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K. Suzuki

Moderator of

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    ED10 - Locally Advanced NSCLC: State-of-the-Art Treatment (ID 279)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Locally Advanced NSCLC
    • Presentations: 4
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      ED10.01 - Chemoradiotherapy of Stage III NSCLC (ID 6481)

      16:00 - 17:30  |  Author(s): F. Mornex

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED10.02 - The Role of Surgery in Stage III NSCLC (ID 6482)

      16:00 - 17:30  |  Author(s): W. Klepetko

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease characterized by either locally advanced tumor infiltration and/or mediastinal lymph node involvement. Due to improvements in chemo (CT)- and combined chemoradiation (CRT) therapy protocols, patients with locally advanced stage III NSCLC become potential candidates for curative resection more frequently. According to the TNM-7 classification, stage III NSCLC can be defined by the following T and N subsets: stage IIIA: T3 N1-2, T4 N0-1, T1-2 N2; stage IIIB: T4 N2, T1-4 N3. Five-year survival of stage III is generally around 25% taken all different therapy strategies together. Several studies have shown that induction treatment before surgery is beneficial in resectable cases and selected patients undergoing radical resection may have encouraging 5-year survival rates up to 60%. However, to date, no worldwide consent exists on the general role of surgery in curative attempt. Furthermore, it is still unclear if resectable patients might have greater benefit from induction CT compared to combined induction CRT and if concomitant CRT should be preferred over a sequential treatment. Only a small number of prospective phase II/III trials are available addressing these issues. A phase III trial comparing induction CRT plus surgery (S) with definitive CRT in patients with stage IIIA/N2 published in 2009 has questioned the role of surgery since there was no difference in overall survival (OS) between the two groups [1]. However, the 30-day mortality was unacceptably high (26%) in the subgroup of patients undergoing pneumonectomy and thus patients with CRT and lobectomy had significantly improved OS compared to those with CRT alone. Moreover, several other retrospective series have reported encouraging long-term survival in selected patients undergoing induction treatment followed by radical surgery. The benefit of adding sequential RT to CT prior to surgery (S) in stage IIIA/N2 has been investigated in a recent phase III trial [2]. Patients undergoing CRT/S had a non-significant superior median OS of 37 months compared to 26 months with CT/S. Both groups had similar disease free survival (DFS) and it was concluded that RT did not add any benefit to induction CT prior to surgery. However, those with CRT/S had an objective response, pathological complete response, a R0 resection rate and a mediastinal downstaging more frequently and less local progression compared to CT/S. The question whether to apply RT concomitantly or sequentially to CT has been investigated in a recent meta-analysis [3]. Pooled data from six prospective trials suggested that concomitant CRT, as compared with sequential CRT, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control. However, these patients were treated without surgery and caution should be taken when transferring these conclusions to the neoadjuvant setting before surgery. From the surgical point of view, patients with local tumor invasion (T3-4 N0-1 including Pancoast tumors) have to be treated by different oncological principles than those with mediastinal lymph node (LN) involvement (N2). In patients with T3 tumors invading the chest wall, diaphragm, mediastinal pleura, phrenic nerve or parietal pericardium and N1 involvement, primary resection can be undertaken. Induction therapy may improve local control rates in larger tumors but it remains unclear if systemic treatment is beneficial prior to or after local resection. Intraoperative frozen section of resection margins should be mandatory and reconstruction of resected structures with synthetic material may be necessary. T4 tumors with invasion to the mediastinal structures or vertebral bodies are a unique subset of locally advanced NSCLC and multidisciplinary treatment can be challenging. Well selected patients may benefit from multimodality therapy including surgery and should be treated in well experienced centers [4, 5]. In patients with suspected N2 disease, invasive staging for histological confirmation has been widely accepted as a standard procedure [6]. In case of multilevel and/or bulky N2 disease, surgery should be avoided due to the expected poor outcome. However, it has been well shown that patients in good performance status with single or two level N2 disease with good response after induction therapy may have improved OS when undergoing curative resection [7, 8]. On the other hand, patients with persistent N2 disease after induction treatment tend to have worse OS and high recurrence rates and thus should not undergo surgery. This finding strengthens the impact of invasive re-staging after induction treatment as proposed by recent staging guidelines. In conclusion, selected patients with stage III NSCLC may have beneficial outcome after surgery combined with CT or CRT. However, this holds truth only for cases with response to induction treatment, nodal downstaging and when R0 resection is deemed achievable. Surgery should be avoided in patients with multilevel/bulky N2 disease or persistent mediastinal LN after induction treatment due to the expected poor outcome. The optimal sequence and modality of induction treatment has yet to be defined in larger prospective trails. References [1] Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32.

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      ED10.03 - New Developments in Radiotherapy of Stage III NSCLC (ID 6483)

      16:00 - 17:30  |  Author(s): J. Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract:
      NSCLC accounts for 80-85% of all lung cancers, and stage III disease constitutes about 40% of the total cases. The main treatment modality in these patients is radiotherapy, usually combined with concurrent chemotherapy. Five-year overall survival in stage III disease is merely 10-15%. Radiotherapy of thoracic tumors poses several challenges, such as tissue heterogeneity, tumor and organ motion and changing anatomy over the treatment course. Main approaches addressing these problems include dose intensification, altered fractionation and advanced radiotherapy techniques. Until recently, dose escalation was considered the main means to increase radiotherapy efficacy. Despite encouraging results of phase I–II studies, the results of recent RTOG trial 0617 were disappointing (1). This study compared high-dose radiotherapy (74 Gy/37 fractions) to a standard-dose (60 Gy/30 fractions) concurrently with weekly paclitaxel/carboplatin, with or without cetuximab. Surprisingly, median overall survival in the high-dose arms was significantly shorter (20 months vs. 29 months in the standard-dose arms; p=0.004) (1). It was speculated that the inefficacy of high-dose radiotherapy could be due to long overall treatment time and accelerated tumor repopulation. Shortening treatment time may be accomplished by accelerated radiotherapy. A phase III study investigating continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy/36 fractions of 1.5 Gy delivered 3 times daily over 12 consecutive days) showed increased efficacy compared to conventional fractionation (2). A CHARTWEL study, using the same fractionation but with weekend breaks, was not superior to conventional fractionation (3). A meta-analysis of 10 trials (2000 patients) demonstrated an absolute 5-year survival benefit of 2.5% with hyperfractionated and/or accelerated radiotherapy over conventional fractionation, at the expense of significantly increased grade 3–4 acute esophagitis (4). Important developments in lung radiotherapy represent new imaging techniques. PET-CT, currently a routine procedure, allows better patient selection for radical radiotherapy and facilitates selective irradiation of involved volumes (5). Image guided radiation therapy (IGRT), such as daily volumetric kilovoltage cone-beam computed tomography (CBCT), provides actual positional information, allowing for online repositioning and more precise tumor localization. Image-guided adaptive radiotherapy (IGART) additionally accounts for changes and deformations occurring during the radiotherapy course, thus allowing treatment re-planning (6). Currently, dose delivery in NSCLC is commonly accomplished by intensity modulated radiotherapy (IMRT). This technique improves the conformality of radiotherapy by modulating the radiation beam intensity profile, and allows decreasing the mean lung dose, particularly in patients with larger tumor volumes (7). The problem of intrafraction motion in thoracic malignancies has been traditionally managed by extension of treatment margins, leading to excessive radiation to normal tissues. Currently, tumor motion may be managed individually by respiratory-correlated 4-dimensional CT (4DCT) based on the acquisition of organ and tumor imaging data at extreme phases of the breathing cycle. An innovative option allowing for safe dose intensification is isotoxic therapy (8). This approach includes dose prescription defined by the maximal doses achievable to normal tissues. More recently, several clinical studies investigated the role of proton beam therapy in NSCLC. A dosimetric advantage of proton- over conventional photon radiotherapy is mediated by its unique properties: low doses upon tissue penetration, maximal dose deposition towards the end of the beam’s path (Bragg peak) and finite range with minimal dose beyond the tumor. Retrospective data and phase II studies suggested promising survival rates, and reduced pulmonary and esophageal toxicity with protons. However, the results of recent phase III trial did not confirm the superiority of this method over IMRT (9). In summary, recent diagnostic and therapeutic advances the use of radiation in stage III NSCLC allow for more accurate treatment planning, more precise dose delivery and managing tumor and organ motion. Some of these developments have been adopted in clinical practice, despite relatively few evidence of their advantages in terms of better local control and survival. The paucity of phase III trials testing new radiotherapy approaches is partly due to relying on better dose distribution and reduced exposure of normal tissues, making comparisons with less advanced techniques an ethical dilemma (10). References 1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16:187-99. 2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161–5. 3. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97–1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76–85. 4. Mauguen A, Le Pe´choux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97. 5. Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. 6. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 2010;20:94-106. 7. Bezjak A, Rumble RB, Rodrigues G, and al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508–20. 8. De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long term survival of patients in stage III NSCLC: a prospective population-based study. Radither Oncol 2012;102:228-233. 9. ZX Liao, J. JJ Lee, R Komaki, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(15S):435s. 10. Dziadziuszko R, Jassem J. Randomized clinical trials using new technologies in radiation oncology: ethical dilemma for medicine and science. J Thor Oncol 2007;7:3-4.

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      ED10.04 - New Developments for Systemic Therapies in Stage III NSCLC (ID 6484)

      16:00 - 17:30  |  Author(s): E.E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease (1). Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies (2). In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy (3). In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed (4). Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented (5). Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result in a survival benefit in RTOG 0612 (6). There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al (7) reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade (8). Updated information on these trials and relevant preclinical data will be presented. References: 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590-9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95.

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Author of

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    MA10 - Facing the Real World: New Staging System and Response Evaluation in Immunotherapy (ID 393)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      MA10.05 - Proposals for the Novel Clinical T Categories Based on the Presence of Ground Glass Opacity Component in Lung Adenocarcinoma (ID 6041)

      14:20 - 15:50  |  Author(s): K. Suzuki

      • Abstract
      • Presentation
      • Slides

      Background:
      In lung adenocarcinomas, the histologic lepidic growth pattern tends to correlate with the ground glass opacity (GGO) component, while solid components correspond with invasive adenocarcinoma. The Eighth edition of the TNM staging system suggests that the tumor size be determined according to the invasive size excluding the lepidic component. However, this new concept causes fatal confusion, i.e., tumors are classified into a same T category despite the part-solid or pure-solid appearances provided they showed a same solid component size.

      Methods:
      Between 2008 and 2012, we retrospectively evaluated 719 surgically resected cN0 lung adenocarcinomas that measures 30mm or less in total dimension to assess the prognostic impact on the presence of GGO among the Eighth TNM classification. According to the new T category, it was defined based on the solid component size as follow: Tis; 0 cm (pure-GGO), T1mi; ≤ 5 mm, T1a; 6-10 mm, T1b; 11-20 mm, T1c; 21-30mm. Furthermore, all tumors were classified into 2 groups, i.e., GGO or Solid arms based on the presence of GGO component.

      Results:
      Of the cases, 133 (18%) were categorized in Tis, 88 (12%) in T1mi, 121 (17%) in T1a, 244 (34%) in T1b and 133 (19%) in T1c, respectively. Multivariate analysis revealed that both a presence of GGO and solid component were independently significant prognostic factors (p=0.007, 0.002). The 5y-overall survival (OS) was 99.2% in Tis, 95.8% in T1mi, 96.5% in T1a, 81.8% in T1b and 66.4% in T1c (p=0.038) with a median follow-up period of 56 months. When we evaluated the impact of T category based on GGO presence, the 5y-OS was significantly different between GGO and Solid arm in each T categories (T1a; 99.0% vs. 95.7%, p=0.045, T1b; 89.8% vs. 73.3%, p=0.004, T1c; 90.0% vs. 62.6%, p=0.046). Furthermore, clinical T categories significantly separated the OS in Solid arm (p=0.015) (T1a vs. T1b; p=0.090, T1b vs. T1c; p=0.037). In contrast, the 5y-OS was approximately 90% or more in GGO arm despite their T categories. Moreover, regarding radiological and pathological correlations, the rates of AIS was only 65% in Tis, and 51% showed invasive adenocarcinoma even in T1mi.

      Conclusion:
      Clinical T category should be considered based on the presence of GGO on thin-section CT, and tumor size should be applied exclusively to radiological solid lung cancer. In contrast, oncological outcomes of the tumor with GGO component were excellent despite their T categories, which should be described as Tis for pure-GGO, and T1a for part-solid tumor.

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    MTE15 - Lymph Node Mapping in Lung Cancer (Ticketed Session) (ID 309)

    • Event: WCLC 2016
    • Type: Meet the Expert Session (Ticketed Session)
    • Track: Radiology/Staging/Screening
    • Presentations: 1
    • Moderators:
    • Coordinates: 12/06/2016, 07:30 - 08:30, Strauss 1
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      MTE15.01 - Lymph Node Mapping in Lung Cancer (ID 6566)

      07:30 - 08:30  |  Author(s): K. Suzuki

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.03 - Poster Session with Presenters Present (ID 455)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 2
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      P1.03-023 - Ground-Glass Opacity (GGO) with Semi-Consolidation: Clinicopathological and Radiological Correlations Compared to Pure-GGOs of the Lung (ID 5656)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      There has been a great advancement in understanding natural history of ground-glass opacity (GGO), which represents histological lepidic growth in early stage pulmonary adenocarcinoma. Among them, some GGO lesions reveal increased density of GGOs without obvious consolidation on thin-section computed tomography (TSCT), i.e., GGO with semi-consolidation. However, little is known regarding clinicopathological and radiological relationship of this new entity.

      Methods:
      During 2004 and 2016, we underwent AAA (2327) surgical resections for clinical-stage IA lung cadenocarcinoma. Among them, 286 (12.3%) GGO lesions without any consolidations were identified based on the findings on TSCT. They were categorized into two groups; pure-GGO (PG) and GGO with semi-consolidation (SC) according to the radiological findings. Semi-consolidation is defined as GGO with increased homogenous density without consolidation on TSCT. Clinicopathological factors were analyzed between these two groups. Survivals were calculated by Kaplan-Meier estimation methods.

      Results:
      Of the cases, 172 (60.1%) showed PG and 114 (39.8%) showed SC. Significant or marginal differences were clinically observed between PG and SG groups regarding age (59.4y vs. 63.0y, p=0.02), pack-year smoking status (10.2 vs. 11.6, p=0.084), tumor size (12.2cm vs. 13.9cm, p=0.06), respectively. Noninvasive lesions including atypical adenomatous hyperplasia, adenocarcinoma in situ or minimally invasive adenocarcinoma were observed in 144 patients (83.7%) of PG and 74 (64.9%) of SC, however, the frequency of invasive adenocarcinoma or lymph-vascular invasions were significantly higher in SC group compared to PG group (15.7% vs 33.9%, p=0.001: 4.3% vs 0.5%, p=0.040) despite their GGO appearances. There was no lymph node metastasis in both PG and SC groups. Overall lung-cancer specific survival is 100% to date in both PG/SC groups with mean follow-up period of 97months.

      Conclusion:
      Despite the conventionally same category as a native GGO appearance on TSCT, invasive adenocarcinoma was frequently observed in radiologically dense GGO lesions, indicating that PG might progress to SC over time. Surgical outcome for both groups are excellent. Therefore, more studies regarding optimal surgical procedures and long-term outcome of these two groups should be warranted.

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      P1.03-071 - Impact of Visceral Plural Invasion to T Descriptors: Based on the Forthcoming Eighth Edition of TNM Classification for Lung Cancer (ID 5702)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      According to the forthcoming eighth edition of TNM classification, T descriptors and M descriptors will be subdivided. Visceral plural invasion of lung cancer has been known as a non-size-based T2 descriptor. However, the definition still lacks in detail, and its validation is not included.

      Methods:
      We retrospectively reviewed 1250 patients, who underwent curative surgical resection for non-small cell lung cancer at Juntendo University Hospital, between January 2008 and December 2014. Patients with pathologic N1 or N2 disease were excluded. We subdivided tumor size based on the eighth edition of TNM classification. Cumulative survival rates were evaluated by the Kaplan–Meier method. Statistical differences in survival status were evaluated using the log-rank test.

      Results:
      In tumor size of 0-4cm, overall survival was significantly different between pl0 and pl1-pl2 in each tumor size; 0-1cm (p<0.0001), 1-2cm (p=0.001), 2-3cm (p=0.007), 3-4cm (p=0.012). In tumor size of over 4cm, overall survival was not different between pl0 and pl1-pl2 in each tumor size; 4-5cm (p=0.825), 5-7cm (p=0.311), over 7cm (p=0.272). In tumor size of 4-5cm with pl0-pl2, a five-year survival rate was 60%. In tumor size of 0-4cm with pl0-pl1, a five-year survival rate was not significant difference with in tumor size of 4-5cm with pl0-pl2; 0-1cm 50% (p=0.799), 1-2cm 71% (p=0.169), 2-3cm 70% (p=0.370), 3-4cm 67% (p=0.609).

      Conclusion:
      In pathologic N0M0 disease, there was no prognostic difference between tumor size of 0-4cm with pl1-pl2 and 4-5cm with any pl. In this study, tumors 4cm or less with visceral plural invasion become classified as T2b, and tumors larger than 4cm but 5cm or less also become classified as T2b regardless of visceral plural invasion.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 2
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      P1.05-002 - The Prognostic Impact of EGFR Mutation Status and Mutation Subtypes in Patients with Surgically Resected Lung Adenocarcinomas (ID 3932)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      EGFR mutation status is a well-established predictor of the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. Recently, the differences in EGFR mutation subtypes were also reported to be associated with the efficacy of EGFR TKIs. However, the prognostic impact of EGFR mutation status and mutation subtypes remains controversial.

      Methods:
      We retrospectively reviewed 945 consecutive patients with surgically resected adenocarcinomas who had their EGFR mutation status analyzed between January 2010 and December 2014. Overall survival (OS) and recurrence-free survival (RFS) were analyzed in three cohorts (all patients, pathological stage I patients, and patients with exon 21 L858R point mutation or exon 19 deletions) using Kaplan-Meier methods and Cox regression models.

      Results:
      The median follow-up time was 42 months. The results for EGFR mutation status, mutation subtype, and the comparison data of OS/RFS are summarized in the attached Table. Positive EGFR mutation status was significantly associated with longer OS/RFS in all patients and was also associated with longer OS in pathological stage I patients. However, no significant differences were observed in OS/RFS between patients with exon 21 L858R point mutation and those with exon 19 deletions. In a Cox regression model for OS, the EGFR mutation status was a significant prognostic factor that was independent of well-established prognostic factors such as age, pathological stage, vascular invasion, lymphatic permeation, and serum CEA level.

      3y-RFS 5y-RFS P 3y-OS 5y-OS P
      All Pts 0.009 < 0.001
      EGFR mut＋ (N = 423) 84.6% 76.7% 95.2% 89.0%
      EGFR mut- (N = 522) 78.8% 71.2% 84.9% 76.5%
      p stage I Pts 0.102 < 0.001
      EGFR mut＋ (N = 352) 93.4% 85.4% 98.2% 94.5%
      EGFR mut- (N = 392) 90.6% 82.8% 92.6% 85.9%
      Subtypes 0.385 0.507
      Ex 21 L858R (N = 224) 84.8% 79.6% 95.2% 90.0%
      Ex 19 del (N = 164) 84.7% 74.3% 97.5% 95.8%


      Conclusion:
      Positive EGFR mutation status is a favorable prognostic factor in patients with surgically resected lung adenocarcinomas. However, EGFR mutation subtypes (exon 21 L858R point mutation or exon 19 deletions) have no prognostic impact.

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      P1.05-051 - Safety and Compliance Data of the Phase III Study of Adjuvant Chemotherapy in Completely Resected P-Stage I Non Small Cell Lung Cancer: JCOG0707 (ID 3877)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract
      • Slides

      Background:
      Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients (pts) with completely resected, pathological (p-) stage I (T1> 2 cm) non small cell lung cancer (NSCLC). This trial aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.

      Methods:
      Eligible pts had undergone complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5[th] Edition UICC TNM) NSCLC, within 56 days of enrollment. Pts were randomized to receive either oral UFT 250mg/M2/d for 2 years (Arm A), or oral S-1 80mg/M2/d for 2 weeks followed by 1 week of rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the results of monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), the study was judged to be underpowered. The study protocol was amended so that the primary endpoint was relapse-free survival (RFS). With a calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 79% and a one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.

      Results:
      From Nov. 2008 to Dec. 2013, 963 pts were enrolled: median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 pts received pneumonectomy. All pts had completed protocol therapy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.6 (3.6/11.9) % in Arm B, respectively. In Arm A, 59.5% of the pts completed protocol therapy, and 70.7% received UFT for >1 year, which was comparable to prior studies. In Arm B, 54.7% completed protocol therapy, and 69.9% received S-1 for > 6 months. There were 4 cases of on-protocol deaths, probably of cardio-vascular origin: 1 in Arm A and 3 in Arm B. Based on the 2[nd] interim analysis in Sep. 2015, the data and safety monitoring committee recommended the follow-up of pts without unmasking of treatment arms. Estimated combined 2-year OS and RFS were 97.3% and 89.6%, respectively.

      Conclusion:
      Both post-operative adjuvant therapies were feasible, with similar compliances. Main results will be available in 2019.

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    P1.08 - Poster Session with Presenters Present (ID 460)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 2
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      P1.08-011 - Feasibility of Surgical Resection for Lung Cancer Patients Aged over 85 Years (ID 5636)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      Pulmonary resections for lung cancer in patients aged 80 years or over have been increasing in the aging society, which are accounted for approximately 10% in Japan. Due to the prolonged life expectancy in the elderly, it is inevitable to assess the feasibility of pulmonary resection for lung cancer especially in patients over 85 years in age.

      Methods:
      From 1995 to 2015, we underwent 3,099 pulmonary resections for lung cancers in our department. Among them, 213 (6.8%) were aged 80 years or older. They were divided into 2 groups based on the age, i.e., “Over80” who were aged from 80 to 84 and “Over85” who were aged 85 or elder. Clinicopathological factors were analyzed between these two groups, using the t-test or the Chi-squared test. Survivals were calculated by Kaplan-Meier estimation methods.

      Results:
      Of the cases, 174 (84%) showed Over80 and 39 (18%) showed Over85. The proportions for male, comorbidity rate, c-stage I disease in the Over85 group were not significantly different than those of the Over80 group (age; 20 (51%) vs. 105 (60%), p=0.189: comorbidity; 36 (92%) vs. 154 (89%), p=0.489: c-stage I; 36 (92%) vs. 143 (82%), p=0.119). The surgical candidates of the octogenarian included 167 (78%) radiological pure-solid lung cancer, however, there was not significant difference between the 2 groups (28 (72%) vs. 139 (80%), p=0.267). Lobectomy was equally performed in 28 (72%) on the Over85 and 126 (72%) of the Over80 (p=0.938), respectively. Perioperative morbidities were observed in 104 (48%) of the patients, though, significant difference was not found between the two study arms (84 (48%) vs. 20 (51%), p=0.734) and the 30-day mortality rates was observed just one patient for the Over80 group. The 5-year overall survival was 51.1% in the Over80 group, 62.6% in the Over85 group (p=0.275), respectively.

      Conclusion:
      In the octogenarians, a patient with radiological pure-solid lung cancer was more common as a surgical candidate for the definitive local management. Although proper patient selection and meticulous perioperative management were mandatory for surgical resection of the very elderly, our results support the finding that radical surgical intervention could be feasible even for the patients with high age over 85 years.

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      P1.08-067 - The Feasibility of Lung Second Surgery for 2nd Primary Lung Cancer (ID 4113)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      2[nd] primary lung cancer often has been encountered because of improvement of treatment outcome for lung cancer. If close follow up was performed after first surgery, 2[nd] primary lung cancer often was detected in early stage. And local therapy was indicated for this 2[nd] primary lung cancer. However, there is no rule whether stereotactic radiation therapy or surgery should be chosen. The aim of this study was to evaluate the feasibility of second surgery.

      Methods:
      We reviewed retrospectively 123 consecutive patients with past history of lung resection who underwent second surgery for 2[nd] primary lung cancer between 2008 and 2015 at our institution. i) These 123 cases were divided into 2 groups, contralateral and ipsilateral surgery groups. The difference between two groups of surgical difficulties (operation time and blood loss) and feasibility (post-operative complication and length of hospital stay) were evaluated by using Mann-Whitney U-test and Fisher’s exact test. ii) 82 cases who underwent contralateral surgery was picked up and divided into 3 groups, both lobectomy, lobectomy and limited surgery and both limited surgery. The difference between 3 groups of surgical difficulties and feasibility were evaluated by using same methods. iii) Furthermore, 41 cases who underwent ipsilateral surgery divided into 4 groups by procedure: completion pneumonectomy, lobectomy, segmentectomy and wedge resection. The difference between 4 groups of surgical difficulties and feasibility were evaluated by using same methods.

      Results:
      i) Not only operation time (161min vs 123min, p<0.001) but blood loss (30g vs 15g, p=0.002) were more in ipsilateral cases than in contralateral cases significantly. However, there was no significant difference in feasibility. ii) In contralateral cases, there were no significant difference between 3 groups in surgical difficulties and feasibility. iii) In ipsilateral cases, completion pneumonectomy had more operation time and blood loss than other procedures significantly (p=0.005, p=0.002, respectively) However, there was no significant difference in occurrence of post-operative complication.

      Conclusion:
      Ipsilateral surgery, especially completion pneumonectomy for 2[nd] primary lung cancer was more difficult procedure. However, ipsilateral and contralateral surgery was equivalent feasibility. Contralateral 2[nd] primary lung cancer is indication for surgery. However, second surgery for ipsilateral 2[nd] primary lung cancer requires careful consideration.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-014 - Retrospective Study of Pleuropneumonectomy for Thymoma with Dissemination (ID 6354)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      We usually perform a chemotherapy for thymoma with dissemination. But it was reported that reduction of thymoma was provided good long term survival.

      Methods:
      we reviewed retrospectively pleuropneumonectomy for thymoma with dissemination to determine the benefit. From 1996 to 2015, there were 172 patients with thymoma underwent. Of 172 patients, there were 4 patients with pleuropneumonectomy for thymoma with dissemination.

      Results:
      4 patients were all male. The previous treatment were included the operation, chemotherapy, and chemo-radiation therapy. Two patients were Masaoka I, and two patients were Masaoka IV. Two patients were with MG. Two patients underwent right pleuropneumonectomy. The complications after the operation were bleeding, cardiac herniation, bronchial fistula, empyema. All patients were alive (from 18 month to 86 month), but two patients have recurrence, vertebra and retroperitoneum.

      Conclusion:
      We revealed that pleuropneumonectomy for thymoma with dissemination is a high morbidity rate. However plueropneumonectomy may provide good long term survival. It is important that the selection of patient for example young male, good performance state.

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    P3.04 - Poster Session with Presenters Present (ID 474)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 3
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      P3.04-023 - Perioperative Management of Antiplatelet Therapy in Patients with Coronary Stent Who Need Thoracic Surgery (ID 4588)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      Guidelines recommend delaying noncardiac surgery in patients after coronary stent procedures for 6 -12 months after drug-eluting stents (DES) and for 6 weeks after bare metal stents (BMS). It is often replaced by bridging heparin for the prevention of perioperative stent thrombosis in Japan, although there is no evidence for heparin replacement. The aim of this study was to investigate the perioperative complication between the patients with continuation of antiplatelet therapy (APT) and that with substitution of heparin after interruption of APT in thoracic surgery.

      Methods:
      A retrospective study was done on 75 patients after coronary stent procedures performed thoracic surgery with APT or bridging heparin in perioperative from June 2008 to October 2015. We evaluated the perioperative outcomes between the patients with APT (APT group) and that with bridging heparin interrupting APT (non APT group).

      Results:
      Males were 13 cases (76%) and median age was 73.5 years in APT group. Fifteen cases (88%) with APT had angina in past history. The type of stent was drug eluting stent (71%), bare metal stent (24%) and biological absorption stent (6%) in APT group. Surgical procedures with wide wedge resection (12%), segmentectomy (12%), lobectomy (71%), and others (6%) were performed in APT group. Median operative time was 119 minutes and median operative blood loss was 18ml in APT group. There was no difference with operative time and blood loss in APT group compared in non APT group (p=0.128 and p=0.923). Cardiovascular events was not observed in both groups. One case had Hemothorax and reoperation in APT group and one case had hemosputum in non APT group. There was no difference in complication in both groups. Perioperative death was not observed in both groups.

      Conclusion:
      There was no difference between the patients with and without the discontinuation of antiplatelet agent in perioperative cardiovascular and embolic events. On the other hand, it seems that the compensatory of bleeding to continue antiplatelet agent is too large, because a few cases were forced completion pneumonectomy and acute exacerbation of interstitial pneumonia due to bleeding. Among the patients with coronary stent undergoing thoracic surgery, it might be less the benefits of the surgery with continuation of antiplatelet agent.

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      P3.04-027 - Feasibility of Lung Cancer Surgery for the Patient with Previous History of Coronary Artery Bypass Grafting (ID 6019)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      Owning to the aging society all over the world, high-risk lung cancer patients with severe cardio-pulmonary complications is more common. Among them, thea likelihood to encounter lung cancer patient with a previous history of coronary artery bypass grafting (CABG) has been increasing in our daily practice. However, pulmonary resections after CABG are technically challenging due to the critical adhesions around the CABG field, which need meticulous surgery.

      Methods:
      Owning to the aging society all over the world, high-risk lung cancer patients with severe cardio-pulmonary complications is more common. Among them, thea likelihood to encounter lung cancer patient with a previous history of coronary artery bypass grafting (CABG) has been increasing in our daily practice. However, pulmonary resections after CABG are technically challenging due to the critical adhesions around the CABG field, which need meticulous surgery.

      Results:
      Overall patients with previous CABG were comprised of 35 (88%) male with an average age of 70 years and high-smoking rate (40 pack-year smoking). Location of the lung cancer was 26(65%) in right side, while 27(68%) were in upper or middle lobe and 11(28%) in lower lobe.[a1] [y2] Clinical-stage of lung cancers were 22(55%) in IA, 6(15%) in IB and 12(30%)in II or more. Coronary CT was performed before the operation in 13(35%). Lobectomy was performed in 27(68%), segmentectomy in 6(15%), wedge resection in 7(18%), and mediastinal node dissection in 12(30%), respectively. Regarding CABG surgery, harvest of left / right internal thoracic artery was performed in 20(50%) / 21(53%). Adhesions around CABG fields were observed in 7(58%) / 5(23%), including 9(75%) upper or middle lobe lung cancer needing perivascular exfoliation without any intraoperative graft damage. Postoperative complications were shown in 13(33%), but the 30days mortality was 0%. The 3-year survival rate was 71.6 %, 3-year lung cancer specific survival rate was 76.1%.

      Conclusion:
      Results Owning to the aging society all over the world, high-risk lung cancer patients with severe cardio-pulmonary complications is more common. Among them, thea likelihood to encounter lung cancer patient with a previous history of coronary artery bypass grafting (CABG) has been increasing in our daily practice. However, pulmonary resections after CABG are technically challenging due to the critical adhesions around the CABG field, which need meticulous surgery.

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      P3.04-029 - A Prospective Randomized Trial of Perioperative Administration of Neutrophil Elastase Inhibitor in Patients with Interstitial Pneumonias (ID 4255)

      14:30 - 15:45  |  Author(s): K. Suzuki

      • Abstract

      Background:
      Although the acute exacerbation of interstitial pneumonia is a lethal complication after pulmonary resection for lung cancer patients with idiopathic interstitial pneumonias (IIPs), there are no established methods to prevent its occurrence. This prospective randomized study was conducted to evaluate whether the perioperative administration of neutrophil elastase inhibitor prevents the acute exacerbation of interstitial pneumonia.

      Methods:
      Between October 2009 and April 2015, 130 IIP patients with suspected lung cancer tumors were randomly assigned to two groups before surgery: in Group A (n=65), sivelestat sodium hydrate was perioperatively administered for 5 days; in Group B (n=65), no medications were administered. The primary endpoint was the frequency of the acute exacerbation of IIPs. The secondary endpoints were perioperative changes in the patients’ LDH, CRP, KL-6, SP-D and SP-A values, and the safety of the preoperative administration of sivelestat sodium hydrate. Multivariate analyses were performed using a logistic regression model to identify the predictors of acute exacerbation.

      Results:
      IIPs was radiologically classified into the following patterns: usual interstitial pneumonia (UIP) (n=23), possible UIP (n=28) and inconsistent with UIP (n=23). Sublobar resection, lobectomy and pneumonectomy were performed in 16, 112, and 2 patients, respectively. There were no statistically significant differences in patient characteristics between the groups. Two patients in group A and one patient in group B developed an acute exacerbation of IIPs. A preoperative partial pressure oxygen (PaO2) level of < 70mmHg was the only predictive factor identified in the multivariate analysis (p = 0.019, HR 19.2). The administration of neutrophil elastase was not associated with the development of an acute exacerbation, or with short- or long-term mortality. The KL-6, SP-D, SP-A levels on postoperative days 1 and 5 were lower in group A than in group B, and the LDH and CRP levels on postoperative day 5 were lower in group B than in group A; however the differences were not statistically significant. No subjective adverse events that could potentially be attributed to the administration of neutrophil elastase inhibitor were observed.

      Conclusion:
      The perioperative administration of neutrophil elastase inhibitor appeared to be safe; however, it could not prevent the development of acute exacerbation after pulmonary resection in lung cancer patients with IIPs.