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K. Zarogoulidis

Moderator of

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    SC13 - Interaction of COPD and Lung Cancer - Consequences for Early Diagnosis and Management (ID 337)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Radiology/Staging/Screening
    • Presentations: 4
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      SC13.01 - Common Pathogenesis of COPD and Lung Cancer (ID 6649)

      11:00 - 11:20  |  Author(s): K. Fong

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC13.02 - Increased Risk for Lung Cancer in COPD (ID 6650)

      12:10 - 12:30  |  Author(s): S. Lam

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Globally, chronic obstructive pulmonary disease (COPD) and lung cancer are among the top 5 causes of death. The two diseases share common risk factors such as tobacco smoking, outdoor and household air pollution. COPD is associated with a two to four fold increased risk for lung cancer independent of smoking.[1,2] COPD can be defined by symptoms, lung function criteria (forced expiratory volume in one second (FEV~1~) <80% predicted for age, gender and height, FEV~1~/ forced vital capacity (FVC) <0.7, or diffusing capacity <80%.[3,4] COPD has also been defined by computed tomography (CT) changes such as pulmonary emphysema by visual examination or by quantitative measurement (percent voxels < -950 HU based on a threshold of 4.8%) or air trapping from comparison between inspiratory and expiratory CT scans.[5,6] In the PLCO~m2012 ~risk prediction model[7], self-reported COPD was significantly associated with lung cancer risk (OR 1.45, 95% CI: 1.25-1.67). The area under the ROC curve (AUC) was 0.559. The AUC of the prediction model with and without a history of COPD was 0.800 and 0.799 respectively (M. Tammemagi, personal communication). A study in British Columbia examined the incremental value of pulmonary function test in 2,596 ever smokers above 40 years of age who had smoked ≥20 pack-years. One hundred and thirty-nine participants developed lung cancer after a median follow-up of 7.7 years.[8. ]Lower FEV~1~% increased the lung cancer risk for both men and women, but did so more strongly for men than in women (interaction P <0.001). FEV~1~% was found to substantially improve lung cancer prediction in a risk prediction model that included age, sex, education level, body mass index, family history of lung cancer and smoking. In this study, although CT detected emphysema was significantly associated with lung cancer in unadjusted analysis (OR 2.22, 95% CI: 1.17 – 3.78; P=0.012), in the fully adjusted model, neither emphysema nor a history of chronic bronchitis, which were significant in other studies, approached significance. A recent case-control study showed that only air trapping on quantitative CT imaging and FEV~1~/FVC <0.7 were independent predictors of lung cancer risk in a multivariable model.[9] Thirty-five percent of lung cancer cases and 55% of the controls had no evidence of COPD on spirometry or air trapping on quantitative CT. Forty-nine percent of lung cancer patients had FEV~1~/FVC >0.7. In the Pan-Canadian lung screening study of 2,537 ever smokers between the age of 50 to 75 with a 6 year lung cancer risk of ≥2% using a prototype PLCO prediction model, 50.6% of the participants had FEV~1~/FVC <0.7 and 42.8% had FEV~1~<80%. Among those who were found to have lung cancer, 63% had FEV~1~/FVC <0.7 and 54.5% had FEV~1~<80%. In those without lung cancer, the corresponding figures were 49.5% and 42% respectively. While COPD detected by pulmonary function test(s) and/or thoracic CT identify smokers at higher risk of lung cancer, a strategy to focus CT screening using these criteria may miss a significant proportion of lung cancers. Quantitative CT imaging of air trapping requires an inspiratory and expiratory CT with added cost and radiation exposure. The US Preventive Services Task Force recommended against screening for COPD in asymptomatic adults.[10 ]Whether identification of COPD by pulmonary function test and/or quantitative thoracic CT imaging can benefit a sub-population who would otherwise not meet the current criteria for lung cancer screening with CT or reduce the frequency and duration of follow-up CTs in a population based lung cancer screening program require further study. References 1. Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med 1986;105:503-7. 2. Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007 Aug 1;176(3):285-90. 3. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013 Feb 15;187(4):347-65. 4. de-Torres JP, Marin JM, Casanova C, et al. Identification of COPD patients at high risk of lung cancer mortality using the COPD-LUCSS_DLCO. Chest 2016; 149:936-42. 5. Lynch DA, Austin JH, Hogg JC, Grenier PA, Kauczor HU, Bankier AA, Barr RG, Colby TV, Galvin JR, Gevenois PA, Coxson HO, Hoffman EA, Newell JD Jr, Pistolesi M, Silverman EK, Crapo JD. CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society. Radiology. 2015 Oct;277(1):192-205. 6. COPDGene CT Workshop Group, Barr RG, Berkowitz EA, Bigazzi F, Bode F, Bon J, et al. A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation. COPD. 2012 Apr;9(2):151-9. doi: 10.3109/15412555.2012.654923. 7. Tammemagi MC, Katki HA, Hocking WG, Church T, Caporaso N, Kvale P, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-36. 8. Tammemagi M, Lam S, McWilliams A, Sin D. Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction. Cancer Prev Res (Phila). 2011 Apr;4(4):552-61. 9. Schwartz AG, Lusk CM, Wenzlaff AS, Watza D, Pandolfi S, et al. Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis. Cancer Epidemiol Biomarkers Prev. 2016 Sep; 25(9):1341-7. 10. US Preventive Services Task Force (USPSTF). Screening for chronic obstructive pulmonary disease. US Preventive Services Task Force recommendation statement. JAMA April 5, 2016; 315(13):1372-1377. Supported by the Terry Fox Research Institute.

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      SC13.03 - Limitation by COPD for Diagnostic Procedures (ID 6651)

      11:20 - 11:40  |  Author(s): G. Ostoros, J. Varga, A. Kerpel-Fronius

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Limitation by COPD for Diagnostic Procedures Ostoros, Gy. Varga, J. and Kerpel-Fronius A. National “Korányi” Institute for Pulmonology Hungary, Budapest Lung cancer and COPD are smoking dependent diseases. Smoking cessation is crucial before and during the diagnostic procedures because of the consequences of smoking (e.g. sputum retention, mucociliary dysfunction and potential other more serious complications after the procedures). Severe obstructive or restrictive pulmonary disorders limit the diagnostic possibilities in patients with malignant pulmonary diseases. The screening of lung cancer with low-dose CT has become the gold standard in the past decade. The two imaging-based phenotypes of COPD can be well distinguished by this technique. CT screening can also help to identify non-diagnosed emphysema patients and may lead to early treatment of the disease. It has been showed that non-smoker emphysema patients have a similar risk of lung cancer as smokers with emphysema. Thus, patients with emphysema may be an eligible subgroup for a more intensive lung cancer screening program. However, once a suspicious lesion is found severe COPD, it can limit the choices available for differential diagnosis seriously - CT guided lung biopsies in COPD patients carry a higher risk of haemorrhage and pneumothorax. Patients with severe COPD and respiratory failure with decreased oxygen saturation limit the indication of diagnostic bronchoscopic procedures as well. The examination of exhaled breath condensate (EBC) is a non invasive process. There are efforts to discriminate lung cancer and COPD with EBC. Lung tumours have influence on lung function. Besides the severity of COPD, the result of the lung function test (LFT) depends on the size and position of the pulmonary tumour as well. In the case of a big central tumour or a huge amount of pleural fluid, the LFT will show rather restrictive than obstructive character. A small peripheral malignancy will not change the shape and volume of the LFT. If the tumour is in the trachea or compresses it's wall, the inspiratory phase of the flow-volume chart could be flat. Sometimes the lung tumours could lead a misdiagnosis of COPD. A centrally located small tumor which is not visible on the chest X-ray but compresses the trachea or any of the pulmonary vessels can cause breathlessness, fatigue and decreased oxygen saturation. A mediastinal conglomerate of lymph nodes can cause similar symptoms. Low physical activity, obesity, smoking and comorbidities are significant negative factors for risk stratification before any pulmonary diagnostic procedure as well. Pulmonary rehabilitation can improve functional reserves if functional capacity is at borderline. Pulmonary rehabilitation has positive effect on cardiovascular function, metabolism, muscle-function and lung mechanics. As for lung function parameters, we need to focus on forced expiratory volume in one second (FEV~1~) and diffusion capacity (DL~CO~). We can follow the common agreement of minimum criteria of the European Society of Chest Surgeon and European Respiratory Society for risk stratification before a diagnostic pleuroscopy. Based on this protocol, FEV~1~ and DL~CO~ need to be >35%pred. In the case of 35%pred< FEV~1 ~and DL~CO~<75%pred, we need to consider VO~2~/kg during a cardiopulmonary exercise test. If VO~2 ~is~ ~<10 ml/kg/min, the patient need a pulmonary rehabilitation program to improve functional reserves. Regarding lung function, we need to focus on lung mechanics and lung kinematics as well. Lung mechanics can be monitored by resting functional reserve capacity (FRC) and residual volume (RV). Lung kinematics can be monitored by chest expansion. Improved resting or dynamic hyperinflation and lung kinematics of the patients with chest physiotherapy and complex pulmonary rehabilitation is also suggested. As a general effect of rehabilitation, training programs can improve the cardiovascular response, oxygen uptake and the metabolism. We may also focus on physical activity, which is a general prognostics marker. Physical activity can be monitored by pedometer. Obesity can influence the complications of the surgical procedure and it has some effect on lung mechanics as well. If we have time, in case of an obese patient we may also consider improving their body composition before the invasive procedure. To sum up, comorbidities have to be considered before an invasive diagnostic procedure of lung cancer. Patients with impaired pulmonary hemodynamics, ischemic heart disease, diabetes or obesity have to be carefully evaluated. de Torres JP. Casanova C. et al. : Exploring the impact of screening with low-dose CT on lung cancer mortality in mild to moderate COPD patients: A pilot study. Respiratory Medicine, 107, 5, 702-707. 2013. Wiener RS. Schwarcz LM. et al. Population-Based Risk of Complications Following Transthoracic Needle Lung Biopsy of a Pulmonary Nodule. Annals of Internal Medicine, 155, 3, 137-144. 2011. GOLD-www.goldcopd.org Brunelli, A. Charloux, A. et al : ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients Eur. Resp. J., 34, 1, 2009.

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      SC13.04 - Limitations by COPD for Treatment (ID 6652)

      11:40 - 12:00  |  Author(s): Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The most common cause of death among patients with COPD is lung cancer as well as respiratory failure, and COPD often co-exists with lung cancer with a range of 40 to 70% (1). While lung cancer survival is generally very low, survival is even lower among patients with COPD, i.e. in one study, it is reported that 26% of lung cancer patients without COPD were still alive 3 years after their diagnosis compared to 15% of lung cancer patients with COPD (2). One of the reasons why prognoses of lung cancer patients with COPD are worse is that treatment options are limited due to affected lung function. For surgical treatment for lung cancer patients with COPD, post-operative residual lung function should be maintained within a certain level. Therefore, patients with severely reduced lung function may be rejected for surgical treatment, or at least they may not able to receive standard surgical procedures. For patients rejected for surgery because of poor lung function, radiotherapy is an alternative treatment option. However, radiotherapy itself affects lung function because of post treatment radiation pneumonia. For drug therapy, drug-induced lung toxicities are emerging issues, especially due to the use of EGF receptor tyrosine kinase inhibitors, ALK inhibitors or immune check point inhibitors (3). In cases whose lung function is severely affected, drug-induced lung toxicities may be lethal, and special attention should be payed to such patients. Therefore, to overcome these limitations of treatment is an urgent issue in the daily practice. For surgical treatment, assessment of preoperative lung function is essential to judge its indication. Both predicted post-operative lung function and DLco values are mainly used as parameters for the indication of surgical treatment. Therefore, optimization of these functions by medical therapy, pulmonary rehabilitation and smoking cessation may extend the opportunities of surgical treatment, resulting in better patients’ outcomes. Regarding with medical therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (4) and American Thoracic Society and the European Respiratory Society guidelines for COPD management point out the usefulness of bronchodilators as well as inhaled corticosteroids. In addition, pulmonary rehabilitations would be recommended for pre-operative lung cancer patients with poor lung function because of its safety, although there are no data clearly showing the efficacy of pulmonary rehabilitations on patients’ outcome. For radiotherapy for lung cancer patients with COPD, newly developed devices appear to show promising outcome. Both stereotactic body radiotherapy (SBRT) and ion beam radiotherapy have such a nice radiation dose distribution that high doses of irradiation are possible with low impact to normal tissues. Some reports suggest that patients’ outcomes by these treatment modalities may be not worse or sometimes better than surgical treatment (5). In addition, smoking cessation is, of course, important issue as a pre- and post- operative management. Since lung cancer patients with COPD are increasing over all area in the world, appropriate treatment should be chosen with the utmost care and attention. In addition, it is an urgent issue to establish more effective and safe treatment modalities to these patients. References 1) Young RP, Hopkins RJ, Christmas T, et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J. 2009;34(2):380-6. 2) Kiri VA, Soriano J, Visick G, Fabbri L. Recent trends in lung cancer and its association with COPD: an analysis using the UK GP Research Database. Prim Care Respir J. 2010;19(1):57-61. 3) De Sanctis A, Taillade L, Vignot S, et al. Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer. Cancer. 2011;117(14):3069-80. 4) Rabe KF, Hurd S, Anzueto A, Barnes PJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55. 5) Chehade S and Palma DA. Stereotactic radiotherapy for early lung cancer: Evidence-based approach and future directions. Rep Pract Oncol Radiother. 2015;20(6):403-10..

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Author of

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    MA05 - Innovative Techniques in Pulmonology and the Impact on Lung Cancer (ID 378)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Pulmonology
    • Presentations: 1
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      MA05.08 - Discussant for MA05.05, MA05.06, MA05.07 (ID 7047)

      16:48 - 17:00  |  Author(s): K. Zarogoulidis

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P1.07-034 - Somatostatin Receptors Expression in Small Cell Lung Cancer Patients (ID 5242)

      14:30 - 14:30  |  Author(s): K. Zarogoulidis

      • Abstract
      • Slides

      Background:
      Somatostatin receptors have been described on the membrane of neoplastic cells and their expression has also been demonstrated on small cell lung cancer (SCLC). In this study we examined if the expression of somatostatin receptors at the time of disease progression correlated with survival and time to progression (TTP) of SCLC patients.

      Methods:
      10 patients with SCLC were studied using 111In-octreotide (111In-OCT) scintigraphy at diagnosis and disease progression. Scintigraphic examinations were performed following intravenous (i.v.) injection of 111 MBq 111In-OCT with whole-body scintigraphy and planar scintigraphy of the thorax as well as the SPECT technique .The scintigraphic results were expressed in comparison with soft tissue intake (normal prices <1.5).

      Results:
      111In-OCT was positive in all 10 SCLC patients at the time of diagnosis and progression of the disease. No statistical correlation was found between somatostatin receptors expression at the progression- mainly subtype 2( SSTR 2)- and survival (p=0.43), nor TTP(p=0.25) .Also the difference in somatostatin receptors expression during diagnosis and progression had no statistical correlation with survival and TTP.

      Conclusion:
      The clinical utility of receptor status characterization obtained with 111In-OCT scintigraphy is rather confined. Our study shows that 111In-OCT scintigraphy, although is a reliable, non-invasive technique to detect primary SLCL and its locoregional or distant metastases, cannot be used as a prognostic or predictive factor in SCLC patients.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P3.02c-018 - Could COX-2 Inhibitors Enhance the Outcomes of Chemotherapeutic Agents in Lung Cancer? (ID 5432)

      14:30 - 14:30  |  Author(s): K. Zarogoulidis

      • Abstract
      • Slides

      Background:
      Lung cancer represents the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Inflammation plays a critical role in multistage tumor development and increased evidence has supported the involvement of cyclooxygenase-2 expression in carcinogenesis. We investigated the potential use of COX-2 inhibitors in cancer proliferation and apoptosis.

      Methods:
      Celecoxib, rofecoxib, etoricoxib, meloxicam, ibufrofen and indomethacin are the COX-2 inhibitors included in this study. Docetaxel and Cisplatin are the chemotherapeutic agents that we combined with COX-2 inhibitors. Lung cancer cell lines (NCI-H1048-Small cell lung cancer, A549- Non-small cell lung cancer) were purchased from ATCC LGC Standards. At indicated time-point, following 24h and 48h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism (version 6).

      Results:
      In Small cell lung cancer cells, following 24h incubation, combinations of docetaxel and meloxicam, docetaxel and ibuprofen, docetaxel and indomethacin, showed increased apoptosis when compared to docetaxel alone (p<0.0001). In Non-small cell lung cancer cells, the 24h incubation was not enough to induce satisfactory apoptosis, but following 48h incubation, docetaxel plus indomethacin showed more cytotoxicity when compared to docetaxel alone (p<0.0001). In addition, the combination of cisplatin plus indomethacin was the only combination to be found with higher cytotoxicity when compared to cisplatin alone after 48h treatment (p<0.0001).

      Conclusion:
      Depending on the drug, the synergistic effect of COX-2 inhibitors plus chemotherapeutic agents has been demonstrated in lung cancer. Our suggestion is that COX-2 inhibitors could be used as additive and maintenance treatment in combination to antineoplastic agents in lung cancer patients.

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      P3.02c-101 - Immunotherapy with Nivolumab in NSCLC Patients: One Centre Preliminary Results (ID 5239)

      14:30 - 14:30  |  Author(s): K. Zarogoulidis

      • Abstract
      • Slides

      Background:
      Nivolumab is an IgG4 monoclonal antagonist antibody to PD-1 that is approved for the treatment of patients with advanced squamous and non-squamous NSCLC with progression of disease on or after standard platinum-based chemotherapy, regardless of tumor PD-L1 protein expression. The aim of our study is to evaluate the efficacy and safety of nivolumab in this group of patients.

      Methods:
      We enrolled 23 patients with squamous and non-squamous NSCLC, stage IIIB-IV,19 males and 4 females, with median age 68 years who had failed two or more lines of systemic platinum based chemotherapy. All patients received at least 4 doses of nivolumab as monotherapy, at a dose of 3 mg/kg once every 2 weeks intravenously, until disease progression or unacceptable toxicity.

      Results:
      3 (13%) of 23 patients had an objective response as assessed by RECIST criteria and all of the responses were ongoing at the time of analysis. 19 (82.6%) of 23 patients had stable disease and one experienced progression of the disease. 2 (9%) of 23 patients reported treatment-related adverse events, including peripheral edema ,one (4%) with pleural effusion and one (4%) with pericardial effusion, which all were well tolerated and treated. No deaths were attributed to nivolumab.

      Conclusion:
      Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, resistant, squamous and non squamous non-small cell lung cancer.

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