The Canada Lymph Node Score Project: A Crossover Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Lung Cancer, Non Small Cell Lung Cancer, Non-small Cell Lung Cancer Stage I, Non-small Cell Lung Cancer Stage II

Intervention / Treatment
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* Diagnostic Test: Selective Targeted Sampling
* Diagnostic Test: Systematic Sampling


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A prospective pan-Canadian, multicentered, non-inferiority crossover study design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selective Targeted Sampling<br>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<br>* 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.<br>* Other names: STS;|
| Active Comparator: Systematic Sampling<br>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<br>* All examined mediastinal lymph nodes are biopsied, regardless of whether they appear normal during PET, CT and EBUS.<br>* Other names: SS;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mediastinal Staging, Nodal Disease, Endobronchial Ultrasound, Diagnostic Testing