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Mar 17, 2010 Download PDF. Cancer's Next Frontier: Addressing High and Increasing Costs. Create a free personal account to download. Purpose of review This review summarizes current immunotherapies in breast cancer, with an emphasis on immune checkpoint inhibitors and vaccines. Recent findings Combination immunotherapy with checkpoint inhibitors and cytotoxic therapies have shown promising results. Active clinical trials are ongoing in both early stage and metastatic settings for triple negative, HER2+, and hormone-positive. Download the Medical Book: Am-medicine Website Provides Free Medical Books PDF For all, In many different Subjects: Dentistry, Anatomy. Modifications to prevent cancer from developing Improvement in staging – detecting many fewer cells or identifying blood tests that tell about the presence of cancer Determining a specific “finger print” of an individual's cancer Selecting a specific treatment, based upon the likelihood of the cancer to respond to that treatment AND.

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Accepted Manuscript Cost-effectiveness of Mediastinal Lymph Node Staging in Non-Small Cell Lung Cancer Kasia Czarnecka-Kujawa, MD FRCPC MPH, Ursula Rochau, MD MSc, Uwe Siebert, MD MPH MSc ScD, Eshetu Atenafu, MSc PStat, Gail Darling, MD FRCSC FACS, Thomas K. Waddell, MD MSc PhD FRCSC FACS, Marc De Perrot, MD MSc, Andrew Pierre, MD MSc, Marcelo Cypel, MD MSc, Shaf Keshavjee, MD MSc FRCSC FACS, Kazuhiro Yasufuku, MD PhD PII:
S0022-5223(17)30176-9
DOI:
10.1016/j.jtcvs.2016.12.048
Reference:
YMTC 11213
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 20 June 2016 Revised Date:
7 December 2016
Accepted Date: 17 December 2016
Please cite this article as: Czarnecka-Kujawa K, Rochau U, Siebert U, Atenafu E, Darling G, Waddell TK, De Perrot M, Pierre A, Cypel M, Keshavjee S, Yasufuku K, Cost-effectiveness of Mediastinal Lymph Node Staging in Non-Small Cell Lung Cancer, The Journal of Thoracic and Cardiovascular Surgery (2017), doi: 10.1016/j.jtcvs.2016.12.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page
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Title: Cost-effectiveness of Mediastinal Lymph Node Staging in Non-Small Cell Lung Cancer.
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The authors:
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Corresponding author: Kasia Czarnecka-Kujawa MD FRCPC MPH
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Assistant Professor, University of Toronto
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Division of Respirology
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Division of Thoracic Surgery
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Toronto General Hospital
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585 University Ave. 9N 941
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University Health Network, Toronto, ON, Canada
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Phone: 416-340-4800 Ext. 4657
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Email: [email protected]
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Ursula Rochau MD MSc
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Institute of Public Health, Medical Decision Making and Health Technology Assessment
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Department of Public Health, Health Services Research and Health Technology Assessment
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UMIT- University of Health Sciences, Medical Informatics and Technology
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Eduard Wallnoefer Center I, A-6060 Hall i.T., Austria
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Uwe Siebert MD MPH MSc ScD
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Institute of Public Health, Medical Decision Making and Health Technology Assessment, UMIT
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University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria;
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ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria;
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Department of Health Policy and Management, Harvard T.H. Chan School of Public Health and
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MGH-ITA, Department of Radiology, Massachusetts General Hospital, Harvard Medical School,
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Boston, MA, USA;
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Center for Health Decision Science, Boston, MA, USA.
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Eshetu Atenafu MSc PStat
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Senior Biostatistician, Biostatistics Dept. Princess Margaret Cancer Center
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University Health Network, Toronto, ON. Canada
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Gail Darling MD FRCSC FACS
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Professor Thoracic Surgery, University of Toronto
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, Toronto. ON., Canada
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Thomas K. Waddell MD MSc PhD FRCSC FACS
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Professor Thoracic Surgery, University of Toronto
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Division Head, Division of Thoracic Surgery (DOTS), University Health Network
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Toronto General Hospital, Toronto ON., Canada
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Marc De Perrot MD MSc
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Associate Professor Thoracic Surgery, University of Toronto
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, Toronto ON., Canada
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Andrew Pierre MD MSc
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Associate Professor Thoracic Surgery, University of Toronto
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, Toronto ON., Canada
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Marcelo Cypel MD MSc
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Associate Professor Thoracic Surgery, University of Toronto
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, Toronto ON., Canada
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Shaf Keshavjee MD MSc FRCSC FACS
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Professor Thoracic Surgery, University of Toronto
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Surgeon-In Chief, Sprott Department of Surgery
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, ON., Canada
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Kazuhiro Yasufuku MD PhD
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Associate Professor Thoracic Surgery, University of Toronto
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Division of Thoracic Surgery
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Toronto General Hospital, University Health Network, Toronto ON., Canada
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Manuscript work count (excluding the abstract, tables, figures): 3492
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Conflict of Interest:
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Dr. Czarnecka-Kujawa is a research consultant with Olympus America
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Dr. Yasufuku is a research consultant and received research support educational grants from Olympus America
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No funding was provided to conduct this research.
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Glossary of abbreviations:
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CAD- Canadian Dollar
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CRMM- Cancer Risk Management Model
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EBUS-TBNA- Endobronchial Ultrasound Transbronchial Needle Aspiration
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EUS-FNA- Esophageal Ultrasound Fine Needle Aspiration 3
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ICER- Incremental Cost Effectiveness Ratio
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LN- lymph node
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Med- Cervical Mediastinoscopy
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MLNM- Mediastinal Lymph Node Metastasis
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MLNS- Mediastinal Lymph Node Staging
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NSCLC- Non Small Cell Lung Cancer
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OR- staging strategy involving only non-invasive mediastinal lymph node staging, followed by surgical resection
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QALY- Quality Adjusted Life Years
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QOL- Quality of Life
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VATS- Video Assisted Thoracoscopic Surgery
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Acknowledgement
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We would like to acknowledge contribution of the COMET Center ONCOTYROL to our work. COMET Center ONCOTYROL is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT).
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Abstract
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Objective: To assess the cost-effectiveness of various modes of mediastinal staging in non-small
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cell lung cancer (NSCLC) in a single payer health care system.
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Methods: We performed a decision analysis to compare the health outcomes and costs of four
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mediastinal staging strategies: 1) no invasive staging; 2) Endobronchial Ultrasound-guided
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Transbronchial Needle Aspiration (EBUS-TBNA); 3) Mediastinoscopy; 4) EBUS-TBNA
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followed by mediastinoscopy if EBUS-TBNA is negative. We determined Incremental Cost
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Effectiveness Ratios (ICER) for all strategies and performed comprehensive deterministic
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sensitivity analyses using a willingness to pay threshold of $80,000/quality adjusted life year
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(QALY).
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Results: Under the base-case scenario, the no invasive mediastinal staging strategy was least
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effective (QALY 5.80) and least expensive ($11,863), followed by mediastinoscopy, EBUS-
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TBNA, and EBUS-TBNA followed by mediastinoscopy with 5.86, 5.87, and 5.88 QALYs,
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respectively. The ICER was ~$26,000/QALY for EBUS-TBNA staging and ~$1,400,000/QALY
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for EBUS-TBNA followed by mediastinoscopy. The mediastinoscopy strategy was dominated.
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Once pN2 exceeds 2.5%, EBUS-TBNA staging is cost-effective (~$80,000/QALY). Once the
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pN2 reaches 57%, EBUS-TBNA followed by mediastinoscopy is cost-effective (ICER
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~$79,000/QALY). Once EBUS-TBNA sensitivity exceeds 25%, EBUS-TBNA staging is cost-
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effective (ICER ~$79,000/QALY). Once pN2 exceeds 25%, confirmatory mediastinoscopy
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should be added, if EBUS-TBNA sensitivity ≤ 60%.
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Conclusion: Invasive mediastinal staging in NSCLC is unlikely to be cost-effective in clinical
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N0 patients if pN2 < 2.5%. In patients with probability of mediastinal metastasis between 2.5%
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and 57% EBUS-TBNA is cost-effective as the only staging modality. Confirmatory
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mediastinoscopy should be considered in high risk patients (pN2 > 57%) in case of negative
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EBUS-TBNA.
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Introduction
Mediastinal lymph node (LN) assessment is a crucial step in lung cancer staging as it
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determines prognosis and guides management. Invasive mediastinal LN staging (MLNS) is
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recommended for patients with clinical stage II disease, but not for patients with clinical stage I
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disease1. This recommendation follows a widespread incorporation of PET scan into the routine
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assessment of patients with Non-Small Cell Lung Cancer (NSCLC).1 Given emerging evidence on improved outcomes in patients with micrometastatic N2
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disease managed with trimodality approach over definitive chemoradiation2,3, invasive
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mediastinal LN staging in patients with clinical stage I disease could be of benefit.
Introduction of needle-based techniques - Endobronchial Ultrasound Transbronchial
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Needle Aspiration (EBUS-TBNA), and Esophageal Ultrasound Fine Needle Aspiration,
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revolutionized approach to MLNS in lung cancer, with the needle techniques being now
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recommended as test of first choice for invasive staging.1
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Our study aim was to examine cost-effectiveness of various approaches to mediastinal LN assessment in patients with clinical N0 disease and T1 peripheral tumors using the Canadian,
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health care system perspective. Our secondary aim was to develop a decision-analytic model to
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predict the optimal staging approach using the cost-effectiveness data and performance
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characteristics of the various assessment algorithms.
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METHODS
Decision-analytic framework We developed a decision tree model synthesizing evidence on clinical and economic
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events with their probabilities to simulate a cohort of hypothetical patients with biopsy-proven or
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suspected NSCLC with clinical N0 disease.4 6
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We compared health outcomes and cost of four mediastinal staging strategies: 1) no invasive staging (OR); 2) EBUS-TBNA; 3) Med; 4) EBUS-TBNA followed by Med if EBUS-
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TBNA is negative (EBUS-TBNA-Med). The analysis accounted for costs incurred as a result of
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procedures and treatments performed based on results of the non-invasive and invasive staging.
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Given the potential benefit of trimodality therapy in patients with micrometastatic mediastinal
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disease, we included this approach in our model. Patients with missed nodal metastasis were
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managed surgically followed by adjuvant chemotherapy.
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Evaluated outcomes include quality-adjusted life years (QALY) over a lifetime horizon, costs and incremental cost effectiveness ratios (ICER) in Canadian dollars (CAD) per QALY
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gained. A third party payer perspective was adopted. Since the analysis focused on outcomes
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resulting from a diagnostic approach of a short duration and life expectancies of patients with
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NSCLC are relatively short, no discounting was applied.
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We followed international modeling guidelines for model development5,6 and validation7
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and international consolidated health economic evaluation reporting standards.8
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Modeling assumptions
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Our model is based on the following assumptions:
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1) All patients were good surgical candidates and would tolerate a lobectomy.
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2) Patients with N2 disease on pre-operative staging received trimodality therapy (neoadjuvant chemotherapy and radiation, followed by surgical resection).
3) All nodal metastases were microscopic. 4) Invasive staging techniques were 100% specific.
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5) All surgical resections were performed using the Video Assisted Thoracoscopic Surgery. Only lobectomy or bilobectomy were included.
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6) All resections were R0.
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7) No consolidation chemotherapy was not performed.
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Model Parameters
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Clinical parameters
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Prevalence of pathological nodal metastasis was derived from published literature. 9 For
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the base-case analysis, we assumed a prevalence of mediastinal metastasis of 9%. Prevalence of
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pN2 disease following EBUS-TBNA was obtained from our institutional data10 (Table 1).
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Health outcomes
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Health status-specific life expectancies conditional on surviving index procedures were based on previously published literature (Table 2).
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Health related quality of life (QOL) was based on quality-of-life indices (utilities). We used life
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expectancies and utilities to calculate QALY.11
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To assign utility values for various stage-specific lung cancer health states specific to a Canadian
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population at diagnosis and during the treatment, a standardized tool was created by Statistics
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Canada-the Classification and Measurement System of Functional Health (CLAMES). 12,13
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Health Care Costs
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We included initial and downstream cost based on the costing index year 2015. All cost
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data were adjusted for inflation to CAD for the price level of May of 2015 using the Consumer
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Price Index from the Bank of Canada.14
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Staging and procedure costs were based on recorded hospital costs of patients managed in our
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lung cancer program at the Toronto General Hospital (TGH) between 01/01/2005 and
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12/31/2014. In this database, a total of 4983 surgical costed cases were identified of which 572
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were Thoracic Surgery cases. We excluded the non-lung cancer cases, and cases performed with
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other than curative intent. The final case count was 499. The search of the endoscopy database
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identified 1044 Thoracic Surgery costed cases. We excluded cases performed for other than lung
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cancer staging or diagnosis purposes, bringing the final count to 750 cases.
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Mediastinoscopy at the TGH is performed as a day procedure, under general anesthesia.
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EBUS-TBNA mediastinal staging at our hospital is a day procedure performed in an endoscopy
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suite under conscious sedation. Given that some programs perform EBUS-TBNA in the
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operating room (OR), we evaluated that strategy in the same model as the other four strategies,
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and after having removed the option of performing EBUS-TBNA in the endoscopy suite.
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We reviewed per-visit fixed and variable costs pertaining to Med and EBUS-TBNA MLNS and VATS lobectomy. We extracted the mean costs for each procedure (Table 3). There
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were no complications associated with EBUS-TBNA. The costs of managing surgical
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complications are included in the average procedure cost. Med average cost was calculated using
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only cost data from procedures where Med was the only procedure performed.
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Costs of medical therapy and related complications including death were extracted from the
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Cancer Risk Management Model (CRMM), a web-enabled platform that allows researchers to
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simulate the impact of different oncologic health policies, such as treatment modalities for
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common malignancies.15 Details regarding the development of the CRMM have been provided
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elsewhere.11 The model was previously validated internally using statistics Canada data and
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externally with Canadian Cancer Registry.16
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For the neoadjuvant therapy regimen we chose the SWOG regimen17 currently utilized at the
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Princess Margaret Cancer Center, the largest Canadian oncology center.18 For the adjuvant
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chemotherapy, 4 cycles of cisplatinum and vinorelbine were administered 6 to 8 weeks following
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surgery (Table 3).19
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Other Model Parameters
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Sensitivity of the EBUS-TBNA and Med for detection of MLNM was based on a recent large systematic review.1 Sensitivity of Med following EBUS-TBNA for detection of MLNM
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was obtained from our institutional data10 (Table 4). Procedure or treatment-related mortalities
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were derived from the CRMM (for the chemotherapy and radiation) and from published
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literature (Med, VATS resections) (Table 5).
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Statistical Analysis
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We performed a decision-analytic deterministic cohort simulation. All analyses were
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performed using the decision-analytic software TreeAge Pro 2015 (TreeAge Software Inc.,
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Williamstown, MA).
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Base-Case Analysis
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To determine comparative clinical effectiveness, we estimated QALYs for each treatment
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strategy. For the cost-effectiveness, we compared clinical outcomes (QALYs) to costs and
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calculated incremental cost-effectiveness ratios (ICER) comparing the different strategies. 20
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Sensitivity Analysis
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We performed deterministic one-way and two-way sensitivity analyses on influential
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model parameters. We performed a one-way sensitivity analysis on prevalence of mediastinal
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nodal metastasis varying the prevalence between 0% and 100% to determine the optimal staging
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strategy for different regions of prevalence and a one-way sensitivity analysis on the sensitivity
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of EBUS-TBNA varying the sensitivity between 10% and 89%, based on published evidence.1
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We performed a two-way sensitivity analysis varying simultaneously the prevalence of MLNM
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and sensitivity of EBUS-TBNA. In our sensitivity analyses comparing results to thresholds of
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ICERs, we used CAD $80,000 per QALY gained as willingness-to-pay threshold (WTP).This
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value has been endorsed as oncological ceiling threshold by the Canadian Expert Drug Advisory
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Committee and the Cancer Care Ontario Policy Advisory Committee.21,22
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The study was approved by the UHN Research Ethics Board.
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RESULTS
Base-case analysis
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In the comparative effectiveness analysis, the remaining quality-adjusted life expectancies ranged from 5.80 QALYs to 5.88 QALYs. Under the base-case scenario the
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invasive staging using EBUS-TBNA followed by Med offered the highest QALYs of 5.88,
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followed by EBUS-TBNA staging (5.87 QALYs), Med (5.86 QALYs) and no invasive staging
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with 5.80 QALYs (Table 6).
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In the cost comparison, the least expensive strategy was the OR with the cost of $11,863, followed by EBUS-TBNA $13,727, Med $18,143, EBUS-TBNA with confirmatory Med
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$19,587, EBUS-TBNA in the OR $20,551 and EBUS-TBNA in the OR with confirmatory Med
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$26,440 (Table 6).
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The cost-effectiveness plane in Figure 1 shows the results of considering both costs and health
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outcomes associated with each strategy. The strategy in the lower left corner is less expensive
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and less effective than the strategy in the right upper corner. After eliminating the dominated
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strategies (A strategy is considered to be dominated if it is more costly and less effective than
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other non-dominated strategy) (Med, EBUS-TBNA- in the OR and EBUS-TBNA in the OR-
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Med) three strategies remained defining the cost-effectiveness frontier: OR, EBUS-TBNA, and
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EBUS-TBNA-Med. The ICER of EBUS-TBNA compared to OR was ~26,000/QALY and the
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ICER of adding Med to EBUS-TBNA was ~1,400,000/QALY (Table 6).
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Sensitivity analysis
The OR is a cost-effective strategy up to a MLNM prevalence of 2.5%. Between MLNM
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prevalence of 2.5% and 57%, EBUS-TBNA is the preferred and cost-effective strategy. Once the
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MLNM prevalence exceeds 57%, EBUS-TBNA-Med is the preferred, cost-effective strategy
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The one-way sensitivity analysis on EBUS-TBNA sensitivity shows that Med is not dominated by EBUS-TBNA, if the sensitivity of EBUS-TBNA is below 79%. However it has a
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high ICERs falling below $100,000 /QALY only if EBUS-TBNA sensitivity is below 19% and
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falling below $80,000 /QALY if EBUS-TBNA sensitivity is below 3%. EBUS-TBNA is the
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preferred strategy and becomes cost-effective if its sensitivity is above 25%
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The two-way sensitivity analysis evaluated the effect of sensitivity of EBUS-TBNA and
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prevalence of MLNM. It shows the preferred staging strategy for each combination of MLNM
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prevalence and EBUS-TBNA sensitivity. For example, with a MLNM prevalence below 11%
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and EBUS-TBNA sensitivity below 20%, OR is the preferred strategy. Once the MLNM
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prevalence exceeds 11%, Med becomes the preferred strategy and can be considered cost-
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effective, if the sensitivity of EBUS-TBNA is below 20%. The minimum prevalence of MLNM
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at which confirmatory Med should be added after a negative EBUS-TBNA is around 25% (if
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sensitivity of EBUS-TBNA is around 60%) (Figure 2).
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Analysis with thoracotomy as the preferred surgical approach did not alter conclusions of
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the analysis. Analysis with EBUS-TBNA performed in the OR (The option of performing the
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EBUS-TBNA in the endoscopy was removed from the analysis) altered the analysis
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significantly. Under the base-case scenario, no invasive staging was cost-effective and OR was
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the preferred strategy. All approaches, Med, EBUS-TBNA and EBUS-TBNA followed by Med
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had ICERs above the WTP threshold of $80,000 (Table 7). In the two way sensitivity analysis,
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evaluating the effect of varying EBUS-TBNA sensitivity and MLNM prevalence, the preferred
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strategy was the surgical resection without invasive staging, regardless of EBUS-TBNA
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sensitivity until MLNM prevalence of ~11%. Once the MLNM prevalence exceeded 11%, Med
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was the preferred staging strategy. EBUS-TBNA with confirmatory Med strategy became cost-
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effective once the prevalence of MLNM became high (~70%) and EBUS-TBNA sensitivity was
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at least 89%. EBUS-TBNA without confirmatory Med was not cost-effective.
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DISCUSSION
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We developed a decision-analytic model to investigate the optimal MLNS pathway for
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patients with NSCLC incorporating the most recent, high quality evidence on performance
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characteristics of the currently recommended invasive staging strategies, local cost data from a
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large Canadian tertiary cancer center and factoring in emerging evidence on the outcomes in
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patients with micrometastatic mediastinal disease.
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In terms of comparative effectiveness, EBUS-TBNA followed by Med is the strategy that results in the highest QALYs. However, it is also the most expensive staging approach. Despite
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a small survival advantage that the combined procedures provide in the analysis, it results in a
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prohibitive ICER of >$1.4 million/QALY.22 Therefore, under our base-case scenario, it may not
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be justifiable to pursue Med after negative EBUS-TBNA. Staging with EBUS-TBNA alone in
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patients with clinical N0 disease and if prevalence of MLNM is 9% can be considered cost-
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effective.
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Our one-way sensitivity analysis provided a more detailed guide to thresholds for
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implementation of different staging strategies depending on the prevalence of MLNM and
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sensitivity of EBUS-TBNA, suggesting that invasive MLNS with EBUS-TBNA is not cost-
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effective if the prevalence of MLNM is 2.5%, but still justifying invasive MLNS in a very low
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risk population (MLNM above 2.5%).
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This finding is in conflict with current guidelines, which do not advocate invasive MLNS in at
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least a proportion of patients included in our study (the clinical stage I disease). 1,23 The
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guidelines have been created without factoring in the WTP thresholds and economic data, which
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may influence the staging recommendation. The aim of our study was to offer clinicians a
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practical guide to the optimal staging strategy taking under consideration the patient and
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individual program’s characteristics. Decision about pursuing invasive MLNS in patients with
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cN0 disease and a low pre-test probability of MLNM (2.5%-10%) should be made on a case by
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case basis. 24
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We explored the impact institutional variability in EBUS-TBNA sensitivity may have on recommendations for the optimal staging strategy. Our sensitivity analysis suggests that in
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programs that cannot ensure EBUS-TBNA sensitivity of at least 20%, Med should be the test of
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first choice for invasive MLNS. This threshold is similar to that reported in prior studies.25 Even
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though such a low sensitivity has not been reported in the EBUS-TBNA staging studies, 1 these
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studies often come from a high volume, tertiary centers, where EBUS-TBNA is performed by
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experts. Our study suggests that ongoing performance quality monitoring is important to ensure
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the optimal invasive staging.
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Another important aspect of MLNS is whether Med should follow negative EBUS-
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TBNA. Studies show that EBUS-TBNA performance characteristics are similar to Med in
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MLNS in NSCLC. 10,26 Guidelines advise confirmatory Med in cases of negative EBUS-TBNA
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in patients with high pretest probability of MLNM.1 In our sensitivity analysis we addressed the
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question: At what MLNM prevalence and EBUS-TBNA sensitivity should the confirmatory
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Med be performed in cases of negative EBUS-TBNA? Our two-way sensitivity analysis
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demonstrated that once the prevalence of MLNM reaches approximately 25% and the EBUS-
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TBNA sensitivity is around 60%, negative EBUS-TBNA should be followed by Med. In cases of
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lower sensitivity of EBUS-TBNA (and MLNM prevalence at least 25%), Med is the test of
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choice. With even higher prevalence of MLNM, the window for EBUS-TBNA-Med opens. For
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example, in patients with a 50% prevalence of MLNM, EBUS-TBNA-Med is the preferred
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strategy if the sensitivity of EBUS-TBNA is between 44% and 88%.Previous studies have shown
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that extensive pre-operative invasive MLNS results in detection of more cases of mediastinal
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metastasis.10,27
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It must be emphasized that the true value of confirmatory Med can only be determined by the
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prevalence of MLNM in the population, the test sensitivities and the WTP threshold of the
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country under study.
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Meyers, looked at mediastinal LN staging in patients with clinical stage I NSCLC
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concluding that invasive MLNS is not economically justifiable.9 However, the study focused on
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Med as the staging strategy and was performed before the EBUS-TBNA era. Four years
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following Meyers study, Steinfort et al. demonstrated that performing EBUS-TBNA with
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confirmatory Med if the EBUS-TBNA was negative, was the least costly staging option in a high
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risk patient population.25
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Our study takes the economic analysis further, providing a novel look at the cost-
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effectiveness of the modalities currently recommended in invasive MLNS. We focused the base-
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case analysis on a population of patients where there may be some controversy as to whether
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invasive MLNS should be pursued or not, given the overall low prevalence of MLNM in this
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population.1,9
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Our model points out that there is a well-defined role for the use different modalities including Med. This stresses the need for ongoing focus on maintenance of competency and skill
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acquisition in Med and EBUS-TBNA by currently practicing and future Thoracic Surgeons,
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respectively.
In some programs EBUS-TBNA is performed in the OR under general anesthesia (GA).
SC
383
RI PT
380
Our cost effectiveness analysis shows that it is more cost-effective to perform Med in patients
385
who need invasive MLNS, than to stage patients with EBUS-TBNA performed in the OR under
386
GA. Higher than Med cost of EBUS-TBNA performed in the OR is consistent with prior
387
literature.28 However, EBUS-TBNA performed under conscious sedation is effective, safe and
388
associated with high patient satisfaction.29-31 We hope the results of our study provide
389
encouragement to clinicians performing EBUS-TBNA under GA in the OR, to change their
390
practice.
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The question of optimal management of patients with N2 disease is controversial with no firm guidelines advocating single management stretegy.1 However, evidence is accumulating
393
suggesting that a select patient population with N2 disease may benefit from neoadjuvant therapy
394
followed by surgery over definitive chemotherapy and radiation.2,3,32,33 Our study incorporated
395
the impact of trimodality therapy for patients with N2 disease. We assumed that trimodality
396
therapy offers a survival advantage over the definitive chemoradiation. Since the outcome data in
397
the studies incorporating trimodality therapy into the treatment algorithm of patients with N2
398
disease comes from a population with clinical N2 disease, we believe that our model, if anything,
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underestimates the survival in the population of patients under our study as there is no published
400
data on outcomes of trimodality therapy in this patient population.
401
As all decision-analyses, our study has several limitations.34 Cost-effectiveness analysis is not a complete procedure for determining all decisions in health care because it cannot
403
incorporate all the values, criteria and individual patient characteristics relevant to such
404
decisions. Rather, it should be used as an aid in the complex decision-making process.35
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402
Our model does not account for the QALYs and costs of management of recurrent
406
disease and the end of life care. This simplification may underestimate costs of diagnostic
407
approaches. However, this is unlikely to substantially affect the differences between the
408
strategies, as these costs are similar across strategies following the initial treatment.
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In our base-case analysis, we used point estimates for procedure sensitivities. As these values may be surrounded by uncertainty and affected by specific settings and heterogeneity, we
411
varied these parameters in sensitivity analyses confirming the robustness of our results.
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It must be emphasized that our results may not be generalizable to all clinical scenarios. In some institutions separate TBNA needles may be used for each LN and Rapid On Site
414
Evaluation may be used. Each of these situations is expected to increase the per-procedure cost.28
415
In contrast, lower costs might be expected if mediastinal staging is performed as a part of a two-
416
staged procedure with EBUS-TBNA and/or Med followed by a surgery if the MLNS is negative.
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We used overall life expectancies for the QALY calculation. However, life expectancies
418
may differ substantially across patients and may be affected by age, comorbidity and other
419
factors. Therefore, any individual clinical decision should carefully consider all individual
420
patient characteristics and preferences before the staging decision is made.
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421
The analysis using thoracotomy as the preferred surgical procedure instead of VATS did not alter our study conclusions. However, we did not have separate utilities for patients managed
423
with thoracotomy. Thoracotomy may be associated with a slightly lower QALY. However, given
424
lower than EBUS-TBNA cost of OR pathway with thoracotomy, this would not alter our
425
conclusions.
426
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422
Procedure costs, have been based on approximately 10% of all surgical cases costed at our institution. We realize that this represents a limitation to our study, as not all procedure costs
428
have been captured. However, the reason for that is administrative and not related to the case
429
itself, therefore it is unlikely that cases captured and not captured were different in terms of per
430
procedure cost. In addition, we compared the average cost of the VATS resection from our
431
database $11,215 (95%CI 9,279, 13,150) with that reported in the CRMM which was ~$12,000.
432
We, therefore, believe that our costed cases capture accurately Canadian procedure costs.
M AN U
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427
We have not accounted for physician fees as they differ across Canada and would not be
434
applicable to other countries. Finally, we have not accounted for indirect costs related to patient
435
and caregiver loss of productivity resulting from the disease and during the diagnostic and
436
management period. Although we believe that it is unlikely that adding these cost would make a
437
major difference for our analysis outcome, taking a full societal perspective and including
438
productivity losses could be a subject of further research.
440 441
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Conclusion and future directions Based on our decision analysis, in patients with clinical N0 disease and estimated low
442
prevalence of MLNM, invasive staging with EBUS-TBNA is cost-effective. The benefit
443
conveyed by detection of mediastinal metastatic disease becomes more apparent as the
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prevalence of MLNM increases, with confirmatory Med becoming cost-effective in cases of
445
negative EBUS-TBNA in patients with moderate to high probability of MLNM. Performing
446
EBUS-TBNA in the OR is not cost-effective and from health economics perspective, if there is
447
no ability to perform EBUS-TBNA in the endoscopy, the more cost-effective strategy is to offer
448
Med to patients who need invasive MLNS.
449
Our model provides an evaluation of the “best case scenario” using the currently available best
450
evidence on procedure performance characteristics, life expectancies, utilities and costs.
451
However, a revised estimate of cost-effectiveness of aggressive pre-operative assessment of
452
patients with lung cancer should be generated once more, and hopefully prospectively collected,
453
real world data from large cohorts of patients with micrometastatic mediastinal disease treated
454
with trimodality become available.
455
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Figure Legends
458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486
Figure 1. Cost-effectiveness plane; base-case analysis. OR: no invasive mediastinal staging strategy, Med: Mediastinoscopy; EBUS-TBNA: Endobronchial Ultrasound Transbronchial Needle Aspiration; WTP: Willingness to Pay Threshold. Effectiveness (represented as QALYs) is expressed on the x axis, while the cost in Canadian dollars (CAD) is expressed on the y axis. The strategy in the lower left corner (no invasive mediastinal staging) is less expensive but also less effective compared to strategy in the top right corner. After eliminating the dominated strategy, Med (the less effective and more expensive than the preceding strategy) three strategies remained defining the cost-effectiveness frontier: 1) the no invasive mediastinal staging strategy (OR); 2) EBUS-TBNA; 3) EBUS-TBNA-Med.
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Figure 2. Two-way sensitivity analysis on prevalence of MLNM and sensitivity of EBUSTBNA affecting incremental cost-effectiveness of different MLNS strategies. A willingness-to-pay threshold of CAD 80,000 per QALY gained was used. Colored areas represent regions of different EBUS-TBNA sensitivity and probability of MLNM over which different staging approaches are cost-effective. OR is the preferred staging strategy up until the MLNM prevalence of ~11% if the EBUS-TBNA sensitivity is below 20%. Once prevalence of MLNM exceeds 11%, and if EBUS-TBNA sensitivity is still below 20% Med is the preferred staging strategy. EBUS-TBNA staging can be considered as test of first choice if its sensitivity is >20% and prevalence of MLNM is between ~11% and ~25%. Once prevalence of MLNM reaches ~25% confirmatory Med should be considered in patients staged with ENUS-TBNA.
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Video legend Dr. Czarnecka-Kujawa explaining the importance of the work presented in the manuscript to the thoracic community.
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Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e211S-250S. Uy KL, Darling G, Xu W, et al. Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery. 2007;134(1):188-193. Darling GE, Li F, Patsios D, et al. Neoadjuvant chemoradiation and surgery improves survival outcomes compared with definitive chemoradiation in the treatment of stage IIIA N2 non-smallcell lung cancer. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2015;48(5):684-690; discussion 690. Siebert U. When should decision-analytic modeling be used in the economic evaluation of health care? . The European Journal of Health Economics. 2003;4(3):143-150. Caro JJ, Briggs AH, Siebert U, Kuntz KM. Modeling good research practices--overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-1. Medical decision making : an international journal of the Society for Medical Decision Making. 2012;32(5):667-677. Caro JJ, Briggs AH, Siebert U, Kuntz KM. Modeling good research practices--overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--1. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2012;15(6):796803. Eddy DM, Hollingworth W, Caro JJ, Tsevat J, McDonald KM, Wong JB. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-7. Medical decision making : an international journal of the Society for Medical Decision Making. 2012;32(5):733-743. Husereau D, Drummond M, Petrou S, et al. Reply to Roberts et al.: CHEERS is Sufficient for Reporting Cost-Benefit Analysis, but May Require Further Elaboration. PharmacoEconomics. 2015;33(5):535-536. Meyers BF, Haddad F, Siegel BA, et al. Cost-effectiveness of routine mediastinoscopy in computed tomography- and positron emission tomography-screened patients with stage I lung cancer. The Journal of thoracic and cardiovascular surgery. 2006;131(4):822-829; discussion 822829. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of endobronchial ultrasoundguided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. The Journal of thoracic and cardiovascular surgery. 2011;142(6):1393-1400.e1391. Louie AV, Senan S, Dahele M, Slotman BJ, Verbakel WF. Stereotactic ablative radiation therapy for subcentimeter lung tumors: clinical, dosimetric, and image guidance considerations. International journal of radiation oncology, biology, physics. 2014;90(4):843-849. McIntosh CN, Connor Gorber S, Bernier J, Berthelot JM. Eliciting Canadian population preferences for health states using the Classification and Measurement System of Functional Health (CLAMES). Chronic diseases in Canada. 2007;28(1-2):29-41. Evans WK, Connor Gorber S, Spence ST, et al. Health State descriptions for Canadians: Cancers. Canada Statistics Canada;2005. http://www.bankofcanada.ca/rates/related/inflation-calculator/. 2015
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580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624
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625
Tables
626
0.83
9
N1 disease
0.08
9
N2
0.09
9
N2 after EBUS-TBNA
0.04
10
SC
N0 disease
Table 1. Prevalence of nodal metastasis.
629 630
Survival (y)
Reference
Resection with pN0
7
36,37
Resection with pN1
4.5
38,39
Resection with pN2 (neoadjuvant)
3.3
32
Resection pN2 (adjuvant)
2.2
40
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Patient status
Table 2. Life expectancies based on pN status.
EP
631
627 Data source
M AN U
628
Prevalence
RI PT
Nodal status
AC C
632
Procedure
Average Cost* (CAD)
Data source
EBUS in the endoscopy
1,468
UHN
Med
6,633
UHN
9,702
31/UHN
Med Death VATS
11,215†
UHN
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14,284
15/UHN
Thoracotomy
15,467
31/UHN
Thoracotomy death
18,536
31/UHN
EBUS-TBNA in the OR
8,319
31/UHN
EBUS in the OR death
11,388
Chemotherapy (adjuvant)
3,539
Radiation
4,429
15
5,537
15
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4,200
15 15
Table 3. Intervention costs; *All costs have been adjusted to 2015 Canadian dollars (CAD) using the Consumer Price Index (Bank of Canada); † includes the cost related to VATS complications (excluding operative death). EBUS-TBNA: Endobronchial Ultrasound-Transbronchial Needle Aspiration; VATS: Video Assisted Thoracic Surgery, OR: Operating Room
Intervention EBUS-TBNA
EP
Med
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638
Sensitivity
Range
Data source
0.89
0.46-0.97
1
0.81
0.78-0.97
1
0.79
10
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Med following EBUS-TBNA 639
31/UHN
Chemotherapy (neoadjuvant)
Chemotherapy/Radiation death 633 634 635 636 637
RI PT
VATS death
Table 4. Sensitivities of diagnostic test procedures.
640 641
Procedure Chemotherapy/Radiation Med
Mortality
Data source
0.016
15
0.0005
41-43 26
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0.01
VATS 642
44-46
Table 5. Treatment-related mortalities.
644
Strategy
ICER (CAD/QALY)*
SC
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Cost Incremental Effectiveness (CAD)* cost (QALY) (CAD)* 11,863 0 5.802 18,143 6,280 5.864 20,551 2,408 5.873
EP
Strategy
Incremental effectiveness (QALY) 0 0.062 0.009
ICER (CAD/QALY)*
0 OR 101,796 Med 258,445 EBUS-TBNA in the OR 26,440 5,890 5.877 0.004 1,433,233 EBUS-TBNA in the OR followed by Med Table 7. Cost-effectiveness results, base-case analysis with EBUS-TBNA performed exclusively in the OR; * costs reported in Canadian dollars (CAD); ICER: Incremental Cost-Effectiveness Ratio (in CAD/QALY). Increments are calculated in comparison to the next best non-dominated strategy; OR- operating room
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651 652 653 654 655
Incremental effectiveness (QALY) 0 0.071 Dominated 0.004
0 OR 26,254 EBUS-TBNA Dominated Med 1,426,019 EBUS-TBNA followed by Med 20,551 963 5.873 Dominated Dominated EBUS-TBNA in the OR 26,440 6,853 5.877 Dominated Dominated EBUS-TBNA in the OR followed by Med Table 6. Cost-effectiveness results, base-case analysis; * costs reported in Canadian dollars (CAD); ICER: Incremental Cost-Effectiveness Ratio (in CAD/QALY). Increments are calculated in comparison to the next best non-dominated strategy; OR- operating room
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645 646 647 648 649 650
Cost Incremental Effectiveness (CAD)* cost (QALY) (CAD)* 11,863 0 5.802 13,727 1864 5.873 18,143 4415 5.864 19,587 5860 5.877
RI PT
643
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