The Canada Lymph Node Score: A Feasibility Randomized Controlled Trial

Study Overview
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Brief Summary
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For patients diagnosed with early stage Non-Small Cell Lung Cancer (NSCLC) on preoperative computerized tomography (CT) and positron emission tomography (PET) scans, surgical resection is usually the preferred method of treatment. However, to be eligible for surgery, current guidelines require that the cancer has not spread to the lymph nodes in the chest cavity. To evaluate these lymph nodes, the standard of care is to undergo an endobronchial ultrasound (EBUS) procedure, where all the visible lymph nodes in the chest are biopsied (sampled) with a needle. Unfortunately, these biopsies are often inconclusive, especially in patients who have no evidence of mediastinal lymph node spread on pre-operative imaging. Currently, the standard of care mandates that inconclusive biopsies should be repeated, either through another EBUS, or through more invasive procedures. Repeat inconclusive biopsies are oftentimes inconclusive as well; leading to a vicious cycle of inconclusive results, a delay in treatment, morbidity for the patient, and increased costs to the healthcare system. To circumvent this issue, the investigators have developed, validated and published a 4-point score, the Canada Lymph Node Score (CLNS), which uses four features observed during EBUS to predict whether the cancer has spread to the lymph nodes or not. Research has demonstrated that lymph nodes which appear benign on both CT and PET scan that also have a CLNS of ≤1/4 are almost certainly benign. As such, it is believed that these triple normal lymph do not require biopsy (or repeat biopsy). The investigators are challenging the current standard of care in lung cancer, which mandates that all the lymph nodes in the chest need to be biopsied (i.e. Systematic Sampling) before surgery, by proposing that triple normal lymph nodes can be omitted, and only those with cancer potential should be biopsied (i.e. Targeted Sampling).To prove this hypothesis, a randomized controlled trial comparing Systematic Sampling to Targeted Sampling is required. A feasibility trial is proposed to determine whether this large-scale randomized trial will be possible.

Official Title
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Routine Systematic Sampling vs. Targeted Sampling of Mediastinal Lymph Nodes Prior to Lung Cancer Treatment: A Feasibility Randomized Controlled Trial

Conditions
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Non Small Cell Lung Cancer

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: Referred to have EBUS for staging of confirmed or suspected NSCLC Completed both a CT and PET scans cN0-cN1 disease indicated on CT and PET scans Exclusion Criteria: Patients with cN0 disease, peripheral tumours and tumours < 2 cm in diameter (they do not require staging) Evidence of cN2 disease or higher on CT and PET scan

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All participants who provide consent for participation and who fulfil eligibility criteria will be randomized with a unique randomization sequence derived from the random permuted block design (with blocks of varying sizes) in a 1:1 ratio. Participants will randomized to either Systematic Sampling (Control) or Targeted Sampling (Experimental).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Systematic Sampling<br>Patients will undergo systematic sampling of lymph node stations in the mediastinum with a minimum sampling of 3 stations: 4R, 4L and 7, as is the standard of care. Other stations may be included at the endoscopist's discretion. CLNS is not used for this arm. | Diagnostic Test: Systematic Sampling<br>* Following routine biopsy of lymph nodes, patients with proven malignant mediastinal lymph nodes will be referred for chemoradiation and patients with proven benign mediastinal lymph nodes will undergo surgical resection as per standard of care guidelines. Final pathology from the resected specimen will be considered the gold standard for analysis of sensitivity and specificity.<br>* Other names: SS;|
| Experimental: Selective Targeted Sampling<br>Patients will first undergo endosonographic assessment of 3 mediastinal lymph node stations (i.e. 4R, 4L, and 7) using the four criteria of the CLNS. Lymph node stations that exhibit a CLNS >1/4 will be biopsied as is standard of care. Lymph node stations with CLNS ≤ 1/4 will be marked as not requiring biopsy but will be biopsied nevertheless, so that there is no deviation from the standard of care. Other stations may be included at the endoscopist's discretion. | Diagnostic Test: Selective Targeted Sampling<br>* After CLNS assessment, patients with proven malignant mediastinal lymph nodes will be referred for chemoradiation and patients with proven benign mediastinal lymph nodes will undergo surgical resection as per standard of care guidelines. Final pathology from the resected specimen will be considered the gold standard for analysis of sensitivity and specificity.<br>* Other names: CLNS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment Rate | Minimum acceptable recruitment rate is 70% | 1 Year | 
| Procedure Length | Calculated in minutes. Recorded for both treatment arms. | 1 Day | 
| Diagnostic Accuracy | The proportion of patients in whom the treatment (CLNS or biopsy) yielded the same diagnosis as the pathology report out of the total number of patients that have received the treatment. Recorded for both treatment arms. | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Each Possible CLNS | The CLNS has five possible scores: 0/4, 1/4, 2/4, 3/4 and 4/4. The number of lymph nodes with each score will be recorded for the Experimental Arm (Targeted Sampling). | 1 Year | 
| Frequency of Biopsies | Number of times lymph nodes had to be sampled with a transbronchial needle per EBUS procedure. Recorded for both treatment arms. | 1 Year | 
| Percent of Inconclusive Biopsies | Number of biopsies that provided an inconclusive diagnosis out of total number of biopsies obtained. Recorded for each treatment arm. | 1 Year | 
| Adverse Events | Number of AEs has classified by the Ottawa TM&M System | 1 Year | 
| Accrual Period | Duration of time to reach sample size | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endobronchial Ultrasound, Diagnostic Imaging, Feasibility, Randomized Controlled Trial, Clinical N0-N1 Disease