The Canada Lymph Node Score Project: A Crossover Trial (CLNS)

Improving Preoperative Lung Cancer Staging Through the Canada Lymph Node Project: A Pan-Canadian Multicentered Crossover Trial

Before deciding on treatment for patients with lung cancer, a critical step in the investigation is finding out whether the lymph nodes in the chest contain cancer cells. This is accomplished with a biopsy of the lymph nodes through the airway wall, known as Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. Guidelines require that every single lymph node in the chest be biopsied through a process called Systematic Sampling. However, emerging data suggests that the lymph nodes that appear benign on imaging and ultrasound do not need a biopsy. A proposed alternative to the inefficient Systematic Sampling is the simplified Selective Targeted Sampling of the lymph nodes, whereby only lymph nodes that look malignant are biopsied. This trial will evaluate the simplified Selective Targeted Sampling of lymph nodes and compare it to Systematic Sampling to see whether it is equally as effective in staging lung cancer.

Study Overview

• Status: Completed
• Conditions: Lung Cancer; Non Small Cell Lung Cancer; Non-small Cell Lung Cancer Stage I; Non-small Cell Lung Cancer Stage II
• Intervention / Treatment: Diagnostic test: Selective Targeted Sampling; Diagnostic test: Systematic Sampling

Detailed Description

Treatment decisions in Non-Small Lung Cancer (NSCLC) are reliant on a thorough staging process that includes imaging with Computed Tomography (CT), Positron Emission Tomography (PET) and Systematic Sampling (SS) of mediastinal lymph nodes (LNs) by Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA). Collectively, the results of these staging procedures dictate whether patients will be treated with surgery, radiation and/or chemotherapy. Current guidelines for SS through EBUS-TBNA mandate the biopsy of at least 3 mediastinal LN stations (4R, 4L and 7) in the chest, even if they appear normal on CT and PET scan. Despite improvements in diagnostic techniques and safety, LN biopsies remain onerous for the patient and costly to our healthcare system. SS is also unreliable, yielding inconclusive pathology results in 42.14% of cases, especially for Triple Normal LNs, which are LNs that appear normal on PET, and CT, and EBUS. In fact, SS results in mostly negative or inconclusive biopsies for Triple Normal LNs, which may be due in part to their very low probability (< 6%) of malignancy. As such, the researchers have proposed to replace the onerous and unreliable process of SS by a simpler Selective Targeted Sampling (STS) staging process. In STS, Triple Normal LNs will not be biopsied, due to the very high negative predictive value (NPV) of malignancy. STS follows the simple notion that only LNs that have the potential to be malignant should be biopsied, whereas LNs which are very likely benign (i.e. Triple Normal LNs) should not be biopsied.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Hamilton, Ontario, Canada, L8S 4L8
      • McMaster University
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
  • Quebec
    • Montréal, Quebec, Canada, H2L 4M1
      • CHUM Endoscopic Tracheo-bronchial and Oesophageal Center
    • Montréal, Quebec, Canada, H4A 3S9
      • MUHC Interventional Pulmonology Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years
• Both CT and PET scans completed prior to EBUS
• Suspected or confirmed NSCLC requiring mediastinal staging
• cN0-cN1 as indicated by CT and PET scans

Exclusion Criteria:

• Patients with cN0 disease AND peripheral tumors AND tumor < 2 cm in diameter, as they do not require mediastinal staging
• Evidence of cN2 disease or higher on CT and PET scans

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Selective Targeted Sampling; During patients' Endobronchial Ultrasound (EBUS) procedure, they will first undergo: Selective Targeted Sampling - endosonographic assessment of at least 3 mediastinal lymph node stations (4R, 4L, and 7) using the four criteria of the Canada Lymph Node Score (predictor of nodal disease during Endobronchial Ultrasound). Each lymph node will be assigned a CLNS ranging from 0 to 4. Triple Normal lymph nodes will be defined as those that appear normal on CT (diameter < 1 cm), AND normal on PET (SUV < 2.5), AND normal on EBUS (CLNS < 2). Lymph nodes that are found to be Triple Normal will be marked as "Not for Biopsy", whereas all other lymph nodes will be biopsied.	Diagnostic test: Selective Targeted Sampling; Mediastinal lymph nodes are assessed with the CLNS, and only those appearing malignant with the score are biopsied. Triple Normal lymph nodes (normal appearing on PET, CT and EBUS) are not biopsied.; Other Names: STS
ACTIVE_COMPARATOR: Systematic Sampling; Upon completion of Systematic Targeted Sampling, all patients will crossover and receive the standard of care: Systematic Sampling - all lymph nodes previously marked as "Not for Biopsy" will be biopsied. At the conclusion of the EBUS procedure, all nodal stations would have been sampled as is mandated by current guidelines.	Diagnostic test: Systematic Sampling; All examined mediastinal lymph nodes are biopsied, regardless of whether they appear normal during PET, CT and EBUS.; Other Names: SS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-Inferiority Margin between Selective Targeted Sampling and Systematic Sampling	A margin of 5% or less would be considered satisfactory for STS to be deemed non-inferior to SS.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic Statistics (between staging methods)	Sensitivity, specificity, negative predictive value and positive predictive value	2 years
Agreement (between staging methods)	Based on Cohen's Kappa statistics	2 years
Inconclusive Biopsy Rate	Percentage of lymph nodes with inconclusive pathology from biopsy	2 years
Diagnostic Yield (accuracy)	Proportion of lymph nodes with a pathological diagnosis for both sampling methods	2 years
Difference in Procedure Length	For each sampling method (in minutes)	2 years
Difference in Cost per Procedure	For each sampling method (sum of dollar costs for EBUS procedure)	2 years

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Collaborators: Health Sciences Centre, Winnipeg, Manitoba; Centre hospitalier de l'Université de Montréal (CHUM); McGill University Health Centre/Research Institute of the McGill University Health Centre; Royal Alexandra Hospital; Toronto General Hospital
• Investigators: Principal Investigator: Waël C Hanna, MDCM, MBA, FRCSC, McMaster University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 30, 2020
• Primary Completion (ACTUAL): June 30, 2022
• Study Completion (ACTUAL): June 30, 2022

Study Registration Dates

• First Submitted: April 8, 2020
• First Submitted That Met QC Criteria: April 8, 2020
• First Posted (ACTUAL): April 13, 2020

Study Record Updates

• Last Update Posted (ACTUAL): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Endobronchial Ultrasound; Diagnostic Testing; Mediastinal Staging; Nodal Disease
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: clns_10696

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No