HI, Carbone M, Yang H, Peikert T, 2018. Progress in the Management of Malignant Pleural Mesothelioma in 2017. Journal of Thoracic Oncology Vol 13 No 5 606-623.

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