Scientific Program

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    ISS06 - Symposium Supported by Medscape: NTRK Fusions in NSCLC - Practice Changing in 2018 and Beyond? (Not IASLC CME Accredited)

    • Moderators:
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      Welcome and Introductions

      07:00 - 07:05  |  Presenting Author(s): Ramaswamy Govindan

      • Abstract

      Abstract not provided

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      A Case Example of Lung Cancer and NTRK Fusions: Making the Diagnosis

      07:05 - 07:20  |  Presenting Author(s): Luis E Raez

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      Abstract not provided

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      A Case Example of Lung Cancer and NTRK Fusions: Management

      07:20 - 07:35  |  Presenting Author(s): Alexander Drilon

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      Abstract not provided

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      Sizing up Resistance: Getting in Front of the Problem

      07:35 - 07:45  |  Presenting Author(s): Trever G Bivona

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      Abstract not provided

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      Personalizing Therapy in Patients With NTRK Fusions: Will It Go the Way of EGFR?

      07:45 - 07:50  |  Author(s): Ramaswamy Govindan

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      Abstract not provided

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      Question and Answer

      07:50 - 07:55

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      Abstract not provided

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    ISS07 - Symposium Supported by Clinical Care Options, LLC: Strategies to Maximize the Clinical Benefit of EGFR TKIs in Advanced NSCLC (Not IASLC CME Accredited)

    • Moderators:
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      Welcome and Overview

      07:00 - 07:05  |  Presenting Author(s): Shirish Gadgeel

      • Abstract

      Abstract not provided

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      Selecting First-line Therapy in the Setting of EGFR-Mutated NSCLC

      07:05 - 07:20  |  Presenting Author(s): Shirish Gadgeel

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      Abstract not provided

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      Selecting Second-line Therapy and Beyond in the Setting of EGFR-Mutated NSCLC

      07:20 - 07:35  |  Presenting Author(s): Heather A Wakelee

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      Abstract not provided

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      Future Directions in Treatment Strategies for EGFR-Mutated NSCLC

      07:35 - 07:50  |  Presenting Author(s): Helena Yu

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      Abstract not provided

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      Conclusions and Audience Question and Answer Session

      07:50 - 08:00  |  Presenting Author(s): Shirish Gadgeel, Heather A Wakelee, Helena Yu

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      Abstract not provided

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    ISS08 - Symposium Supported by Foundation Medicine: Implementing Liquid Biopsies into Clinical Practice: Challenges, Achievements and Progress (Not IASLC CME Accredited)

    • Moderators:
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      Welcome and Opening Remarks and Introduction of Presenters

      07:00 - 07:05

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      Abstract not provided

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      The Current State and Critical Role of Liquid Biopsy

      07:05 - 07:20  |  Presenting Author(s): Nir Peled

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      Abstract not provided

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      Integrating Tissue - and Liquid - Based Approaches into Practice

      07:20 - 07:35  |  Author(s): Ruben Cabanillas

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      Abstract not provided

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      The Future State of Liquid Biopsy

      07:35 - 07:50  |  Presenting Author(s): Sai-Hong Ignatius Ou

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      Abstract not provided

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      Question and Answer

      07:50 - 08:00

      • Abstract

      Abstract not provided

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    MTE01 - Preclinical Models of Lung Cancer (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Biology
    • Moderators:
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      MTE01.01 - GEMM of Lung Cancer

      07:00 - 07:30  |  Presenting Author(s): Sarah Ann Best

      • Abstract

      Abstract

      The primary induction of lung cancer is difficult to study in humans because patients often present very late in the course of their disease. Genetically engineered mouse models (GEMMs) have therefore emerged as crucial bridging strategies between understanding pathogenic mechanisms and clinical translation. Importantly, they reveal insights on the events and processes underlying tumor initiation and progression, studies which are not possible when employing transplantation or chemically-induced model systems.

      The recent advent of next-generation sequencing technologies has provided us with an in-depth characterization of the cancer genome of lung adenocarcinoma (LUAD) (1), squamous cell carcinoma (LUSC) (2) and small cell lung cancer (SCLC) (3). While these studies have highlighted the genetic complexities of lung cancers, attention is now focused on elucidating “driver” mutations that confer a growth advantage, from “passenger” mutations that have little impact on malignant transformation. Investigating the loss or gain-of-function of individual genes, alone or in combination, can be directly addressed using GEMM systems.

      The “gold-standard” lung cancer models are based on Cre-LoxP recombination technology that enable the formation of autochthonous tumors from a limited number of somatic cells in a spatial and temporal fashion. Critically, tumors arise sporadically within the lung, in the setting of an intact immune microenvironment. GEMMs are designed to harbor genetic mutations frequently identified in human lung cancer. Cre-inducible alleles are engineered to disrupt tumor suppressor genes (LoxP sites flanking key exons (floxed), that are removed upon recombination) and/or activate oncogenes (LoxP-flanked stop codons (lox-stop-lox) that result in gene expression upon recombination). Cre-recombinase is delivered to the lung via inhalation or intra-tracheal injection of a recombinant adenovirus (Ad5) expressing Cre-recombinase under the control of a ubiquitous cytomegalovirus (CMV) promoter. Expression of Cre-recombinase directs the recombination of floxed alleles in a variety of epithelial cell types in the adult mouse lung (4,5). Utilizing this approach enabled investigators to interrogate the functional consequences of genetic alterations found in human lung cancer through the generation of models of LUAD, SCLC and more recently lung LUSC (6). Moreover, the recent advent of CRISPR-Cas9 gene-editing technology now enables us to interrogate the functional interaction between multiple genetic alterations in a high-throughput setting (7). Furthermore, the generation of cell type specific Ad5-Cre viruses, that restrict Cre expression, and thus recombination, to alveolar type II (ATII) (Ad5-SPC-Cre), club (Ad5-CC10-Cre), neuroendocrine (Ad5-CGRP-Cre) and basal (Ad5-K5-Cre, Ad5-K14-Cre) (8) cells, have provided insights into the cellular origins of different subtypes of lung cancer (9,10). Critically, unlike patient-derived xenograft (PDX) models, one additional advantage of GEMMs is the ability to interrogate the interplay between tumor cells and immune cells present in the tumor microenvironment. Such studies are crucial given the success of immune checkpoint inhibitors in lung cancer patients.

      This presentation will outline lung cancer GEMMs commonly used in the field and how these models can be utilized to identify cancer initiating cells, understand the molecular pathways underlying tumorigenesis, the immune microenvironment of lung cancer, and importantly to identify vulnerabilities that can be exploited for the design of improved treatment modalities for patients.

      References

      1. The Cancer Genome Atlas Research Network, Comprehensive molecular profiling of lung adenocarcinoma (2014) Nature, 511 (7511) 543-550.

      2. The Cancer Genome Atlas Research Network, Comprehensive genomic characterization of squamous cell lung cancers (2012) Nature, 489 (7417) 519-525.

      3. George et al., Comprehensive genomic profiles of small cell lung cancer (2015) Nature, 524 (7563) 47-53.

      4. Best et al., Combining cell type-restricted adenoviral targeting with immunostaining and flow cytometry to identify cells-of-origin of lung cancer (2018) Methods in Molecular Biology, 1725 15-29.

      5. DuPage et al., Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase (2009) Nature Protocols, 4 (7) 1064-1072.

      6. Farago et al., SnapShot: Lung cancer models (2012) Cell, 149 (1) 246-246e1.

      7.Rogers et al., A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo (2017) Nature Methods, 14 (7) 737-742.

      8. Ferone et al., SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin (2016) Cancer Cell, 30 (4) 519-532.

      9. Sutherland et al., Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung (2011) Cancer Cell, 19 (6) 754-764.

      10. Sutherland et al., Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma (2014) Proc. Natl. Acad. Sci. USA, 111 (13) 4952-2957.

      • Abstract

      Abstract

      Establishment of preclinical lung cancer models that closely match patient tumor biology is imperative for developing therapeutic strategies with the most translational relevance. Non small cell lung cancer (NSCLC) cell lines grown under 2D conditions or as cell line-derived xenografts (CDXs) are the most widely used models. They have been complemented with murine models engineered to develop lung cancer after introduction of specific genetic alterations (GEMMs). Lung cancer cell lines are readily amenable to mechanistic studies and economical high-throughput drug screening. However, for many NSCLC cell lines, the spectrum of mutations and copy number alterations have drifted considerably relative to patient tumors 1. This finding, in conjunction with long-term adaption to heterologous in vitro growth conditions, raise concerns about the extent to which cell line biology and potential drug responses may have deviated from clinical tumors. GEMMs are powerful tools for studying specific oncogenic mechanisms in isolation in vivo, but these models lack the intratumoral heterogeneity of patient tumors, which is thought to play a major role in the development of drug resistance. Furthermore, ideally, GEMMs should be constructed using the appropriate cell of origin context, which is challenging, as there are differences in the compositions of human and murine airways, and the cellular origins for most forms of lung cancer have not been established.

      NSCLC patient-derived xenografts (PDXs) overcome some of the limitations of these other models. They show much less genetic drift than cell lines, and their mRNA expression and the phospho-tyrosyl proteome more closely match patient tumors 1, 2. We have established a large collection of NSCLC PDXs from surgically resected tumors and endobronchial ultrasound-guided (EBUS) and CT-guided biopsies. Tumor specimens were initially implanted in the subcutaneous flanks of NSG mice (NOD SCID gamma, non-obese diabetic severe combined immunodeficiency, gamma). The PDX tumors have been viably cryopreserved and can be serially passaged in NOD SCID mice. Most of our collection comprises the major histologic subtypes of NSCLC [52 adenocarcinomas (LUAD) and 62 squamous cell carcinomas (LUSC)]. They, along with the primary patient tumors, are being molecularly profiled at multiple levels so that they can be optimally used for personalized medicine studies and novel integrated approaches to understand NSCLC pathogenesis, prognosis, and treatment. These levels include copy number variations, exome mutations, DNA methylation, mRNA and miRNA expression, and proteomics. In general, the PDX models recapitulate the mutation spectrum, copy number variations, and gene expression of matched patient histologies. They also recapitulate sensitivity and resistance to known targeted therapeutics (e.g. EGFR inhibitors), and thus, can be used to dissect mechanisms underlying differential drug responses. Such studies are ongoing, including investigation of potentially new biomarker-targeted therapeutic combinations. We have also found that not all patient tumor fragments engraft successfully, and that successful engraftment correlates with poor prognosis of the patient 3. We are using this relationship to discover a new molecular fingerprint to predict clinical outcome, as well as understand the bases that distinguish less and more aggressive tumor behavior.

      In parallel, we have developed methods to grow organoids from primary patient tumors and PDX models in 3D culture using Matrigel (PDO and XDO, respectively). For LUAD, both the PDO and XDO success rate of establishing bona fide organoid models is ~20%. Our stringent criteria include a minimum capacity of 10 passages and a split ratio of at least 1:3. LUSC has been more difficult to establish as organoid models, with a success rate of 17%, and only from PDXs, so far. Using these methods, we have established 4 models of each histology, which we have confirmed form tumors when transplanted into mice. Molecular profiling indicates that the organoids maintain the same mutation spectrum and copy number variations of their parental tumor tissue. These models offer distinct advantages over PDXs and cell lines. As compared to standard 2D cultures, they recapitulate the appropriate tissue histology, and thus, possibly clinically relevant growth control mechanisms, even while growing ex vivo. This notion is further supported by the ex vivo conditions supporting gene expression patterns, which allows the organoids to be segregated into their respective tumor histologies when using signatures derived from patient or PDX material. Given the low cost, rapid growth rates, and ease of in vitro manipulation, these models are ideally suited for rapid discovery and testing of new therapeutic strategies that can be matched to specific patient molecular profiles.

      In summary, generation of molecularly profiled PDX and organoid models offer great opportunity for translational and personalized medicine in NSCLC.

      1. Gao, H. et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 21, 1318-1325 (2015).

      2. Wang, D. et al. Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors. Int. J. Cancer 140, 662-673 (2017).

      3. John, T. et al. The ability to form primary tumor xenografts is predictive of increased risk of disease recurrence in early-stage non-small cell lung cancer. Clin. Cancer Res. 17, 134-141 (2011).

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    MTE02 - Update on WHO Classification and Staging of Lung Cancer (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Pathology
    • Moderators:
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      MTE02.01 - Update on WHO Classification and Staging of Lung Cancer

      07:00 - 07:30  |  Presenting Author(s): Sanja Dacic

      • Abstract

      Abstract

      The most significant changes in the 2015 WHO classification of the lung tumors include classification criteria for small biopsy and cytology specimens, use of immunohistochemistry, integration of molecular testing, adoption of the IASLC/ATS/ERS adenocarcinoma classification and a strict definition of large cell carcinoma limited to surgical resection specimens only. 1,2 Tumors that show unequivocal morphology of adenocarcinoma or squamous cell carcinoma on a small specimen should be diagnosed without immunohistochemistry. Immunohistochemical work up of poorly differentiated tumors should be limited to TTF-1and p40/p63, while neuroendocrine markers should be used only if morphologically indicated. This approach should reduce the diagnosis of NSCC, NOS to less than 5 % and preserve tissue for molecular testing. 1,2

      Major changes in the adenocarcinoma classification for resected specimens include addition of adenocarcinoma in situ (AIS) to preinvasive group that already includes atypical adenomatous hyperplasia. Minimally invasive adenocarcinoma (MIA) defined as a solitary, lepidic predominant adenocarcinoma presenting measuring in gross size 3 cm or less and with invasion of ≤
5 mm was added as a new category. These tumors are also recognized by the 8th edition of the AJCC staging of lung cancer and include Tis(adenocarcinoma) and T1a-mi. T stage of non-mucinous lepidic predominant adenocarcinomas is based on the microscopic size of invasion, but gross size should be recorded in the pathology reports. Multifocal ground glass opacities/lung nodules most frequently present as MIAs and should be classified by the T category of the lesion with the highest T along with the number of lesions (#) or simply (m) for multiple indicated in parentheses, and with a single N and M category that applies to all of the multiple tumor foci. This approach should be applied to grossly or microscopically identified lesions occurring in the same or in different ipsilateral or contralateral lobes.3 For non-lepidic adenocarcinoma T stage is determined by gross size in 1.0 cm increments as each size subgroup carries prognostic significance.

      Former mucinous BAC are reclassified as invasive mucinous adenocarcinoma, excluding tumors that meet criteria for AIS or MIA. Signet ring and clear cell carcinomas are considered to represent cytologic variants rather than specific subtypes.

      Invasive adenocarcinomas should be subtyped by semi-quantitatively estimating the percentage of the various subtypes in 5% increments. 1,2 Reproducibility for lung adenocarcinoma predominant subtypes among pulmonary pathologists was good to moderate (κ-values 0.44 to 0.72).4 For untrained pathologists, κ-values were lower ranging from 0.38 to 0.47, but these improved after a training session and particularly for individual reviewer. 5

      The 2015 WHO classification defines large cell carcinomas based on morphology, as carcinomas without morphologic evidence of glandular, squamous or neuroendocrine differentiation, and also based on null immunophenotype and genotype. 1This change in definition reflect what was already happening in the pathology practice. According to National Cancer Institute (NCI) Surveillance Epidemiology and End Results registry the diagnosis of large cell carcinoma started to decline about the time that TTF-1 was introduced into clinical diagnosis. 6

      References:

      Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer, 2015.

      
Travis WD. Et al. The 2015 World Health Organization Classification of Lung Tumors Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015; 10 (9); 1243-1260

      Frank C. Detterbeck, MD et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification . J Thorac Oncol 2016;11(5): 639-650

      Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol 2012;25:1574–1583. 


      Warth A, Cortis J, Fink L, et al.; Pulmonary Pathology Working Group of the German Society of Pathology. Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ ATS/ERS classification. Virchows Arch 2012;461:185–193. 


      Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer 2014;120:2883–2892. 


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      MTE02.02 - Update on WHO Classification and Staging of Lung Cancer

      07:30 - 08:00  |  Presenting Author(s): Teh-Ying Chou

      • Abstract

      Abstract

      Squamous cell carcinoma comprises approximately 20% of lung cancer cases and is classified into keratinizing, non-keratinizing and basaloid types (1,2,3). The p40 (or p63) immunohistochemical stain is helpful in diagnosing squamous cell carcinoma, if keratinization of the tumor cells is not appreciable.

      Neuroendocrine tumors comprises of four categories: small cell carcinoma, large cell carcinoma, typical carcinoid and atypical carcinoid (1), with variable degrees of malignant potential. Small cell carcinoma comprises approximately 14% of lung cancer cases and is further categorized into small cell carcinoma and combined small cell carcinoma (1,4,5). The tumor is composed of densely packed small-size tumor cells with scant cytoplasm, finely granular chromatin, and absence of distinct nucleoli. Mitotic figures and apoptotic bodies are frequently seen. Nuclear molding and smearing may be observed. Rosette formation and peripheral palisading, characteristics of neuroendocrine tumors, are consistently found. Large cell neuroendocrine carcinoma has the cytological morphology of large cell carcinoma and the growth pattern of neuroendocrine tumor. Both small cell carcinoma and large cell neuroendocrine carcinoma are high grade tumors. Carcinoid tumors are usually centrally located with endobronchial growth and are further divided into two categories: typical carcinoid (intermediate grade) and atypical carcinoid (low grade).

      Adenosquamous carcinoma is rare and comprises 0.4-4% of lung cancer cases (1,6,7). Presence of both adenocarcinoma and squamous cell carcinoma components and each component comprising more than 10% is required.

      Sarcomatoid carcinoma comprises less than 1% of lung cancer cases and is further subcategorized into pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (1,8). Given the marked histological heterogeneity, sarcomatoid carcinoma need to be thoroughly sampled before the final diagnoses are made.

      Salivary gland-type carcinomas include mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma, arising from the salivary-type glands of the bronchial mucosa (1).

      In summary, the major types of lung carcinomas are outlined in Figure 1.

      180629 histology lung cancer classification.jpg

      References:

      1. William D. Travis EB, Allen P. Burke, Alexander Marx, Andrew G. Nicholson (Eds.). WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (4th Edition). 4 ed: IARC: Lyon; 2015.

      2. Tomashefski JF, Jr., Connors AF, Jr., Rosenthal ES, Hsiue IL. Peripheral vs central squamous cell carcinoma of the lung. A comparison of clinical features, histopathology, and survival. Archives of pathology & laboratory medicine. 1990;114(5):468-74.

      3. Funai K, Yokose T, Ishii G, Araki K, Yoshida J, Nishimura M, et al. Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung. The American journal of surgical pathology. 2003;27(7):978-84.

      4. Fraire AE, Johnson EH, Yesner R, Zhang XB, Spjut HJ, Greenberg SD. Prognostic significance of histopathologic subtype and stage in small cell lung cancer. Hum Pathol. 1992;23(5):520-8.

      5. Mangum MD, Greco FA, Hainsworth JD, Hande KR, Johnson DH. Combined small-cell and non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1989;7(5):607-12.

      6. Fitzgibbons PL, Kern WH. Adenosquamous carcinoma of the lung: a clinical and pathologic study of seven cases. Hum Pathol. 1985;16(5):463-6.

      7. Ishida T, Kaneko S, Yokoyama H, Inoue T, Sugio K, Sugimachi K. Adenosquamous carcinoma of the lung. Clinicopathologic and immunohistochemical features. Am J Clin Pathol. 1992;97(5):678-85.

      8. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Archives of pathology & laboratory medicine. 2010;134(11):1645-58

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    MTE03 - Clinical Trial Design With Novel Lung Cancer Therapy (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Targeted Therapy
    • Moderators:
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      MTE03.01 - Inclusion/Exclusion Updates (CNS Mets, Multiple Prior Cancers, Organ Dysfunction)

      07:00 - 07:30  |  Presenting Author(s): Peter Michael Ellis

      • Abstract

      Abstract

      Introduction

      Randomized clinical trials (RCTs) represent the gold standard trial design for the evaluation of treatment interventions. Advancing knowledge in oncology has relied heavily on data from high quality RCTs focusing on important outcomes such as overall survival (OS) and more recently progression free survival (PFS). Many examples exist, even in recent times, where the use of alternate study designs, such as cohort and case control series, have concluded benefit for a therapy that was subsequently disproven by RCTs. Nevertheless, an increasing number of therapies are being approved by licensing authorities such as the FDA, based on intermediate outcomes such as objective response rate (ORR) from phase II clinical trials.

      Pragmatic versus explanatory trials

      RCTs can be either explanatory or pragmatic. Explanatory trials evaluate a treatment intervention under ideal conditions. They tend to have more restrictive inclusion and exclusion criteria to minimize the potential for confounding due to coexistent health problems. Pragmatic trials, on the other hand, evaluate treatment interventions in real life practice conditions. Inclusion and exclusion criteria are generally less restrictive and the results are considered more generalizable to the broad population of people with the underlying condition.

      RCTs in oncology are often explanatory in design. Inclusion criteria generally limit eligibility to the highest functioning patients. They often specify the type of diagnostic material needed and require samples to be available for correlative studies. Trials are generally very restrictive in regard to prior therapy that patients may have received and most trials require normal, or near normal organ function for eligibility. Exclusion criteria contain lengthy lists of criteria that make patients ineligible. Many trials exclude patients with brain metastases unless they have been treated and stable for some time. There are often lengthy lists of coexistent health problems, such as cardiac disorders, that commonly coexist in patients with lung cancer, that make an individual ineligible. The end result is that the generalizability of many RCTs is limited and healthcare providers need to extrapolate trial findings to a large proportion of their patients who might not have met inclusion and exclusion criteria for the trial generating the evidence of efficacy.

      Why should we rethink our current approach

      Historically, most advances from RCTs in lung cancer have represented small incremental gains in OS or PFS. Under these conditions, dependence on explanatory trials with multiple inclusion and exclusion criteria may well have been appropriate to minimize the confounding effects from intercurrent problems. However, many changes have taken place in therapeutic options for lung cancer patients over the last decade. Our understanding of underlying molecular abnormalities important in lung cancer development and growth has increased greatly. Multiple agents targeting underlying molecular abnormalities have demonstrated ORR almost twice that of conventional chemotherapeutic agents, with similarly impressive improvements in PFS. Additionally, many newer agents have been developed that cross the blood brain barrier and have demonstrated significant anti-tumor activity in patients with CNS metastases as well. Given the improved tolerability of these agents and increased expectation of benefit from therapy, less stringent inclusion and exclusion criteria should be considered. Trials of targeted therapies should include a broader spectrum of patients including those with lower performance status and untreated CNS disease. Criteria focusing on organ function should be limited to known toxicity concerns for the therapy under evaluation.

      The emergence of treatments targeting activation of the immune system also represents a significant therapeutic advance. Some trials evaluating immune checkpoint inhibitors have been very restrictive for patients with CNS metastases. Nevertheless, responses are seen in patients with CNS metastases, questioning the need for such restrictive exclusion criteria. Patients with underlying autoimmune disorders are excluded from the majority of trials of immunotherapy agents. Some emerging data exists though suggesting that these agents may be safely given to patients with underlying autoimmune diseases. These findings highlight the need to modify inclusion and exclusion criteria for trials of immunotherapy agents to gain information of safety and efficacy in these populations of patients and to increase the generalizability of trial findings.

      Conclusions

      The advancement of knowledge in oncology remains dependent on well conducted RCTs. However, we need to question the rigidity of a number of common inclusion and exclusion criteria in an attempt to improve the pragmatic aspect of many trials and increase the generalizability of current RCTs.

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      MTE03.02 - Novel Trial Design for Precision Medicine

      07:30 - 08:00  |  Presenting Author(s): Fiona Blackhall

      • Abstract

      Abstract

      Trial design for precision medicines has shifted to increasing use of platform protocols, ‘liquid’ biopsy and the practice of co-clinical trials using patient or circulating tumour cell derived (PDX/CDX) models. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were the first class of precision medicine approved for advanced non-small cell lung cancer (NSCLC) but initially for unselected patients following the traditional convention of phase I evaluation in heavily pretreated populations, phase II evaluation also in pretreated, ‘all comers’, and then in large, randomised, phase III, double blind, placebo controlled studies versus best supportive care. The linkage between sensitising EGFR mutations and their prediction for efficacy came later. It now seems remarkable that these agents made it through to standard of care and is questionable whether they would have been approved for all comers in the current health economic climate. The ‘EGFR story’ catalysed the current goal to integrate drug-target linkage early in clinical development. This was achieved for the first in class ALK inhibitor, crizotinib, initially developed as a MET inhibitor but on discovery of ALK gene fusion and its potency for ALK a strategy to enrich for patients with tumours positive for ALK gene fusion by fluorescent in situ hybridisation (FISH) ensued. The phase I trial (PROFILE 1001) led to accelerated approval within 4 years on the basis of response rate, setting the paradigm of ‘enrichment’ studies for precision medicine development. (2) In parallel, platform studies using ‘umbrella’ or ‘basket’ protocol designs emerged to screen prospectively for multiple targets simultaneously and enrol the patient to a study arm designed for the target/biomarker(s) present. The first of these studies to be conducted in lung cancer was the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial (3) and subsequent examples ongoing are the Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400 (4) and the National Lung Matrix Trial in the UK (5). Obvious strengths for umbrella studies are a single protocol, screening for a panel of molecular alterations simultaneously and flexibility to add new study arms (and testing modalities) but criticisms include a high attrition rate both due to sample inadequacy for molecular testing and lack of a study arm for the biomarker(s) identified. Regardless of the study design, translational science to rigorously evaluate serial predictive biomarkers of response and resistance is crucial and in this regard new technologies for liquid biopsy are proving transformational, overcoming the reliance on tissue biopsy that can be a barrier to participation in trials (6), and in the resistance setting may not be representative due to evolution and heterogeneity. Of note the 3rd generation EGFR-TKI, osimertinib, designed to target the EGFR T790M resistance mutation, was developed in trials that included serial tissue and ‘liquid’ biopsy for analysis of plasma circulating tumor DNA (ctDNA). While the application of ‘liquid biopsy’ proved the clinical utility of this approach and is now a standard of care (7), the high response rate rendered the second biopsy on treatment uninformative in many patients (8). A further use of tissue and liquid biopsy in precision medicine trials that is likely to increase is the practice of so-called ‘co-clinical trials’. This involves obtaining a fresh tumour biopsy and/or a circulating tumour cell sample from blood to establish as a xenograft mouse model from a patient at study entry and again on progression. The resultant patient derived or CTC derived explant model (PDX or CDX) is used to identify molecular mechanisms and candidate predictive biomarkers for subsequent clinical validation and is particularly applicable to trials for patients with small cell lung cancer (SCLC) (9,10). Although traditional, all comer, early phase study designs may soon be obsolete new designs of precision medicine trials will only be as effective as the enrichment strategy, scientific rationale and pharmacology underpinning them. To this end ‘team science’ approaches with close collaboration between academia and pharma will be essential for the golden age of precision medicines to be fully realised for lung cancer.

      (1) Tan DSW et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016. JTO 2016 Vol 11, Issue 7, Pages 946–963

      (2) Blackhall F and Cappuzzo F. Crizotinib: from discovery to accelerated development to front-line treatment. Ann Oncol. 2016 Sep;27 Suppl 3:iii35-iii41.

      (3) Kim ES et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011 Jun;1(1):44-53.

      (4) Herbst RS et al. Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clin Cancer Res. 2015 Apr 1;21(7):1514-24.

      (5) Middleton G et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol. 2015 Dec;26(12):2464-9.

      (6) Lim C et al. Patients with Advanced Non-Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials? J Thorac Oncol. 2016 Jan;11(1):79-84.

      (7) Oxnard GR et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer.

      J Clin Oncol. 2016 Oct 1;34(28):3375-82.

      (8) Thress KS et al. Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial. J Thorac Oncol. 2017 Oct;12(10):1588-1594.

      (9) Lallo A et al. Circulating tumor cells and CDX models as a tool for preclinical drug development. Transl Lung Cancer Res. 2017 Aug;6(4):397-408.

      (10) Drapkin BJ et al. Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discov. 2018 May;8(5):600-615.

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    MTE04 - Comparison of Various Risk Models (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Screening and Early Detection
    • Moderators:
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      MTE04.01 - Comparisons of Risk Models

      07:00 - 07:30  |  Presenting Author(s): Christine Berg

      • Abstract

      Abstract

      Lung cancer unfortunately remains the leading cause of cancer death in the world. Lowering lung cancer mortality in the near term while efforts continue to halt the tobacco use epidemic would result from early detection with low-dose helical CT screening in countries with the health care resources to support this complex endeavor. Current guidelines from groups like the United States Preventive Services Task Force (USPSTF), the Centers for Medicare and Medicaid Services (CMS) and the Canadian Task Force on Preventive Health Care follow criteria for entry to screening that mimic the National Lung Screening Trial entry criteria. Many researchers have shown that these guidelines may not be optimal for achieving the maximal lung cancer mortality reduction attainable through screening. Also, there is variability from country to country in lung cancer risk depending upon demographics, ethnic and racial mix, smoking intensity patterns and types of tobacco products. Individual risk models that have been validated in the country and population group in which they will be used will assist in optimizing effectiveness and efficiency. Where to set the risk-threshold will be a function of cost-effectiveness and other considerations and will be the subject of a separate presentation.

      What are the components of a risk model and how do the various risk models compare, and which ones are available to use? This talk will review the risk models published to date. Also, several groups have compared several of the risk models with each other demonstrating some advantages to certain models. The complexities of these model comparisons will be elucidated. Country to country variability will also be discussed. Models also differ in the number of variables they include. There are advantages to the parsimonious models as they may be easier to use in practice. However, they may do less well in better defining risk. Given that different racial and ethnic groups have different risk profiles it should be important to characterize this risk and have one useable model that incorporates it rather than separate models for different groups. Another major issue is how to incorporate risk models into facilitating entry into screening programs. What are the strengths and limitations of electronic medical records for this process? CMS requires an “informed decision making” visit with a health-care provider prior to lung cancer screening. What ideally should this include and how should risk be discussed?

      As the field of oncology moves to a “precision medicine” approach lung cancer screening can be at the forefront of this effort. The goal of an effective and efficient strategy will hopefully translate into the most numbers of lives saved for the screenings done. It is a challenge our community can meet.

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      MTE04.02 - Where Should Health Programs Set Threshold for Tailored Screening?

      07:30 - 08:00  |  Presenting Author(s): James L Mulshine

      • Abstract

      Abstract

      Since the publication of the U.S. Preventive Services Task Force recommendation statement on lung cancer screening much discussion has focused on what is the critical information required to make an informed decision regarding the benefit of undergoing thoracic CT screening (1). Ever more sophisticated modeling approaches are being developed to better characterize the risk: benefit consequences of screening. This session will explore the current state of this complex issue. Yet as screening implementation builds momentum, more information is emerging about the information gleaned from thoracic CT obtained in a population of heavily tobacco-exposed individuals that may profoundly effect the screening health benefit discussion.

      A comprehensive analysis of diseases, injuries and risk factors across the United States from 1990 to 2016 was recently reported by a jointly sponsored consortium from the National Institutes of Health and The Bill and Melinda Gates Foundation, as a guide to investment for research, care and public health policy in the United States (2). According to that report, lung cancer including both the trachea and the bronchi was and remains the second leading cause of years of life lost across the 26 year time interval of that study due to an increase by 26.8% in the number of lung cancer deaths. In that analysis, the most lethal disease process was ischemic heart disease (IHD) which accounted for over 544,000 deaths in 2016. Even though, there was a 15% reduction in IHD mortality since 1990, ischemic heart disease still results in over 2.84 times more deaths than lung cancer. However, for both of these diseases, the age-standardized death rate is fortunately declining.

      In contrast for the third leading cause of death, chronic obstructive pulmonary disease (COPD), over that same 26 year interval, the total number of deaths has increased by 86.9%. Collectively, these three diseases, IHD, lung cancer and COPD account for over 44% of the mortality from the top 25 causes of years of life lost in 2016.

      As we consider risk developing risk models for lung cancer screening, it is useful to step back and consider the information being shared with the individual considering their screening benefit. Currently, in the United States that person being screened is most likely an over 55 years old, current or former smoker with over 30 pack year exposure to tobacco combustion products. As we have just reviewed, the most likely determinants of that individual’s life expectancy are the three most lethal diseases, IHD, lung cancer and COPD.

      Even as we are beginning to screening tobacco-exposed populations, we know that there large numbers of individuals found in the course of their lung cancer screening CT, who will also be found that have asymptomatic but objective evidence of COPD or coronary calcification (3-7). For both IHD and COPD, NIH is encouraging measures to improve the early detection of these two major diseases so that pre-emptive strategies can be employed, before the development of symptoms and avoid the disabling burden of largely incurable advanced disease. Guidelines have already been published for managing the extent of coronary calcium found on thoracic CT scans as promulgated by cardiac professional societies (8). In parallel developments, the pulmonary community is also finding compelling evidence for cardiovascular disease when evaluating for COPD (9). Finding from both of these thoracic CT-detected diseases are frequently being reported on the radiologists’ report for lung cancer screening.

      Considerable progress has been made in developing predictive risk models for lung cancer in the screening setting (10, 11). However, from a screening subjects’ perspective, a lung cancer-only risk analysis does not include the vast majority of risk-for-death information that is relevant to a heavy smoker that could be available on their screening CT in regard to the first and third leading cause of death (IHD or COPD) (2-9). Therefore when considering developing future risk outcomes tools for an individual deciding on whether or not to undergo CT screening for lung cancer, we perhaps need a more inclusive evaluation of health outcomes that consider the major knowable consequences of extensive tobacco exposure. The most recent Surgeon General's Report released in 2014 and summarizing 50 years of studying tobacco health consequences, reaffirmed the causal inference of tobacco smoke to a lengthy list of diseases including most prominently, cancers, cardiovascular disease and chronic obstructive pulmonary disease (12). In discussions about other major chronic diseases such as diabetes or hypertension, people are educated about the multi-organ involvement of these diseases, so they have the information to better protect their health.

      The three leading causes of loss of life (IHD, lung cancer and COPD) in the United States cumulatively account for over 13,500 years of loss of life per year. However, from a heavily tobacco-exposed individual’s perspective, lung cancer only accounts for 26% of this mortality burden. A thoracic CT scan can provide actionable risk information for all three leading tobacco-related causes of death. The most recent draft research plan for the United States Preventive Services Task Force is explicitly evaluating lung cancer screening outcomes for impact on all-cause mortality. It is a critical time to consider more comprehensive tools to transparently inform about the relevant health information available with the use of thoracic CT imaging in heavily tobacco-exposed individuals.

      References:

      1) Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Mar 4;160(5):330-8. doi: 10.7326/M13-2771.

      2) PMID: 24378917The Burden of Disease Collaborators; Mokdad AH, Murray CJL, Khan AR, et al. The state of US health, 1990-2016: burden of diseases, injuries, and risk factors among US states. JAMA. doi:10.1001/jama.2018.0158.

      3)Seijo LM and Zulueta JJ. Understanding the links between lung cancer, COPD and emphysema: A key to more effective treatment and screening. Oncology 2017; 31: 93-100.

      4) Shemesh J, Henschke CI, Shaham D, et al. Ordinal scoring of coronary artery calcifications on low-dose CT scans of the chest is predictive of death from cardiovascular disease. Radiology. 2010;257(2):541-548.

      5) Chiles C, Duan F, Gladish GW, et al. Association of Coronary Artery Calcification and Mortality in the National Lung Screening Trial: A Comparison of Three Scoring Methods. Radiology. 2015;276(1):82-90.

      6) Takx RA, de Jong PA, Leiner T, et al. Automated coronary artery calcification scoring in non-gated chest CT: agreement and reliability. PLoS One. 2014 Mar 13;9(3):e91239. doi: 10.1371/journal.pone.0091239. eCollection 2014.

      7) Malcolm KB, Dinwoodey DL, Cundiff MC et al. Qualitative coronary artery calcium assessment on CT lung screening exam helps predict first cardiac events. J Thorac Dis. 2018. 10: 2740-2751 doi: 10.21037/jtd.2018.04.76.

      8) Harvey S. Hecht, Paul Cronin, et al.SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: A report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. Journal of Cardiovascular Computed Tomography, Volume 11: 74-84, 2016.

      9) Bhatt SP, Kazerooni EA, Newell JD Jr et al. Visual estimate of coronary artery calcium predicts cardiovascular disease in COPD, CHEST (2018), doi: 10.1016/j.chest.2018.05.037.

      10) ten Haaf K, Jeon J, Tammemägi MC et al. Risk prediction models for selection of lung cancer screening candidates: a retrospective validation study., PLoS Med, 2017, vol. 14 pg. e1002277.

      11) Katki HA, Kovalchik SA, Petito LC, et al. Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-2701. [Epub ahead of print].

      12) US Department of Health and Human Services, The Health Consequences of Smoking: 50 Years of Progress: a Report of the Surgeon General, 2014 Atlanta, GAUS Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

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    MTE05 - Role of Pneumonectomy in N2 Disease (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
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      MTE05.01 - Role of Pneumonectomy in N2 Disease

      07:00 - 07:30  |  Presenting Author(s): Jessica Donington

      • Abstract

      Abstract

      Stage III non-small cell lung cancer (NSCLC) presents a significant treatment challenge. Patients are treated with curative intent, but only 20-30% achieve that goal, and acceptable treatment plans vary dramatically. Chemotherapy-based multimodality is the standard of care, but the ideal local therapy is unclear. Definitive concurrent chemo-radiotherapy without surgery is accepted by many as the treatment of choice, but local relapse is the first site of failure in up to >30%. Therefore, adding surgery to improve outcomes is attractive.

      Lung resection following induction chemo-radiotherapy to 45 Gy has been prospectively shown to be safe in numerous clinical trials. The use of pneumonectomy after induction therapy has been far more controversial. Multiple single institution series report on the safety of pneumonectomy following induction chemo-radiotherapy, even to doses of 60Gy, but results from multi-institutional prospective trials have not been as good, with reported peri-operative mortality up to 20-25%.

      The Intergroup trial 0139 was designed to evaluate the utility of adding surgery to chemo-radiotherapy for the treatment for N2+ IIIA NSCLC. The primary endpoint was improved overall survival, but was not met despite a significant improvement in progression-free survival. Some of this discrepancy was due to a high number of patients undergoing pneumonectomy and excessive mortality following pneumonectomy. Some of this was felt to be attributed to lack of surgical expertise both for pre-operative and intra-operative decisions.

      A recent evaluation of two prospective RTOG trials (0229 and 0839) which evaluated full-dose induction chemo-radiotherapy to 60 Gy followed by resection, reported increased peri-operative mortality (19%) with extended resections (pneumonectomy or bilobectomy). Results were complicated by the use of an EGFR antibody in the induction therapy, since 60% of grade 5 Adverse Events occurred in those who received both the EGFR antibody in addition to an extended resection.

      It is important to note that two large European prospective trials concentrated at experience surgical centers, reported excellent peri-operative outcomes with no increase in surgical mortality with use of pneumonectomy after induction chemo-radiotherapy.

      Stage IIIA NSCLC is a heterogeneous cohort of patients and treatment decisions need to be tailored to the individual patient and tumor. A pneumonectomy required for a large or central tumor with small volume nodal disease is distinct from tumors with bulky or infiltrative mediastinal nodes that require a pneumonectomy both in terms of short and long-term outcomes. Similarly outcomes vary by laterality, with mortality nearly twice as high for those on the right. While pneumonectomy needs to be used judiciously in this setting, eliminating it from all treatment decisions reduces the ability to achieve local control and long-term cure in a significant population.

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      MTE05.02 - Role of Pneumonectomy in N2 Disease

      07:30 - 08:00  |  Presenting Author(s): Paula Ugalde

      • Abstract

      Abstract

      The therapeutic management of stage IIIA-N2 non-small cell lung cancer (NSCLC), which represents a locally advanced disease with ipsilateral mediastinal lymph node involvement, remains controversial despite the results of several randomized controlled trials [1-2]. By definition, stage IIIA-N2 represents a very heterogeneous population ranging from incidental discovery of N2 disease during surgery, through single mediastinal nodal involvement to bulky N2 disease where individual lymph nodes are difficult to identify and resect. Thus, treatment algorithms are controversial and guidelines are ambiguous.

      Patients with proven or suspected clinical stage IIIA-N2 NSCLC, are staged with contrast chest computed tomography (CT), integrated positron emission tomography – computed tomography (PET-CT) and brain magnetic resonance imaging (MRI) or CT. Additionally, before any treatment, histological proof of nodal involvement should be obtained either by a minimally invasive (EBUS) or invasive technique (mediastinoscopy). This is justified by the relatively high rate of false positive nodes [3] and also for complete mediastinal staging which includes the number of positive stations and the type of nodal infiltration. Proper lung cancer staging allows precise oncological treatment.

      When N2 disease is detected during surgery, in an entirely staged patient, this is referred as incidental, unsuspected or “surprise” N2 [4]. Here, if complete oncological resection can be achieved through lobectomy or pneumonectomy, the surgeon should proceed with the procedure. Adjuvant chemotherapy prolongs survival and is currently recommended in this setting. Major controversy occurs when N2 disease is confirmed either by staging EBUS or mediastinoscopy. A properly staged mediastinum has biopsies of stations 4R, 7 and 4L. Due to the absence of internationally accepted definition, the term “potentially resectable N2” is usually applied when mediastinal involvement is limited and surgery can potentially offer R0 resection.

      According to guidelines, patients in this sub-group should be treated by definitive concurrent chemo-radiotherapy or neoadjuvant therapy followed by surgery or definitive radiotherapy. In the recently published Swiss Cancer League trial, no significant difference was found when comparing those two strategies [5]. Specific controversy exists regarding the role of surgery versus radiotherapy and the acceptable extent of resection post-induction therapy.

      The Intergroup trial [6], a randomized study published in 2009 and comparing neoadjuvant chemoradiotherapy plus surgery to chemoradiotherapy alone, issued caution regarding pneumonectomy in the context of multimodality therapy. This was largely due to inexplicable surgical results in this series, which demonstrated morbidity and mortality higher than published averages (26%). Yet pneumonectomy continues to be advocated in this setting by high volume centers that achieve superior surgical morbidity and mortality [7-10]. A systematic review of pneumonectomy followed by neoadjuvant therapy was published in 2012 [11]. The report included 27 studies from 1990–2010, and included 4 randomized controlled studies, including the Intergroup trial. Mortality at 30 days was 7% and at 90 days was 12%, suggesting traditional reporting of 30-day mortality may not be the ideal marker of perioperative mortality for pneumonectomy patients. The ideal treatment for patients with locally advanced NSCLC, who require pneumonectomy for resection, remains controversial.

      Reference:

      1. Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol 2015; 26:1573-88.

      2. Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA-N2 and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 2015; 33:4194-201.

      3. 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.

      4. Van Schil P. Stage IIIA-N2 non-small-cell lung cancer: from “surprise” involvement to surgical nightmare. Eur J Cardiothorac Surg 2016; 49:1613-4.

      5. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S et al. Induction chemo-radiotherapy in stage IIIA/N2 non-small cell lung cancer: a phase 3 randomised trial. Lancet 2015; 386(9998):1049-56.

      6. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86.

      7. Kim AW, Faber LP, Warren WH, et al. Pneumonectomy after chemoradiation therapy for non-small cell lung cancer: does "side" really matter? Ann Thorac Surg 2009;88:937-43; discussion 944.

      8. Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac Cardiovasc Surg 2010;139:1424-30.

      9. Krasna MJ, Gamliel Z, Burrows WM, et al. Pneumonectomy for lung cancer after preoperative concurrent chemotherapy and high-dose radiation. Ann Thorac Surg 2010;89:200-6; discussion 206.

      10. Cerfolio RJ, Bryant AS, Jones VL, et al. Pulmonary resection after concurrent chemotherapy and high dose (60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Eur J Cardiothorac Surg 2009;35:718-23; discussion 723.

      11. Kim AW, Boffa DJ, Wang Z, et al. An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non-small cell lung cancer. J Thorac Cardiovasc Surg 2012;143:55-63.

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    MTE06 - Symptom Management in Mesothelioma (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Mesothelioma
    • Moderators:
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      MTE06.01 - Role of Pleurectomy in Palliation of Symptoms

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

      • Abstract

      Abstract not provided

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      MTE06.02 - How to Register Toxicity and Guide Patients

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

      • Abstract

      Abstract

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

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

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

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

      References

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

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

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

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

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    MTE07 - Management of Pleural Recurrence (Ticketed Session)

    • Type: Meet the Expert Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Moderators:
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      MTE07.02 - From Surgical Perspective

      07:00 - 07:30  |  Presenting Author(s): Robert J Korst

      • Abstract

      Abstract

      The pleural space represents the most common location for recurrence following resection of thymic epithelial tumors (TET). The rationale to include surgical resection in the management plan for these patients is based on small case series and reports, many of which demonstrate long periods of survival following pleural metastasectomy. Two large, retrospective series of patients with pleural disease have been recently published, both of which reflect pooled data from multiple institutions; one from Europe and the other from Japan1,2. Despite this, little prospective data address this issue. In addition, the management strategy for pleural disease in patients with TET is extrapolated from the management of primary TET in the mediastinum, where surgical resection plays an important role.

      Prognostic factors after surgical resection for pleural disease mirror those that are most consistently reported for primary mediastinal TET. Most case series of patients undergoing resection for pleural disease (either recurrence or initial presentation) suggest that the ability to completely resect the disease is an important prognostic factor. Indeed, both of the aforementioned larger series confirm that complete resection is associated with enhanced survival1,2. The Japanese report of 136 cases of pleural dissemination of thymoma at initial presentation (not recurrence) also determined that lower disease burden in the pleural space positively affects survival2. Although the large European Society of Thoracic Surgery (ESTS) Thymic Working Group Project (152 patients with either pleural recurrence and pleural disease at initial presentation) did not report disease burden, it confirmed the importance of complete resection in maximizing survival1. This later study also determined that thymic carcinoma patients experienced significantly shorter survival after resection of pleural disease than patients with thymoma. Thymic carcinoma, pleural disease burden and the ability to perform a complete resection can all be considered surrogates for individual tumor biology, which may be the most important underlying prognostic factor.

      Surgical approaches for patients with TET that has spread to the pleural space include metastasectomy and extrapleural pneumonectomy (EPP). The surgeon’s goal is the complete gross resection of disease, which is dependent on the burden and location of disease. In cases of pleural recurrence, the surgical approach is typically through a lateral thoracotomy since this incision provides the best exposure of the entire pleural space and the mediastinal tumor has already been resected at an earlier time. More recently, video assisted thoracic surgery (VATS) approaches have been used selectively to approach these patients depending on the expertise of the operator. The surgeon wishes to perform the least amount of resection possible while still rendering the patient grossly disease free. Metastasectomy may range from the resection of a single pleural lesion to an extensive parietal pleurectomy with or without pulmonary resection(s) for visceral pleural involvement of metastatic deposits. On occasion, the surgeon may explore the chest of a patient with the intent of performing metastasectomy, but instead encounters diffuse innumerable visceral and parietal pleural metastatic deposits. In this case, EPP may be the only option to render the patient grossly disease free. The surgeon should always be prepared for this development whenever operating on a patient for metastatic TET, so that an educated decision can be made to proceed with EPP at the time of exploration, if necessary. EPP, however, may not be a good option for patients with thymic carcinoma that has metastasized to the pleural space given the magnitude of this approach combined with the significantly worse survival after resection in patients with metastatic pleural disease, when compared to thymoma.

      Pleural treatments used as an adjunct at the time of surgical resection for patients with pleural metastases from TET are becoming more popular. Heated intrapleural chemotherapy (HIPC) represents the most commonly used modality in this regard. After resecting all gross disease, the surgeon perfuses the hemithorax with heated chemotherapy for a period of time ranging from one to two hours. This strategy has been demonstrated to be safe with an acceptable complication rate in several small case series of patients with TET3. Although survival rates appear to be encouraging, definitive data demonstrating a survival benefit to HIPC are lacking. Intrathoracic photodynamic therapy (PDT) has also recently been reported for patients with TET that has metastasized to the pleural space4.

      Although the use of neoadjuvant chemotherapy has been reported in several case series of patients with pleural metastases at the time of initial presentation5, data are lacking specifically in the scenario of pleural recurrence. The rationale for this approach mimics that for locally advanced TET in the mediastinum – to reduce the disease burden in hopes of increasing the likelihood of complete resection. Once again, this strategy appears to be safe and associated with encouraging rates of complete resection and survival, but definitive data confirming a benefit are lacking.

      In summary, the surgical resection of pleural recurrence of TET is associated with prolonged survival in selected patients, as reported in many case series. However, given the lack of controlled studies, it is unclear if prolonged survival is a direct result of the surgical approach or simply selection of patients with more forgiving tumor biology. Despite this, a rational approach may be to invoke a surgical approach as the initial strategy in patients with thymoma whose disease appears to be resectable. Once surgical options have been exhausted, or the disease is clearly unresectable, systemic therapy and/or radiotherapy can be utilized to achieve further disease control.

      References:

      1. Moser B, et al. Surgical therapy of thymic tumours with pleural involvement: an ESTS Thymic Working Group project. Eur J Cardiothorac Surg 2017;52:346-55.

      2. Okuda K, et al. Thymoma patients with pleural dissemination: Nationwide retrospective study of 136 cases in Japan. Ann Thorac Surg 2014;97;1743-9.

      3. Maury J-M, et al. Intra-thoracic chemo-hyperthermia for pleural recurrence of thymomas. J Thorac Dis 2017;9:E1137-9.

      4. Chen K-C, et al. Pleural photodynamic therapy and surgery in lung cancer and thymoma patients with pleural spread. PLOS one 2015;10:e0133230.

      5. Shapiro M, et al. Surgical Approaches for stage IVa thymic epithelial tumors. Front Oncol 2014;3:332.

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      MTE07.01 - From Radiation Oncology Perspective

      07:30 - 08:00  |  Presenting Author(s): Andreas Rimner

      • Abstract

      Abstract

      Radiation therapy (RT) plays an important role in the multimodality management of thymic malignancies and is an effective local treatment modality with the goal of reducing the risk of local recurrence. It can be employed in the neoadjuvant, adjuvant, definitive or palliative setting. It is important to evaluate the role of RT for pleural recurrence in the context of surgery and systemic treatment options as part of a multimodality approach and carefully coordinate the three modalities for optimal outcomes. Studies on the specific role of RT in pleural recurrences are sparse. However, there are several recent large database and population-based studies that indicate which patient subsets may benefit the most from RT.

      The indication and clinical setting for RT (perioperative versus definitive RT) depends on surgical resectability and operability of the patient. The adjuvant setting is the most extensively studied setting for RT in thymic malignancies. The greatest benefit of adjuvant RT appears to be in patients with newly diagnosed locally advanced stage III and IV thymomas, including patients with pleural dissemination.1-4 For thymic carcinomas the impact of adjuvant RT appears more significant.5-7 For incompletely resected thymic tumors there is a stronger rationale for adjuvant RT based on emerging data and general oncologic principles. The principles of adjuvant RT may be applied to surgically resected pleural recurrences as well.

      A range of modern radiation therapy techniques is available to aid the radiation oncologist in optimally targeting the tumor bed, while maximally reducing the radiation dose to surrounding organs at risk.8,9 The radiation technique should be uniquely tailored to the needs of each individual patient’s presentation. Techniques include 3D conformal radiation therapy, intensity-modulated radiation therapy, proton therapy and intraoperative radiation therapy using high dose rate brachytherapy or low dose rate seed implantation. The extent of the radiation treatment field will depend on the intraoperative findings, pathologic results, proximity to and dosimetric assessment of critical organs at risk. This may vary from treatment of a small tumor bed of a single pleural metastasis to hemithoracic pleural RT following an extrapleural pneumonectomy or lung-sparing pleurectomy/decortication in select cases.

      For inoperable or unresectable patients definitive RT is an excellent treatment option. A subset of patients is technically or medically inoperable, due to invasion of critical structures such as the heart, great vessels, spine, esophagus etc. or comorbidities. In general, thymic malignancies are radiosensitive, allowing for long-term local control rates, even when treated with definitive RT in the absence of surgery. Stereotactic ablative RT may be used for oligometastatic disease as an alternative to surgical resection and has been shown to be a highly effective treatment modality with >90% long-term local control rates and minimal morbidity in multiple histologies of intrathoracic metastases, including thymic tumors.10

      Lastly, palliative RT should be considered whenever surgical management or definitive radiation treatment options are not feasible. Conventional palliative RT is an important modality to improve quality of life by alleviating pain, treating SVC syndrome, airway compression and other symptoms.

      1. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: A surveillance, epidemiology, and end results database analysis. Journal of Thoracic Oncology. 2010;5(9):1454-1460.

      2. Rimner A, Gomez DR, Wu AJ, et al. Failure patterns relative to radiation treatment fields for stage II-IV thymoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014;9(3):403-409.

      3. Rimner A, Yao X, Huang J, et al. Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2016;11(10):1785-1792.

      4. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. American journal of clinical oncology. 2016;39(2):120-125.

      5. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg. 2015;149(1):95-100, 101.e101-102.

      6. Omasa M, Date H, Sozu T, et al. Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study. Cancer. 2015;121(7):1008-1016.

      7. Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014;9(4):541-548.

      8. Gomez D, Komaki R. Technical advances of radiation therapy for thymic malignancies. Journal of Thoracic Oncology. 2010;5(10 SUPPL. 4):S336-S343.

      9. Gomez D, Komaki R, Yu J, Ikushima H, Bezjak A. Radiation therapy definitions and reporting guidelines for thymic malignancies. Journal of Thoracic Oncology. 2011;6(7 SUPPL. 3):S1743-S1748.

      10. Baschnagel AM, Mangona VS, Robertson JM, Welsh RJ, Kestin LL, Grills IS. Lung metastases treated with image-guided stereotactic body radiation therapy. Clinical oncology (Royal College of Radiologists (Great Britain)). 2013;25(4):236-241.