Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

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.

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.

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.

Selective Targeted Sampling

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.

Systematic Sampling

Waël C Hanna, MDCM, MBA, FRCSC

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.

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).

Trial participants will remain blinded to their randomized treatment. Additionally, the biostatistician performing the analysis will be blinded as to which intervention arm participants were allocated to, as the group allocations will be coded as Group A and Group B. Provided this is an endoscopic trial, endoscopist blinding will not be feasible. Nonetheless, all patients deemed surgical candidates after EBUS will have their pathology compared to EBUS staging in order to ensure appropriate diagnosis. Pathologists performing such pathology report will be blinded to which intervention arm participants are allocated to.

The Canada Lymph Node Score: A Feasibility Randomized Controlled Trial

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

Minimum acceptable recruitment rate is 70%

Calculated in minutes. Recorded for both treatment arms.

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.

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).

Number of times lymph nodes had to be sampled with a transbronchial needle per EBUS procedure. Recorded for both treatment arms.

Number of biopsies that provided an inconclusive diagnosis out of total number of biopsies obtained. Recorded for each treatment arm.

Number of AEs has classified by the Ottawa TM\&M System

McMaster University

St. Joseph's Healthcare Hamilton

Head of Endoscopy Services, Thoracic Surgeon

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

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.

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.

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.

All examined mediastinal lymph nodes are biopsied, regardless of whether they appear normal during PET, CT and EBUS.

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.

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.

A prospective pan-Canadian, multicentered, non-inferiority crossover study design

The Canada Lymph Node Score Project: A Crossover Trial

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

A margin of 5% or less would be considered satisfactory for STS to be deemed non-inferior to SS.

Sensitivity, specificity, negative predictive value and positive predictive value

Percentage of lymph nodes with inconclusive pathology from biopsy

Proportion of lymph nodes with a pathological diagnosis for both sampling methods

For each sampling method (sum of dollar costs for EBUS procedure)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Canada Lymph Node Score: A Feasibility Randomized Controlled Trial	NCT03859349	Non Small Cell ...	Selective Targe... Systematic Samp...	18 Years -	St. Joseph's Healthcare Hamilton
The Canada Lymph Node Score: A Feasibility Randomized Controlled Trial	NCT03859349	Non Small Cell ...	Selective Targe... Systematic Samp...	18 Years -	St. Joseph's Healthcare Hamilton
The Canada Lymph Node Score Project: A Crossover Trial	NCT04342377	Lung Cancer Non Small Cell ... Non-small Cell ... Non-small Cell ...	Selective Targe... Systematic Samp...	18 Years -	St. Joseph's Healthcare Hamilton

Spots Global Cancer Trial Database for systematic sampling