Neoplasms

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Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

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Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Minimally Invasive Echo-Endoscopic Lymph Node Evaluation and Biopsy

Endoscopic Ultrasound (EUS)

Minimally Invasive Echo-Bronchoscopic Lymph Node Evaluation and Biopsy

Endobronchial Ultrasound (EBUS)

Moishe Liberman, MD, PhD

The purpose of this study is determine if performing endobronchial ultrasound (EBUS) in addition to standard endoscopic ultrasound (EUS) can increase the precision and accuracy of staging esophageal cancer in comparison to EUS alone. The expectation is that EBUS can be used to biopsy lymph nodes that: (1) because of their position in the mediastinum would be inaccessible to EUS, or (2) would be inaccessible due to their position behind the esophageal tumor.

1. Problem:

   Endoscopic ultrasound techniques are becoming more and more popular. The safety of these technologies has been demonstrated on multiple occasions. These minimally invasive trans-luminal techniques do not require general anesthesia and can be performed, rapidly, accurately and at low cost. Endobronchial ultrasound (EBUS) has been used by pulmonologists and thoracic surgeons primarily for the staging, diagnosis and management of lung cancer. Its efficacy and safety has been demonstrated in multiple studies.

   EBUS is not currently utilized by most centers in the staging of esophageal cancer. To date, no study has explored the possible use of EBUS for peritumoral lymph node biopsy, nor for biopsy of any suspicious mediastinal lymph nodes, not accessible by EUS. At Notre Dame Hospital, Centre Hospitalier de L'Universite de Montreal, all patients diagnosed with esophageal cancer undergo complete EUS staging followed by EBUS during the same procedure, in order to examine all the lymph nodes near or far from the primary tumor amenable to EBUS guided trans-bronchial biopsy. This is important because it allows physicians to bypass the primary tumor and pass through the normal (non-cancerous) bronchial wall, eliminating any chances of tumoral contamination of the sample. In addition, this also provides a much more complete mediastinal staging as it allows biopsy of a population of lymph nodes non-accessible to EUS biopsy. Thus far, we have performed EBUS in six patients with esophageal cancer with upstaging of the N stage of the tumor in two of these patients (33%). There have been no morbidities and all patients have been discharged home on the day of the procedure. EBUS was therefore able to change the treatment strategy, without adding any morbidity, discomfort or additional procedural time for two out of six patients.

   The proposed project will be the first study ever to evaluate the impact of EBUS on esophageal cancer staging as well as on the choice of therapy. This study consists of a prospective cohort study with no placebo group, all patients will have EBUS and stages obtained with and without EBUS will be compared as well as changes to the treatment plan based on EBUS staging.
2. Objectives:

   * Examine the impact of adding EBUS to the gold standard work-up on esophageal cancer staging.
   * Examine the impact of adding EBUS to the gold standard work-up on the treatment plan for patients newly diagnosed with esophageal cancer.
3. Methodology:

   The study consists of a prospective cohort study. Each patient will serve as his/her own control. All patients currently undergoing esophageal cancer staging in the Division of Thoracic Surgery at the CHUM will be approached for enrolment into the study.

   EUS followed by EBUS will be performed during the EUS staging procedure. The order of procedures for all patients is as follows: (1) Flexible Esophagoscopy with endoluminal biopsy, (2) Radial EUS for T staging (3) Linear EUS for lymph node biopsy and N staging, (4) Flexible Bronchoscopy for evaluation of the left mainstem bronchus for tumor invasion, (5) Linear EBUS for trans-tracheal and trans-bronchial lymph node biopsy.

   All FNA samples will be evaluated using standard methods by cytopathologists at the CHUM. Results will be evaluated for: (A) positivity, (B) negativity (no tumor cells, positive lymphocytes), (C) inadequacy (no tumor cells, no lymphocytes). A minimum of two passes will be performed into each lymph node.

   Patients will be discharged on the same day, as their procedure. Results will be discussed with them in a follow-up clinic appointment with their thoracic surgeon within 3 weeks of the procedure. Any procedure-related morbidity will be documented in the post-procedural period as well as at their follow-up appointment.
4. Expected Results:

We believe that by adding EBUS to the gold standard work up and staging of esophageal cancer, we can make a significant difference in esophageal cancer staging. This may also significantly change the choice of therapy.

Endobronchial Ultrasound (EBUS) for Nodal Staging in Esophageal Cancer

C.E.T.O.C. - CHUM Endoscopic Tracheobronchial and Oesophageal Center

Marcel and Rolande Gosselin Chair in Thoracic Surgical Oncology

Fonds de la Recherche en Santé du Québec

Centre de Recherche du Centre Hospitalier de l'Université de Montréal

Centre hospitalier de l'Université de Montréal (CHUM)

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Patients with (suspected) lung cancer requiring MLN staging after CT-PET during routine work-up according to existing staging guidelines.

Use of dedicated virtual bronchoscopy navigation software using 4D CT-PET scan spacial data.

Virtual Bronchoscopy Navigation

Sayed Hashemi, MD

Hans Daniels, MD

Emiel Comans, PhD

Otto Hoekstra, PhD

Piet Postmus, PhD

Tom Sutedja, PhD

The purpose of this study is to determine wether CT-PET virtual bronchoscopy guided transbronchial needle aspiration is suitable for the investigation of mediastinal lymph nodes which is needed for correct staging of lung cancer.

Accurate staging of mediastinal lymph nodes (MLNs) in patients with lung carcinoma (LC) is paramount as the N stage largely determines treatment strategy, prognosis and outcome. Surgical staging such as mediastinoscopy is considered the gold standard. A less invasive alternative is transbronchial needle aspiration (TBNA). This technique is limited however by moderate and operator dependent accuracy. Recently less invasive strategies such as esophageal ultrasound guided fine needle aspiration (EUS-FNA) and endobronchial ultrasound guided TBNA (EBUS-TBNA) were introduced. These strategies have largely complemented TBNA and surgical staging, with high accuracy and low morbidity. Disadvantages compared to TBNA however are required specific expertise, higher equipment and maintenance costs, the need for more assisting personnel and the need for sedation. Advances in computer generated image processing based on available CT and PET images enable (quasi) real-time virtual bronchoscopy that can assist minimal invasive surgical performance including bronchoscopy. Optimizing the traditional TBNA procedure with these modern imaging techniques might be equally accurate and more cost effective.

Virtual Bronchoscopy Transbronchial Needle Aspiration(TBNA): a Proof of Concept Study

CT-PET Virtual Bronchoscopy Guided Transbronchial Needle Aspiration for Mediastinal Lymph Node Staging in Suspected Lung Cancer

Feasibility of virtual bronchoscopy in showing the presence or abscense of N2/N3 mediastinal lymph node (MLN) metastasis with accuracy of 0.6 in puncturing MLN \> 15 mm (CT images) and accuracy of 0.8 for MLN \< 15 mm in the second phase of the study.

Philips Healthcare

Amsterdam UMC, location VUmc

T.G. Sutedja, MD, PhD

Carcinoma, Non-Small-Cell Lung

Endobronchial-ultrasound controlled transbronchial needle aspiration (EBUS-TBNA) in combination with a transoesophageal-ultrasound controlled needle aspiration of mediastinal lymph nodes

Thoracic endosonography

Christophe Dooms

Kurt Tournoy

This is a prospective non-randomized multicenter clinical trial performing endobronchial and esophageal ultrasound for mediastinal lymph node staging of operable and resectable cT1-T2-selectedT3 cN1 cM0 NSCLC.

Provided no mediastinal lymph node metastases are proven by echoendoscopy, all patients will subsequently undergo surgical staging. Patients without tissue proof of mediastinal nodal disease at surgical staging will undergo a thoracotomy with systematic lymph node dissection. Provided mediastinal lymph node metastases are proven by echoendoscopy, the patient goes off study protocol and can further be assessed/treated according to local clinical practice.

Assessment of Invasive Mediastinal Staging in cN1 Lung Cancer.

Assessment of Surgical Mediastinal sTaging Added to Endoscopic Ultrasound in cN1 Lung canceR.

Universitaire Ziekenhuizen KU Leuven

Cervical Mediastinoscopy

The gold standard techniques to assess the extent of disease and decide on therapy for patients with lung cancer consists of cervical mediastinoscopy, which is a surgical procedure which entails an incision in the neck and the removal of lymph nodes from around the airway. Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) are new, non-surgical techniques that have been available for the past several years and are proving invaluable in lung cancer evaluation. These techniques are minimally invasive and can be performed without surgery.

To date, there have been no head-to-head studies on the same group of patients using both the old and new techniques. The study will consist of a study which compares traditional staging techniques in lung cancer patients to new, less invasive techniques.

The significance of the proposed project is tremendous. If the new strategies prove to be equivalent (or superior) to traditional techniques, these techniques will be considered the new gold-standard tests. This will change the way lung cancer is evaluated. An equivalent or superior result will also significantly impact on patient care, cost and morbidity due to the speed, convenience and lack of operating room requirement as well as the lack of general anesthesia.

1. Problem:

   The gold standard techniques to stage and diagnose the mediastinum in patients with lung cancer consist of cervical mediastinoscopy (CM). CT, PET and PET-CT scans have improved the radiological staging of the mediastinum; however these techniques are unable to provide a tissue diagnosis and are inaccurate. Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) have been available for the past few years and are proving invaluable in the diagnosis and staging of the mediastinum. These techniques rely on imaging of mediastinal lymph nodes (LN) through the airway (EBUS) and the esophagus (EUS) using miniaturized ultrasound probes mounted on the tip of flexible bronchoscopes (EBUS) and esophagoscopes (EUS). Once a LN is visualized and identified using either of these techniques, a needle is passed through the airway (EBUS) or esophageal (EUS) wall into the LN and biopsies are performed. These minimally invasive trans-luminal techniques do not require general anesthesia and can be performed safely, rapidly, accurately and at low cost.

   Due to the cost, inconvenience and risks associated with traditional surgical mediastinal diagnosis and staging, many physicians are foregoing tissue diagnosis of the mediastinum, resulting in incomplete pre-operative staging for patients. The endoscopic techniques are quickly replacing traditional techniques in some centers; however, when replacing a gold standard test with a new modality, one must first prove equivalence in safety and efficacy. Until such a study is completed, we do not have compelling data to be able to offer these techniques as equivalent alternatives to patients. The proposed project will be the first head-to-head comparison of both endobronchial (EBUS) and endoscopic ultrasound (EUS) in addition to transluminal biopsy with gold standard invasive surgical staging techniques in the diagnosis and staging of NSCLC.
2. Objectives:

   * Define and compare the sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio and accuracies between traditional and minimally invasive mediastinal diagnostic and staging techniques for lung cancer.
   * Compare morbidity, convenience, cost and efficiencies between traditional and minimally invasive diagnostic strategies.
   * Examine the impact on decisions regarding changes in treatment plans (neoadjuvant chemoradiotherapy, prevention of thoracotomy) based on minimally invasive mediastinal staging compared to conventional staging strategies.
3. Methodology:

   The study design consists of a prospective comparison of diagnostic test findings on a consecutive case series with each subject serving as his or her own control. In order to do this, we will enroll N subjects (N=166), and will subject each of the subjects to K procedures (K=3). One of those procedures, the "traditional" one (K-1), is considered to be the gold standard for comparison. We will compare the diagnostic findings from the K-2 and K-3 alternative procedures (EBUS and EUS, respectively) with the gold standard across the N subjects. We will compare them singly and in combination with the gold standard. All patients with a new or suspected diagnosis of lung cancer will be prospectively enrolled in the study. All patients will undergo standard mediastinal staging, EBUS and EUS in the operating room, during one procedure. Patients will be included in the study if they meet one of the following criteria: (A) Lung lesion with mediastinal lymphadenopathy and/or positive PET scan in the mediastinum, (B) Lung lesion without mediastinal lymphadenopathy or positive PET scan in the mediastinum. Sample size has been calculated to be 166 patients.

   Results of traditional staging techniques will be considered as the "gold standard" tests for mediastinal diagnosis and staging. These tests will be used as the standard to which other modalities and combinations of modalities are compared. Data will be collected and analyzed as a whole (all patients with mediastinal LN sampling) and separately based on pre-biopsy diagnosis, post-biopsy diagnosis, mediastinal LN size (CT scan), LN station and PET avidity. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and accuracies will be calculated and used to compare EUS and EBUS (transluminal strategy) to traditional staging, EUS to EBUS, EUS to traditional staging and EBUS to traditional staging. Subanalysis based on pre-biopsy patient and imaging (CT and PET) characteristics as well as ultrasound imaging characteristics during biopsy will be used to develop predictive models for minimally invasive mediastinal diagnosis, in order to better define patients at increased or decreased likelihood of successful diagnosis using these techniques. ROC curves will be constructed and used to discriminate results between diagnostic tests.

   The primary focus of this project and the hypothesis for which the sample size calculations were designed around is whether or not minimally invasive trans-luminal mediastinal LN biopsy is as accurate as traditional "gold standard" techniques in the diagnosis and staging of the mediastinum. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy will be calculated for both strategies (minimally invasive and traditional) and compared. Receiver operating curves will be used to compare the two strategies at differing sensitivity and 1-specificity values. Relative operating characteristic curves will be used to compare the two strategies at different true positive and false positive rates. The study is estimated to be completed in three years. Sample size calculation has determined that 166 patients are required for the study. The thoracic surgery division at the CHUM estimates that accrual will be approximately 1.5 patients per week (6 patients/month).
4. Expected Results:

We expect to find that minimally invasive mediastinal LN staging and diagnosis is not only equivalent in terms of accuracy to traditional staging strategies, but is actually superior. This superiority is possible, secondary to the additional LN basins accessible via these techniques.

Minimally Invasive, Diagnosis and Staging of Lung Cancer

Minimally Invasive, Trans-Luminal Diagnosis and Staging of Lung Cancer: A Prospective Head-to-Head Comparison With Traditional Gold Standard Diagnostic Techniques

Define and compare the sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio and accuriacies between traditional and minimally invasive mediastinal diagnostic and staging techniques for lung cancer.

Compare morbidity, convenience, cost and efficiencies between traditional and minimally invasive diagnostic strategies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Endobronchial Ultrasound (EBUS) for Nodal Staging in Esophageal Cancer	NCT01038544	Esophageal Canc...	Endoscopic Ultr... Endobronchial U...	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
Virtual Bronchoscopy Transbronchial Needle Aspiration(TBNA): a Proof of Concept Study	NCT01077492	Lung Cancer	Virtual Broncho...	18 Years -	Amsterdam UMC, location VUmc
Assessment of Invasive Mediastinal Staging in cN1 Lung Cancer.	NCT01456429	Non-small Cell ...	Thoracic endoso...	18 Years -	Universitaire Ziekenhuizen KU Leuven
Assessment of Invasive Mediastinal Staging in cN1 Lung Cancer.	NCT01456429	Non-small Cell ...	Thoracic endoso...	18 Years -	Universitaire Ziekenhuizen KU Leuven
Endobronchial Ultrasound (EBUS) for Nodal Staging in Esophageal Cancer	NCT01038544	Esophageal Canc...	Endoscopic Ultr... Endobronchial U...	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
Minimally Invasive, Diagnosis and Staging of Lung Cancer	NCT01011595	Lung Cancer	Cervical Medias... Endobronchial U... Endoscopic Ultr...	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
Minimally Invasive, Diagnosis and Staging of Lung Cancer	NCT01011595	Lung Cancer	Cervical Medias... Endobronchial U... Endoscopic Ultr...	18 Years -	Centre hospitalier de l'Université de Montréal (CHUM)

Spots Global Cancer Trial Database for mediastinal lymph nodes