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P.E. Postmus



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    G01 - Progress in Lung Cancer: Celebrating 40 Years of IASLC and Research Progress (ID 14)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      G01.2 - Early Detection, Etiology, Epidemiology, Pulmonology and Radiology (ID 437)

      P.E. Postmus

      • Abstract
      • Slides

      Abstract
      Etiology and epidemiology Awareness that lung cancer is for many patients a self-inflicted disease has become common knowledge and its incidence can only be reduced by an active fight against smoking . The IASLC has always considered this as very important (1). The last decade much attention was given the non-smokers who developed lung cancer. These patients have specific characteristics, of which EGFR mutation is one (2). What is responsible for this class of lung cancer is unknown. With an estimated number of 300,000/year, it is far from an orphan disease (3). Early detection Lung cancer cure rates are far from impressive (4). For those diagnosed with symptoms the outcome is grim, cure is extremely rare, palliative needs are common (5). The 5 year survival rates in patients with resectable tumors is decreasing with increasing stage (6). Finding early stage lung cancer with state-of -the-art CT technology resulted in an impressive 10 yr survival rate of 88% (7). This modern CT technologywas evaluated in the largest lung cancer screening study ever performed (8). For the first time it was demonstrated that screening is effective and results in a relative reduction in mortality from lung cancer of 20.0%, and death from any cause by 6.7% (95% CI, 1.2 to 13.6; P = 0.02). Still many questions remain unanswered and confirmation is needed (9)? How to treat these lesions with minimal invasive surgery (10) or stereotactic radiotherapy (11). Pulmonology Autofluorescence bronchoscopy improves the detection of mucosal abnormalities (12) such as pre-invasive lesions (13), carcinoma in situ (14) and radiologically occult lung cancer (15). Through the EBUS (endobronchialultrasound) scope virtually every lymph node adjacent to the bronchial tree can be reached (16). In combination with the ultrasound from inside the oesophagus (17) this results in a sensitivity of > 90% (18). In a RCT it was demonstrated that combining these techniques should be done before thinking of a mediastinoscopy as their yield is comparable to mediastinoscopy (19). Bronchoscopy became important for treatment as well, ranging from palliative to really curative. Stenting the airway but should be used with great caution as migration is common, it seriously affects mucus clearance and narrowing of the airways through granulation tissue might develop (20). A desobstruction technique such as Nd-YAG laser, electrocautery or argon plasma coagulation can be used if intraluminal tumor gives obstruction (20). In specific situations with very limited cancer within the bronchial wall endobronchial treatment might even lead to cure, an example of this is photodynamic therapy (21). Radiology Within the last 40 years imaging techniques have improved considerably. With the introduction of computed tomography, it became possible to visualize the primary tumor as well as mediastinal lymphnodes in a much better way. A further technical improvement, the Positron Emission Tomography (PET) and the use of 18-fluorodeoxyglucose (18-FDG) improved this (22). Further developments of imaging may lead to decision making on treatment (23). References 1 Tobacco policy recommendations of the International Association for the Study of Lung Cancer (IASLC): a ten point program. Lung Cancer 1994; 11: 405-407 2 Ren JH, et al. EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. Environ Mol Mutagen. 2012 Jan;53(1):78-82 3 Sun S, et al. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7(10):778-790. 4 Goldstraw P, et al. The International Association for the study of lung cancer. The International staging project on lung cancer. J ThoracOncol 2006; 1: 281-286. 5 Ferrell B, et al. Palliative care in lung cancer. SurgClin North Am 2011; 91: 403-418. 6 Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification for Lung Cancer. J Thor Oncol 2007; 2: 706-714. 7 The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage I Lung Cancer Detected on CT Screening. N Engl J Med 2006; 355:1763-1771. 8 National lung screening trial research team, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395-409. 9 Field JK, et al. Prospects for population screening and diagnosis of lung cancer. Lancet 2013; 382: 732-741. 10 Nakamura K, et al. A phase III randomized trial of lobectomy versus limited resection for small sized peripheral non-small cell lung cancer. Jpn J ClinOncol 2010; 40: 271-274. 11 Senan S, et al. Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? Lancet Oncol 2013; 14: 270-274. 12 Venmans BJW, et al. Clinically relevant information obtained by performing autofluorescence bronchoscopy. J Bronchol 2000; 7: 118-121. 13 Breuer RHJ, et al. The natural course of preneoplastic lesions in bronchial epithelium - A longitudinal study. Clin Cancer Res 2005; 11: 537-543. 14 Venmans BJW, et al. Outcome of bronchial carcinoma in situ. Chest 2000; 117: 1572-1576. 15 Vonk-Noordegraaf A, et al.Bronchoscopic treatment of patients with intraluminal microinvasiveradiographically occult lung cancer not eligible for surgical resection: a follow-up study. Lung Cancer 2003; 39: 49-53. 16 Herth FJ, et al. Transbronchial and transoesophageal (ultrasound-guided) needle aspiration for the analysis of mediastinal lesions. EurRespir J 2006; 28: 1264-1275. 17 Silvestri GA, et al. Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer. Ann ThoracSurg 1996; 61: 1441-1445. 18 Wallace MB, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008; 299: 540-546. 19 Annema JT, et al. Mediastinoscopyvsendosongraphy for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010; 304: 2245-2252. 20 Bolliger CT, et al. Therapeutic bronchoscopy with immediate effect: laser electrocautery, argon plasma coalgulation and stents. EurRespir J 2006; 27: 1258-1271. 21 Cortese DA, et al. Photodynamic therapy for early stage squamous cel carcinoma of the lung. Mayo ClinProc 1997; 72: 595-602. 22 Silvestri GA, et al Methods for staging lung cancer. Chest 2013; 143: 211S-250S. 23 Bahce I, et al. Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res. 2013; 19: 183-193.

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    HOD3 - Tuesdays Highlights of the Day - Surgery, Staging, Imaging and Pulmonary (ID 227)

    • Event: WCLC 2013
    • Type: Highlight of the Day Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      HOD3.2 - Imaging and Pulmonary (2 Day Coverage) (ID 4047)

      P.E. Postmus

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.09 - Small cell lung cancer in daily practice; SCOT registry (Small cell lung Cancer treatment and OuTcome) (ID 2300)

      P.E. Postmus

      • Abstract
      • Presentation

      Background
      The SCOT registry is an international, multicenter, observational registry of newly diagnosed patients with SCLC. The treatment plan remained the responsibility of the patient’s physician and data collected in this registry reflect a "real world" approach for the diagnosis and treatment of patients with SCLC.

      Methods
      56 centers included 507 evaluable patients between 10[th] of November 2009 to 18[th] of August 2010. Participating countries are from Western Europe, Eastern Europe and Korea. Data has been entered into an electronic CRF via the internet.

      Results
      Mean age was 65.4 years, 73% of the patients were male, mean BMI was 25.5 Kg/m2. Smoking status showed 50% were current and 46% former smokers. The most common symptoms at presentation (>25%) were cough, dyspnea, weight loss and fatigue. Patients presented with an ECOG status of 0 (24%; 33% for limited disease (LD) and 19% for extensive disease (ED)), ECOG 1 (52%), ECOG 2 (19%) and ECOG 3 (5%). Histology was small cell carcinoma in 98% of patients and 66% presented with extensive disease. Chemotherapy alone was given to 59% of patients in the first 6 months of treatment. 58% of patients had one line of therapy, 26% had 2 lines, 11% had 3 lines of therapy and 4% had 4 lines or more. The agents most commonly used in each line of therapy are below: Table 1: Chemotherapy agents by line of therapy in SCOT (% within the treatments of the line)

      AGENT/LINE FIRST SECOND THIRD > 3
      Platinum/Etoposide 90.7 26.8 14.5 10.5
      Topotecan 0.2 25.7 20.2 2.3
      Taxanes 2.1 9.3 21.7 26.3
      Cyclophosphamide 3.9 10.9 11.6 15.8
      Cyclo/Vincristine 3.9 12.0 11.6 15.8
      Vinorelbine 0.2 1.1 2.9 2.3
      Gemcitabine 0.0 2.2 0.0 6.8
      67 % of patients with LD received chemo + thoracic radiotherapy. PCI in the first 6 months was given in 26% of patients (LD 34% ED 22%). Best overall response at 6 months in patients with combined chemoradiotherapy was PR=51%, CR=22%, SD=16%, PD=11%. Median overall survival (OS) was 10.6 months [95%CI 9.6, 12.1] with 17.8mo for limited disease and 8.7mo for extended disease. Western Europe and Korea showed OS of 11.5mo and 11.3mo respectively whereas in Eastern European median OS was 9.1 months.

      Conclusion
      This observational study captured real world data of the current treatment paradigm of SCLC. Patients are commonly treated with etoposide/platinum or chemoradiotherapy as first line. The combination of platinum and etoposide remains by far the first choice of chemotherapy in 1[st] line and often at relapse, followed by topotecan starting from second line and beyond. Details on patterns of disease, treatment and efficacy by region and smoking status plus medical resource utilisation will be available at the meeting.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-021 - Validation of DNA Hypermethylation Analysis in Sputum for the Diagnosis of Lung Cancer (ID 1774)

      P.E. Postmus

      • Abstract

      Background
      Lung cancer has the highest mortality of all cancers worldwide with a 5 year survival rate of <15%. The prognosis improves dramatically when the disease is detected at an early stage, and when curative treatment is possible. Current (low dose CT) screening and diagnostic procedures are suboptimal with low specificity. Thus, novel detection methods for lung cancer as stand alone or in combination with other methods are needed. DNA hypermethylation of biomarkers in sputum have shown to distinguish lung cancer cases from cancer-free controls. The aim of the present study was to validate the usage of DNA hypermethylation of biomarkers in sputum samples of lung cancer patients and controls for lung cancer diagnosis, in comparison with sputum cytology.

      Methods
      We prospectively collected sputum of lung cancer patients and controls during 3-9 days in the Amsterdam and Nieuwegein area, The Netherlands. From this sputum bank, a learning set (n=80 lung cancer patients, n=91 controls) and validation set (n=173 lung cancer patients, n=164 controls) were randomly composed. DNA promoter hypermethylation of the following biomarkers was assessed by means of quantitative methylation specific PCR: RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3. Cut-off values for positive hypermethylation were calculated using Youden’s index. Sputum cytology analysis was performed for all sputum samples. McNemar’s test was used to compare the difference between sensitivity of hypermethylation and sputum cytology for lung cancer diagnosis. A two-sided p-value <0.05 was considered significant.

      Results
      RASSF1A was best able to distinguish cases from controls, with sensitivity of 37-41% and specificity of 91-97% in both learning and validation sets. In multivariate analysis, a panel of RASSF1A, 3OST2 and PRDM14 showed highest sensitivity of 82% [95% confidence interval (CI): 76 – 88%] with a specificity of 68% [95% CI: 61 – 74%] in the learning set, with consistent results in the validation set. Molecular analysis was superior (P<0.001) over sputum cytology (sensitivity of 15%). The sensitivity of the biomarker panel did not improve when it was combined with sputum cytology. There was no association observed between DNA hypermethylation and clinical parameters such as age, smoking status, tumor stage, and histology.

      Conclusion
      This study validates hypermethylation analysis in sputum for the diagnosis of lung cancer. RASSF1A hypermethylation showed high specificity and thereby can have an important role in lung cancer diagnosis in symptomatic patients. A panel of biomarkers RASSF1A, 3OST2 and PRDM14 showed high sensitivity, but relatively low specificity.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-022 - Retrospective Longitudinal Chart Review of Patients with Advanced Non-Small Cell Lung Cancer in the Netherlands: A Quantification of Disease Burden (ID 1855)

      P.E. Postmus

      • Abstract

      Background
      The availability of novel therapeutic regimens has led to increase in duration of treatment and utilization of healthcare in non-small cell lung cancer (NSCLC). Although medical resource use and costs were assessed in previous studies, characterization of disease burden exclusively for advanced-stage, in real-world setting is scarce. The aims of our study were to quantify medical costs of stage IIIB/IV NSCLC and identify components of care, that are likely to alter in light of new developments, in Dutch clinical practice.

      Methods
      A retrospective longitudinal chart review was performed to obtain healthcare utilization of patients, age ≥18 years, with stage IIIB/IV NSCLC (based on the sixth edition of tumor-node-metastasis classification) who received first- and subsequent-line of systemic anti-cancer therapy (SACT). As part of the LUng Cancer Economics and Outcomes Research (LUCEOR), a multi-country retrospective patient chart review, two academic and two non-academic Dutch hospitals participated in the study. Patients who deceased before April 2010 were included. The components of care, from the initiation of first-line SACT until death, were quantified by twelve distinct categories. Total and monthly medical costs attributable to each component were calculated and expressed in 2012 US dollars. Outcomes were fit with statistical models to compare trends. Potential predictors of lifetime NSCLC costs and variability were examined.

      Results
      A total of 134 patients, 65% (87/134) males, of age 63 ± 9.7 (mean ± SD) years were included. While 34% (46/134) of patients were presented with adenocarcinoma, the proportion of large-cell carcinoma, squamous cell carcinoma and NSCLC not otherwise specified were 33% (44/134), 29% (39/134) and 4% (5/134), respectively. The clinical stage at the start of first-line SACT were 28% (37/134) IIIB and 72% (97/134) IV. Aside from the relatively small subset of patients (12%, 16/134) harboring oncogenic drivers, platinum-based combination chemotherapy regimens were the mainstay of treatment. For a median survival of 7.1 months (95% CI 5.9-8.1), total lifetime costs were averaged to $39,992 ± $20,928 per patient. The influential cost-drivers across all lines of therapy were hospitalizations ($15,521± $16,511) and SACT ($11,628± $7,583), mainly platinum-based gemcitabine or docetaxel. Monthly costs per patient were amounted to $11,932± $14,571. The degree of associations between predictors and outcomes were observed for clinical stage of disease at the start of SACT, administration of prior treatment and smoking history. Although clinically imperative, age and gender were not predictors of variability of healthcare costs at alpha ≤0.05.

      Conclusion
      Real-world medical costs, in particular hospital admissions and SACT, are substantial in the management of stage IIIB/IV NSCLC in the Netherlands. In a molecularly enriched patient population, biomarker-driven treatments are expected to result in higher likelihood of clinical benefit. Consequently, the average hospitalization costs and long-term management of treatment-related events are likely to reduce. Future research assessing the quantification of disease burden based solely on molecularly targeted agents in daily practice is encouraged. These results may collectively inform decision-making of registration, reimbursement and pricing of interventions in NSCLC.

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      P1.11-023 - Molecular Screening in Advanced Non-Small Cell Lung Cancer: A Systematic Review of Cost-Effectiveness Analyses for First-Line Therapy (ID 1931)

      P.E. Postmus

      • Abstract

      Background
      Novel molecularly targeted therapies are increasingly licensed in conjunction with companion diagnostics to stratify patients with oncogenic aberrations and to help improve patients' likelihood of clinical benefit. Cost-effectiveness analyses (CEAs) are now expected to examine the value of molecular screening as well as traditional costs and benefits of therapeutic choices. The aim of this study was to assess the impact of first-line predictive biomarker screening on the cost-effectiveness of molecularly targeted agents in locally advanced or metastatic non-small cell lung cancer (NSCLC).

      Methods
      A systematic literature review was performed using MEDLINE, EMBASE and NHS EED. CEAs of epidermal growth factor receptor (EGFR)-, Kirsten RAS (KRAS)-, and anaplastic lymphoma kinase (ALK)-guided screening prior to first-line treatment were appraised according to a priori eligibility criteria. The impact of screening guided patient management was quantified by incremental cost-effectiveness ratios (ICERs) and expressed in 2013 US dollars. Sensitivity analyses were explored to examine the influence of extracted parameters on the ICERs. Methodological quality of the studies was assessed by standardized checklists.

      Results
      Based on the explicit test-treat combined strategy, eight CEAs met the inclusion criteria. Although six EGFR- and two ALK-guided diagnostic-therapeutic pairings were reviewed, none of the retrieved CEAs explored the potential benefits of KRAS mutation screening on the molecularly targeted agents in the front-line setting. Country-specific decisions regarding utilization of healthcare were conducted from the perspectives of the United States, England and Wales, France, Singapore and China. Efficacy data including biomarker prevalence (ALK: 1.6-4.4%, EGFR: 16.6-60%), sensitivity of the test (ALK: 67-100%, EGFR: 92-100%), specificity of the test (ALK: 93-100%, EGFR: 96-100%) and Quality-Adjusted Life Years (QALY) gained (ALK: 0.009-0.014, EGFR: 0.04-0.5) were extracted. Base-case costs for ALK- and EGFR-guided screening were $98-$1,421 and $105-$516, respectively. The ICERs of EGFR-guided test-treat strategy ranged from being less costly/more effective to unlikely to be cost-effective (ICER range: dominant-$160,123/QALY gained). The ICERs of ALK-guided strategy ranged from likely to be cost-effective to unlikely to be cost-effective (ICER range: $59,240-$213,869/QALY gained). Sensitivity analyses revealed that ICERs of molecularly enriched patient groups were profoundly dependent on the monthly costs of targeted agents (erlotinib, gefitinib, crizotinib) and duration of treatment. Conversely, at low biomarker frequencies, ICERs were influenced by the cost of the screening test. Test specificity, the proportion of advanced NSCLC patients correctly identified as not having EGFR/ALK positivity, was more influential than the test sensitivity. Although clinically imperative, re-biopsy and subsequent therapy were not explored. Furthermore, critical assessment of the CEAs revealed that justification of preferred methods, transparency of input parameters and generalizability of results affected quality.

      Conclusion
      This study investigates indications of cost-effective screening of 'actionable' molecular aberrations and highlights the impact of clinical and cost parameters on the ICERs. While advancements in mechanisms of resistance and histological transformations will shed light on the future of lung cancer care, CEAs of novel diagnostic-therapeutic pairings will continue to help informed decision-making of all stakeholders.

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    P1.17 - Poster Session 1 - Bronchoscopy, Endoscopy (ID 182)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 3
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      P1.17-006 - Early Bronchoscopic Interventional Strategy in Highly at Risk Morbid Ageing Cohort (ID 2322)

      P.E. Postmus

      • Abstract

      Background
      We retrospectively reviewed our longitudinal data (1992 - 2012) with regard to early interventional techniques using advancements of non- and minimally invasive techniques (NiMiT) as alternatives for early intervention in squamous carcinogenesis in highly at risk -including frail elderly individuals. >50% lung cancer develops in >70 years age cohort and cancer and ageing are becoming an important health care issue in our society.

      Methods
      So far, 159 surgically non-resectable candidates with various comorbidities (Previous LC/ENT primaries, COPD, etc.) have been closely monitored using autofluorescence bronchoscopy for suspicious endobronchial lesions (e.g. dysplasia, carcinoma in situ and microinvasive squamous cancer). End points were the development of squamous cancer and its outcome with the use NiMiT (Chest 2001;120:1327; Respiration 2004;71:391

      Results
      Patient characteristics and outcome are shown in the table. Cohort analyses of age ≤70 years versus over, showed a significant longer time of survival in the elderly cohort (35.9 vs 18.5 months; p = 0.01). Lung cancer specific mortality was low ,respectively 15% and 22%. Table: Longitudinal carcinogenesis study in cohorts highly at risk to develop (subsequent) squamous cancer primaries and its outcome.

      Age cohort (years) n patients <70 112 >70 47 p-value
      Gender - Male - Female 93 (83%) 19 (17%) 39 (83%) 8 (17%) NS
      Mean age years (range) 60(42-70) 74(70-83)
      Indication for close surveillance: - Previous LC /ENT cancer - Suspicion occult lung cancer 55 (49%) 57 (51%) 19 (40%) 28 (60%) NS
      Mean pack-years smoked (range) 44(4-120) 49(20-137) NS
      COPD Non-COPD Unknown 72 (64%) 32 (29%) 8 (7%) 29 (62%) 10 (21%) 8 (17%) NS
      Interval to (subsequent) primaries (months) 69(0-198) 54(1-184) NS
      Acquiring (subsequent) squamous ca. Recurrences of previous primaries 41 (37%) 4 (4%) 12 (26%) 2 (4%) NS NS
      Death due to lung cancer Other causes 25 (22%) 31 (28%) 7 (15%) 17 (36%) NS NS
      Survival after curative treatment (months) 19 (0-110) 36 (0-106) 0,01

      Conclusion
      In contrast to the undocumented belief about less aggressive cancer, the need for less aggressive treatment, potential toxicities in the co-morbid elderly and their expected shorter life span, the outcome shows that early interventional strategy is warranted. LC mortality is relatively low despite the highly negative selection bias, especially in the frail – ageing – subcohort. This warrants further studies to increase the cost-effectiveness of NiMiT in our ageing population.

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      P1.17-007 - A proposal for a new clinical strategy and follow-up in patients with bronchial carcinoids initially treated bronchoscopically. (ID 2468)

      P.E. Postmus

      • Abstract

      Background
      Bronchial carcinoids (BC) belong to the wide spectrum of neuroendocrine tumors; ranging from tumorlets, typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), to highly malignant large cell neuroendocrine and small cell carcinoma. The Travis classification (Am J SurgPathol 1998; 22:934) seems essential for choosing the best treatment strategy based on retrospective analyses of surgically resected specimens. We implemented an initial bronchoscopic treatment (IBT) strategy and its long term outcome have been reported with update of the final analysis (J Thorac Cardiovasc Surg. 2007 Apr;133(4):973; Abstract IASLC Sydney submitted). The long-term outcome seems to justify IBT and the histological differentiation between typical versus atypical seems to matter much less, while conservation of normal lung parenchyma is optimal. We question how optimal the close surveillance strategy of IBT protocol should be, i.e. in performing regular high resolution CT (HRCT) and/or bronchoscopy after the initial success of bronchoscopic treatment.

      Methods
      In the IBT protocol, HRCT and bronchoscopy were performed 6-monthly in the first two years and annually until the fifth year. Thereafter a yearly check-up was advised to the referring pulmonologists. We analyzed retrospectively the value of HRCT and/or bronchoscopy in this IBT cohort for early detection of local recurrences, that require surgical salvage.

      Results
      So far, IBT was successful in 57 of the 133 patients (43%). Sixty-seven patients (50%) could be immediately identified to be surgical candidates without further delay due to obvious extraluminal tumor growth. Four patients (3%) developed extraluminal tumor recurrence and surgical salvage was performed at 47, 104, 115, 192 months. In all four cases follow-up HRCT suggested local extraluminal tumor growth, which were confirmed by bronchoscopy. The surgical outcome was radical and did not lead to more extensive resections than initially anticipated. Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable. Local regrowth after successful bronchoscopic removal was infrequent (3%) and was timely detected by HRCT. HRCT can be performed much less frequent and regular bronchoscopy was redundant if IBT attempt was successful. The significance of an iceberg phenomenon is questionable.

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      P1.17-008 - Results of a close surveillance strategy for subjects with pre-invasive endobronchial squamous lesions (ID 2678)

      P.E. Postmus

      • Abstract

      Background
      The dismal overall 5-year survival of non-small cell lung cancer (NSCLC) patients is mainly due to advanced stage of disease at time of initial diagnosis in most and the inability to cure metastatic disease in all patients. In contrast, the prognoses of in situ mucosal and small parenchymal lesions are excellent. Early detection strategies might result in the identification of early-stage, (pre-)invasive lesions that are still eligible for curative treatment. The present study was set out to characterize the risk of lung cancer development in a cohort of high-risk subjects harboring pre-invasive endobronchial lesions and to assess the results of surveillance using autofluorescence bronchoscopy (AFB) and computed tomography (CT) scan.

      Methods
      Between November 1995 and December 2012, one hundred and sixty-four at risk individuals with pre-invasive endobronchial lesions were monitored by repeated AFB and CT. During the course of surveillance, progression of lesions to cancer (in situ), recurrences and second primary cancers were treated with different modalities (e.g. endobronchial techniques, surgery, radiotherapy), depending on tumor stage and location. Log-rank tests were performed to examine the relation between baseline characteristics and progression-free and overall survival (PFS and OS, respectively). Cox regression was used for multivariate survival analysis.

      Results
      Demographical and clinical variables of the cohort are shown (Table). At inclusion, 80 individuals were identified with one or more high-grade pre-invasive lesions (severe dysplasia or CIS; HGD), whereas 84 subjects were identified solely with lower grade pre-invasive lesions (LGD). During close surveillance (median follow-up (FU) of 30 months, range 4-152), sixty-one lung cancers were detected (26 CT-detected, 35 AFB-detected cancers) in 55 individuals within a median time to event of 16.5 months. Mean PFS was similar between individuals with radiographically occult lesions vs. FU after surgery for early-stage NSCLC/ENT ca (122.3 vs. 126.9 months, p=0.237) and COPD vs. non-COPD (118.8 vs. 136.8 months, p=0.162). There was a relatively large difference in PFS between LGD and HGD groups (142.6 vs. 93.7 months, p=0.057). Independent risk determinants for OS were indication for surveillance (FU after surgery for early-stage NSCLC/ENT ca vs. radiographically occult lesions, p=0.008) and COPD-status (COPD vs. non-COPD, p<0.001).

      Referral for radiographically occult lesion Follow-up after surgery for early-stage NSCLC / ENT ca
      total
      individuals, n 164 92 72
      Gender
      male 134 72 62
      female 30 20 10
      Age at baseline
      years, mean (range) 64.2 (42-83) 64.8 (42-81) 64.0 (43-82)
      Smoking status
      current smoker 75 44 31
      former smoker 74 36 38
      unknown 15 12 3
      Smoking history
      Pack-years, mean (range) 45 (4-137) 45 (4-120) 40 (15-137)
      COPD-status
      COPD 100 56 44
      non-COPD 45 22 23
      unknown 19 14 5
      AF Bronchoscopies
      Number, mean (range) 7 (1-27) 5 (2-27) 6 (1-18)
      CT-scans
      Number, mean (range) 3 (0-20) 2 (0-20) 3 (0-18)
      No. of detected lung cancers
      During surveillance period 61 29 32
      Parenchymal cancer 21 12 9
      Site-specific lesion progression 24 13 11
      Interval cancer 10 4 6
      Recurrences previous primaries 6 0 6
      Patient outcome
      alive 80 56 24
      died of lung cancer 33 13 20
      died of other/unknown cause 51 23 28

      Conclusion
      Our findings demonstrate that individuals with pre-invasive endobronchial lesions are at high risk of developing (second primary) lung cancers. Combined surveillance using AFB in addition to CT screening facilitated early detection and early (endobronchial) intervention in most patients. Future clinical trials are warranted to determine whether the current approach improves patient outcome.

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    P2.17 - Poster Session 2 - Bronchoscopy, Endoscopy (ID 183)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P2.17-006 - Long term outcome of initial bronchoscopic treatment strategy in patients with bronchial carcinoids (ID 2447)

      P.E. Postmus

      • Abstract

      Background
      Bronchial carcinoids are considered low-grade malignancies and, traditionally, are treated surgically. Tumor biology and advances in diagnostic and therapeutic techniques, however, enable a less invasive approach such as surgical bronchoplasty can preserve normal lung parenchyma. We previously reported favourable outcome for initial bronchoscopic treatment (BT) strategy in patients with intraluminally located bronchial carcinoids. We now present our long term results.

      Methods
      In patients presenting with a bronchial carcinoid, an initial diagnostic therapeutic bronchoscopy is attempted for complete tumor eradication for sampling sufficient tissue for the proper differentiation between typical (TC) and atypical (AC) histologic type apart from to optimally improve pre-surgical condition. A high resolution computed tomography is performed six weeks later, to determine intra- versus extraluminal tumor growth. In case of intraluminal growth of TC bronchoscopic removal attempt can be repeated. We perform surgical resection in case of extraluminal disease, or failure to bronchoscopic radical resection (i.e. recurrence or persistent residual tumor). Complete bronchoscopic resection of AC histological type is currently not followed by surgical resection.

      Results
      So far, 133 patients have been treated; 76 females, 67 males, median age 46 (range 16 – 85 years). Median follow up was 87 (range 2 – 264) months. Ninety-nine patients (84%) had TC, and 34 (26%) had AC. Bronchoscopic eradication was successful in 57 (43%) patients (51 TC, 6 AC). Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable with excellent long term outcome. It should be implemented in the standard algorithm for patients with bronchial carcinoids.

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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-004 - DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer (ID 1166)

      P.E. Postmus

      • Abstract

      Background
      Individuals who present with squamous metaplastic and dysplastic lesions are considered at high risk of lung cancer. However, these lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer. We recently identified a DNA copy number aberration (CNA)-classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia (van Boerdonk et al, AJRCCM, 2011). The current study was set out to validate this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.

      Methods
      DNA copy number profiles (i.e., chromosomal gains and losses) were determined in a set of endobronchial lesions (8 squamous metaplasia (SqM), and 28 dysplasias (Dys) of various grades), identified and biopsied during autofluorescence bronchoscopy, of 36 high-risk subjects using a nested case-control design. Of the 36 patients, 12 cases had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer-free (median 78 months, range 21-142). DNA copy number profiles were related to lesion outcome. The prediction accuracy of the predefined CNA-based classifier to predict endobronchial carcinoma (in situ) in this series was determined.

      Results
      All SqM and Dys lesions of controls showed no or a relatively low number of CNAs (i.e., quiescent profile with on average 0.2% altered probe features, range 0.0 – 2.4%), while the majority of lesions of cases showed multiple CNAs (i.e. highly aberrant profile with on average 38.8% altered probe features, range 0.0 – 76.7%). The previously defined CNA-classifier demonstrated 92% accuracy for cancer (in situ) prediction in the current series. All nine subjects with CNA-classifier-positive endobronchial lesions at baseline had cancer as final outcome (i.e., a positive predictive value of 100%). The negative predictive value of the classifier was 89%, i.e., all 24 controls and 3 cases were classified as being low-risk.

      Conclusion
      CNAs are a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic interventions.

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    P3.21 - Poster Session 3 - Diagnosis and Staging (ID 171)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.21-007 - <em>EGFR</em> mutation analysis in sputum of lung cancer patients: a multicenter multitechnique study (ID 1782)

      P.E. Postmus

      • Abstract

      Background
      Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in lung adenocarcinomas and are associated with a high response to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples. The aim of the present study was to determine whether EGFR mutation analysis is feasible on sputum samples, employing different assays in a multicenter study.

      Methods
      Sputum samples were collected from 10 lung cancer patients with confirmed EGFR mutation in their tumour tissue, 10 lung cancer patients without evidence of an EGFR mutation, and 10 patients with chronic obstructive pulmonary disease (COPD). DNA was isolated from the sputum and used for mutation analysis by Cycleave PCR, COLD-PCR, PangaeaBiotech SL technology (PST), and High Resolution Melting, respectively. Targeted resequencing (TruSeq Amplicon Cancer Panel) and droplet digital PCR were additionally performed on the 10 samples with EGFR mutation.

      Results
      Dependent on the assay, EGFR mutations could be detected in 30-50% of the sputum samples of patients with EGFR mutations (Table). The different techniques revealed consistent results, with slightly higher sensitivity for PST. Neither the lung cancer patients without EGFR mutation nor the COPD controls tested positive for EGFR mutations in their sputum samples, indicating high clinical specificity of all assays.

      Subject Gender Age (years) Tumour stage EGFR mutation status of tumour tissue[1] EGFR mutation analysis on sputum specimens[2]
      Cycleave PCR COLD-PCR PST[3] HRM-sequencing Cytology[4]
      A F 72 IV Del E746-A750 0 0 0 0 0
      B M 66 I Del E746-A750 0 2 0 0 0
      C[6] F 78 IV Del E746-A750 1 1 1 1 2
      D F 46 III Del E746-A750 0 0 1 0 0
      E[6] M 54 IV Del E746-A750 1 1 1 1 0
      F F 49 III Del E746-A750 & c.2369C>T [p.T790M] 0 0 0 0 0
      G F 54 IV Del E746-A750 & c.2369C>T [p.T790M] 0 0 1[5] 0 1
      H F 73 IV c.2753T>G [p.L858R] 0 0 0 0 0
      I F 61 IV c.2753T>G [p.L858R] 0 0 0 0 0
      J[6] M 60 IV Del E746-A750 1 1 1 1 2
      [1 ]del E746-A750= deletion exon 19 [2] mutation identified: 0=no, 1=yes, 2=dubious [3] exclusively del19 and L858R were assessed [4] tumour cells: 0=no, 1=yes, 2=in related sample of same patient [5 ]only del19 detected [6 ]TSACP and ddPCR both tested EGFR mutation (del19) positive.

      Conclusion
      EGFR mutations can be detected in sputum samples from patients with EGFR-mutated non-small cell lung cancer, which may replace biopsy procedure for some patients.