Bronchoscopy With and Without Needle-based Confocal Laser Endomicroscopy for Peripheral Lung Nodule Diagnosis: Protocol for a Multicenter Randomized Controlled Trial (CLEVER Trial)

Rationale: Lung cancer screening and the increasing use of chest-computed tomography (CT) has led to an increase in the number of (incidental) found suspected malignant lung lesions. Since tissue acquisition for pathological analysis is prerequisite for diagnosis and optimal treatment, a drastic increase in the number of patients that need to undergo bronchoscopy is expected.

Over 70% of the suspected lesions develop in the periphery of the lung and are therefore not visible during conventional bronchoscopy. Although several bronchoscopic navigational techniques demonstrated an improved navigation towards the target lesion, the diagnostic yield remains suboptimal due to a substantial near-miss rate. As a result, the need for complementary bronchoscopic guidance that provides real-time feedback on the correct positioning of the biopsy instruments is urgent.

Needle-based Confocal laser endomicroscopy (nCLE) is a novel high-resolution imaging technique that uses an excitation laser light to create 'real-time' microscopic images of tissues. nCLE can be integrated into the biopsy needle, allowing real-time cancer detection at the tip of the biopsy needle during bronchoscopy. The confocal microscope captures autofluorescence of tissues or, combined with intravenously (IV) infused fluorophores (such as fluorescein) allows imaging of individual tumor cells. Recent studies on nCLE-imaging in lung tumors and metastatic lymph nodes have identified and validated nCLE criteria for malignancy (enlarged pleomorphic cells, dark clumps and directional streaming) and airway/lung parenchyma (alveoli, elastin fibres of the conducting airway, bronchial epithelium and still image) and granulomas. A recent study demonstrated that these nCLE-criteria can be used in real-time to fine-tune the needle positioning during ongoing bronchoscopy and thereby potentially improve the diagnostic yield.

This randomized controlled trials aims to evaluate the added value of nCLE-imaging (smart needle) to the conventional used bronchoscopic approach for peripheral lung lesion analysis.

Objective: This multicenter, randomized controlled trial, aims to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared to conventional bronchoscopy without nCLE in the diagnosis of peripheral lung nodules.