Robotic-assisted and electromagnetic navigation bronchoscopy for multi-focal lung cancers: a narrative review

Introduction

With the development of low-dose computed tomography (CT), an increasing number of ground-glass nodules are being detected, many of which are diagnosed as lung cancers (1). Notably, the proportion of multi-focal lung cancers (MFLCs) has also increased (2). Therefore, to aid in the clinical management of MFLCs, an increasing number of studies have begun to explore this condition (3,4). Our early research also focused on the occurrence and development of multi-focal primary lung cancers through transcriptome analysis, single-cell techniques, and in vitro experiments (5). Multi-focal primary lung cancers refer to the occurrence of two or more independent primary lung tumors that arise separately within the lungs. In contrast, intrapulmonary metastasis (IPM) involves the spread of cancer from a primary lung tumor to another location within the lungs. Although both conditions may require surgical resection in their treatment algorithm, differentiating between them is crucial, as the treatment strategies and prognostic implications diverge significantly (6). According to the ninth edition of the Tumor-Node-Metastasis (TNM) Classification for Lung Cancer, published by the International Association for the Study of Lung Cancer, each lesion in patients with multi-focal primary lung cancers should be staged independently based on its own tumor size and characteristics, whereas IPM is classified as T3 if within the same lobe, T4 if located in another ipsilateral lobe, and M1a if contralateral. Although imaging, histopathological analysis, and molecular testing aid in distinguishing these conditions, the diagnosis remains challenging in certain cases, especially when multiple lesions are located in different parts of the lungs or near vital structures, complicating surgical resection (7).

In clinical practice, it may not be in the best interest of the patient to surgically resect all the MFLCs, even if anatomically and physiologically feasible. The decision is often driven by the need to balance effective tumor control with the preservation of lung function (8). This is particularly concerning in patients with underlying lung disease, where preserving lung function is essential (9). Loss of an entire lung or two lung lobes is an independent risk factor for perioperative complications and mortality (10). Moreover, incomplete resection can result in a loss of accurate diagnosis, which in turn can affect the decisions surrounding treatment planning. When complete surgical resection is not possible, the risk of local recurrence and metastasis increases, making systemic therapies such as chemotherapy, targeted therapy, and immunotherapy important adjuncts to treatment (11,12). However, these therapies are often associated with systemic side effects and may not provide the precision of localized interventions (13,14).

Robotic-assisted bronchoscopy (RAB) and electromagnetic navigation bronchoscopy (ENB) have emerged as endobronchial platforms that enable minimally invasive treatment strategies (15,16). Recent developments in navigation accuracy and instrument compatibility enable clinicians to evaluate multiple pulmonary lesions within a coordinated procedural workflow. Shape-sensing and electromagnetic systems allow sequential access to nodules in different lobes, facilitating comprehensive tissue sampling and molecular characterization to distinguish synchronous primary tumors from IPM. In selected cases, and under multidisciplinary planning, same-session bronchoscopic ablation or dye marking can be performed following diagnostic confirmation, minimizing the need for repeat procedures (17-19). Integration with other modalities, such as same-session video-assisted thoracoscopic resection combined with transbronchial microwave ablation (MWA), allows bilateral or multi-segment disease to be managed in patients with limited pulmonary reserve (18). These integrated workflows are particularly relevant for MFLCs, where multiple lesions often coexist and individualized, parenchyma-sparing strategies are essential to preserve lung function. Accordingly, this review therefore focuses on MFLC-specific management pathways, hybrid diagnostic-therapeutic algorithms, and lung-function-preservation strategies that are facilitated by developments in RAB and ENB, distinguishing its scope from prior reviews that examined these platforms in general lung cancer contexts. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-943/rc).

Methods

A literature search of PubMed, Embase, and Web of Science was performed with a primary search on February 28, 2025 and a final update on September 30, 2025; only English-language publications were included. Keywords included “multi-focal lung cancer”, “multiple primary lung cancer”, “intrapulmonary metastasis”, “robotic-assisted bronchoscopy”, “electromagnetic navigation bronchoscopy”, “non-electromagnetic navigation”, “cone-beam CT”, “bronchoscopic ablation”, “diagnosis”, “treatment”, as well as synonyms such as “multi-site lung tumors”, and “navigational bronchoscopy ablation” with Boolean operators AND/OR. We also screened reference lists of key review articles and major original studies to identify additional relevant publications. Eligible studies included prospective or retrospective original articles, case series, clinical trials, or abstracts that reported use of bronchoscopic navigation including robotic or navigational for diagnosis or ablation of pulmonary nodules. We excluded studies limited to central airway tumors, those solely reporting central airway tumor ablation, nonhuman or ex vivo experiments, and editorials, letters without primary data. Two independent reviewers first screened titles and abstracts to exclude obviously irrelevant records. For all remaining records, both reviewers independently assessed full texts against inclusion/exclusion criteria. Disagreements were resolved by discussion or by consulting a third reviewer. To ensure transparency and scholarly rigor, two reviewers independently assessed the reporting quality and potential intrinsic biases of each included study. The evaluation considered whether the studies clearly described patient and lesion selection criteria, navigation platform and ablation technical details, follow-up protocols, and endpoint definitions; whether there was risk of selection bias such as only reporting “accessible” lesions, underreporting of unsuccessful or complication cases, or incomplete data or high loss to follow-up. The search strategy is detailed and shown in Table 1.

Diagnostic challenges and approaches

Currently, there is no universally accepted “gold standard” for distinguishing between multi-focal primary lung cancers and IPM. Several diagnostic approaches, including imaging evaluation, histopathological analysis, and, importantly, molecular genetic testing, have been proposed to assist differentiation (4,20). In particular, next generation sequencing testing for driver mutations or deletions, such as epidermal growth factor receptor (EGFR) mutations, has become fundamental in differentiating multi-focal primary lung cancers from IPM, as distinct lesions in multi-focal primary lung cancers frequently exhibit unique molecular profiles, whereas IPM typically shares identical molecular alterations with the primary tumor (21). The presence of multiple lesions significantly complicates the diagnostic process, as nodules may represent independent primary tumors or metastases. While IPM lesions usually share histopathological and molecular features with a known primary tumor, multi-focal primary lung cancers typically demonstrate distinct genetic alterations (22). Clearly distinguishing multi-focal primary lung cancers from IPM through molecular profiling is essential, as this significantly impacts treatment decisions and patient prognosis (23).

Current management of MFLCs and limitations

The National Comprehensive Cancer Network (NCCN) management guidelines for MFLCs recommend a multidisciplinary evaluation involving thoracic radiology, pulmonary medicine, thoracic surgery, medical oncology, and radiation oncology. If the disease is stable or very slow-growing, observation and surveillance are recommended. For dominant nodules with evidence of growth, the treatment plan depends on whether definitive local therapy is possible. If local therapy is feasible, parenchymal sparing resection, radiation, or image-guided thermal ablation may be preferred initially, followed by surveillance. If local therapy is not possible, palliative chemotherapy with or without local therapy or observation may be considered. In cases of recurrence or metastatic disease, further systemic therapy or targeted treatments may be required. All recommendations are category 2A unless otherwise specified (24).

Surgical approaches

Surgical resection remains the standard approach for treating localized lung cancer (25); however, it poses significant challenges when dealing with MFLCs, especially when multiple lesions involve different lung lobes or segments (26,27). Achieving complete resection is difficult due to complex tumor distribution, the necessity of preserving lung function, and limited patient tolerance for extensive surgery (28). Precise localization of small peripheral tumors can be challenging, complicating efforts to secure adequate surgical margins. Additionally, lesions adjacent to vital mediastinal structures such as great vessels and pericardium, can increase risks of severe hemorrhage or cardiac injury. Consequently, many patients are either unsuitable for extensive resections or limited to less radical procedures like segmentectomy or wedge resection, which may increase the risk of local recurrence due to small surgical margins and incomplete tumor removal.

Radiotherapy and systemic treatments

Radiotherapy and systemic therapies play important roles in advanced or unresectable MFLCs but have limitations when compared with localized bronchoscopic interventions. Stereotactic body radiation therapy (SBRT) delivers high-dose radiation with precise targeting yet can cause skin burns, esophagitis, rib fractures, brachial plexus neuropathy or even fatal pneumonitis, with toxicity risk particularly high for tumors located within 2 cm of the main bronchial tree or mediastinum (29-33). Systemic chemotherapy, immunotherapy and molecularly targeted agents are generally reserved for unresectable or metastatic disease, with combined chemo-immunotherapy now first-line for advanced non-squamous non-small cell lung cancer (NSCLC) and targeted inhibitors used when actionable mutations such as EGFR or anaplastic lymphoma kinase (ALK) are present (34-39). In contrast, early-stage MFLCs often derive limited benefit from systemic therapy (40), emphasizing the need for parenchyma-sparing local strategies including navigation-guided ablation and minimally invasive surgery to preserve lung function and reduce treatment-related toxicity.

Non-electromagnetic navigation platforms

Beyond electromagnetic tracking systems, certain bronchoscopic navigation platforms employ non-electromagnetic guidance methods to overcome magnetic interference limitations and expand intraoperative flexibility. One notable example is Broncus Medical Archimedes^TM System (San Jose, CA, USA), which functions as a virtual bronchoscopic navigation system. It reconstructs CT scans into a three-dimensional (3D) airway and vascular model, overlays the lesion path on a virtual bronchoscopic view, and integrates fused fluoroscopy without relying on an electromagnetic sensor for catheter tracking. The platform supports creation of tunneled parenchymal routes to reach peripheral nodes beyond airway branches without electromagnetic guidance (41). In early human series, Archimedes achieved an overall diagnostic yield of 69–77%, with no major procedural adverse events in tunneled cases (42,43). It also allowed compatibility with conventional bronchoscopes without dedicated consumables (44). These non-electromagnetic frameworks offer robust alternatives when electromagnetic tracking is compromised and can integrate readily with preoperative CT or fluoroscopic workflows to confirm positioning and guide sampling or ablation.

RAB and ENB

RAB and ENB are advanced, minimally invasive endobronchial platforms used in the diagnosis and treatment of pulmonary diseases, including MFLCs (40,45). Both techniques utilize cutting-edge technology to enhance the accuracy, precision, and flexibility of bronchoscopic navigation and procedures, offering significant advantages over traditional bronchoscopy. RAB involves the use of a robotic platform to control a flexible bronchoscope, allowing for enhanced precision and dexterity during the procedure. The robotic system provides real-time and 3D augmented visualization (46). The robotic arms provide precise movement access difficult-to-reach lung areas, such as those located peripherally or near critical structures like large blood vessels or the pleura (Figure 1). RAB offers enhanced ergonomics and the ability to scale movements (47). ENB, on the other hand, utilizes electromagnetic navigation technology to guide the bronchoscope in real-time. ENB uses pre-procedure CT imaging to map lung anatomy (46) (Figure 2).

Figure 1 CBCT-guided robotic-assisted bronchoscopy navigation. (A) Pre-procedural 3D reconstruction. (B) Intra-operative navigation guided by real-time bronchoscopic vision, AI airway recognition, electromagnetic navigation, showing the target lesion and its spatial relationship to adjacent vessels and airways, guiding the robotic arm to the peripheral lesion. (C,D) Biopsy of the target lesion under robotic guidance assisted by augmented fluoroscopy and CBCT. 3D, three-dimensional; AI, artificial intelligence; CBCT, cone-beam computed tomography.

Figure 2 ENB planning and tracking. (A) Pre-procedural CT 3D reconstruction showing the intrapulmonary lesion and planned pathway. (B) Illustration of the electromagnetic sensor (locatable guide) position within the ENB system and the real-time navigation pathway. (C) After correction for CT-body divergence using tomography from C-arm. (D) Biopsy of the target lesion by ENB guidance and confirmed by CBCT. 3D, three-dimensional; CBCT, cone-beam computed tomography; CT, computed tomography; ENB, electromagnetic navigation bronchoscopy.

Benefits of using robotic or electromagnetic navigation in bronchoscopy

RAB’s robotic arms and ENB’s electromagnetic tracking facilitate precise navigation. RAB offers greater flexibility through the use of articulated robotic arms (47). ENB guides the bronchoscope using pre-mapped pathways (48). Recent studies comparing ENB with CT-guided transthoracic needle biopsy/transthoracic needle aspiration (TTNB/TTNA) have provided robust evidence supporting the use of ENB and RAB. For example, one retrospective study of 114 patients with nodules located in the mid-lung segments reported a positive diagnostic yield of 76.1% for ENB versus 73.1% for CT-TTNA, with no statistically significant difference (49). Another two retrospective multicenter study reported positive diagnostic yields of 87.6% for RAB versus 88.4% for CT-TTNA (P=0.85), and 85.7% for RAB versus 88.5% for CT-TTNA (P=0.65), respectively (50,51). In a larger study of 1,006 biopsy cases, ENB achieved a diagnostic accuracy of 57.1% and a specificity of 100%, compared to 75.9% accuracy with a specificity of 61.5% for CT-TTNA. Although ENB sensitivity was slightly lower (40% vs. 77.5%), its specificity was clear (52). The most definitive evidence comes from the VERITAS multicenter randomized controlled trial (RCT), which demonstrated a diagnostic yield of 79.0% for ENB using the ILLUMISITE^TM platform, equivalent to CT-TTNA (73.6%) at twelve months (P=0.003 for noninferiority; P=0.17 for superiority) (53). Recent evaluations have demonstrated that RAB achieves diagnostic performance comparable to or exceeding that of ENB. A retrospective comparative cohort study demonstrated comparable diagnostic yields (77% vs. 80%) between RAB and ENB (P=0.40) (54). Beyond diagnosis, the same navigation platforms also support bronchoscopic ablation; in inoperable stage I NSCLC, bronchoscopic transbronchial MWA has shown efficacy comparable to CT-guided percutaneous ablation (55), with details summarized in Table 2. A large multicenter community study of the Monarch RAB platform reported an index diagnostic yield of 85.2% (95% CI: 80.9–89.5%) and a 12-month yield of 79.4%, compared to the 72.9% 12-month yield observed in the NAVIGATE ENB study (56,57). Moreover, a recent meta-analysis of navigational bronchoscopy technologies encompassing 95 studies and over 10,000 nodules found pooled diagnostic yields of 76.5% for RAB versus 70.3% for ENB (58). Another meta-analysis restricted to RAB studies estimated a diagnostic yield of 84.3% (59). In summary, these data indicate that ENB and RAB are on par with CT-TTNA in diagnostic accuracy.

Enhanced precision reduces the risk of complications, which are more common in traditional transthoracic or bronchoscopic approaches. A retrospective study reported the overall complication rates after biopsy of 0% for ENB versus 22.6% for CT-TTNA, but no statistically significant difference (49). Another retrospective multicenter study reported the pneumothorax rates of 7.4% for RAB versus 21.1% for CT-TTNA, with no significant difference, too (P=0.14) (51). One retrospective multicenter study reported a lower overall complication rate of 4.4% for ENB than 17.0% for CT-TTNA (P=0.002) (50). An overall comparative table was shown in Table 2. A multicenter study reported that pneumothoraces requiring admission or chest tube placement associated with ENB biopsy, with Common Terminology Criteria for Adverse Events grade 2 or higher, occurred in 2.9% (56). Another meta-analysis of ENB and RAB biopsies showed an overall pneumothorax rate of 2.5% (58). A retrospective study on common transbronchial biopsy found radiographic evidence of pneumothorax in 38 patients (15.4%) (60). Our research, conducted at this center, indicates that the complications of ENB ablation, including pneumothorax requiring drainage, occur in approximately 5–6% of cases (61,62). A meta-analysis revealed a significant hemorrhage rate of 0.5% for biopsies performed using the RAB platform (59). Additionally, a multicenter, single-arm, prospective trial utilizing the ENB platform for biopsy reported a bleeding rate of 2% (63). A retrospective study of common transbronchial biopsy found a bleeding rate in 91 patients (64.5%) (64). These findings highlight the need for RCTs to compare the safety and effectiveness of the ENB and RAB platforms with conventional platforms in biopsy procedures in the future.

Indications for RAB and ENB in the treatment of MFLCs

Both RAB and ENB can be used to biopsy (65). Ablation techniques, including radiofrequency ablation (RFA), MWA, cryotherapy, pulsed electric fields (PEF), and laser ablation, can destroy tumors (17). When multiple lesions are present in both lungs or across different lung segments, RAB and ENB provide a platform to access lung nodules, facilitating diagnostic and therapeutic interventions. Our previous research demonstrated that transbronchial MWA, guided by these platforms, can effectively treat contralateral nodules while reducing operative and anesthetic time, shortening hospital stays, and offering a more cost-effective alternative to segmentectomy or lobectomy for contralateral tumors (66). RAB or ENB bronchoscopic facilitate localized treatments for patients requiring lung preservation. This is particularly relevant for patients with multifocal disease, where preserving lung capacity is essential for maintaining quality of life. Additionally, studies have shown that the incidence of secondary primary lung cancer is rising (67). Bronchoscopic approaches expands diagnostic and therapeutic options.

Technological advancements

Both RAB and ENB have undergone significant technological advancements improving their capabilities and expanding their clinical applications. Initially, robotic bronchoscopy systems offered basic control and visualization (59,68). However, newer robotic systems, such as the Ion Endoluminal System (Intuitive) and the Monarch Platform (Auris Health), now provide high-definition 3D imaging, real-time video feedback, and more precise control of the bronchoscope (47,69). Systems are increasingly integrated with navigation tools for enhanced movement. Additionally, robotic systems now offer enhanced ergonomic design, which reduces operator fatigue during long procedures and improves the overall success of the procedure. Similarly, newer ENB systems such as Illumisite Navigation System (Medtronic) has evolved with the inclusion of more sophisticated image fusion and electromagnetic tracking systems (56). Earlier versions relied largely on pre-procedural CT scans, whereas today’s advanced setups integrate real-time imaging with augmented reality elements, allowing for dynamic adjustments during the procedure (70). Enhanced accuracy facilitates biopsy and therapeutic ablation.

In recent years, there has been an increased push to combine RAB and ENB with other technologies to enhance their effectiveness. For instance, CT-guided bronchoscopy and optical coherence tomography can now be used in conjunction with RAB and ENB for real-time tissue analysis and visualization (71). Likewise, specialized robotic-compatible biopsy instruments and ablation devices now enable integrated procedural workflows, in which tissue diagnosis and, when pre-planned under multidisciplinary guidance, bronchoscopic ablation can be performed within a single anesthetic session. Moreover, the incorporation of artificial intelligence (AI) and machine learning into these platforms holds promise for improved lesion detection, optimized navigation pathways, and reduced operator error (72). Several centers have begun exploring the use of RAB and ENB combined with dye marking to locate pulmonary nodules in a hybrid operating room (73-75) (Figure 3).

Figure 3 ENB-guided dye marking of peripheral pulmonary nodules. (A) Intra-operative CBCT image showing placement of the dye-injection needle via ENB to the designated location. (B) Real-time monitoring of ICG fluorescent dye injection. (C) Uniportal VATS view of the marked lesion. (D) Successful resection of the marked lesion. CBCT, cone-beam computed tomography; ENB, electromagnetic navigation bronchoscopy; ICG, indocyanine green; VATS, video-assisted thoracic surgery.

Bronchoscopic ablation techniques

Principles of bronchoscopic ablation

Bronchoscopic ablation involves the use of various energy-based methods to treat pulmonary tumors (76). The primary goal of bronchoscopic ablation is to destroy the tumor tissue while preserving surrounding healthy lung tissue. RFA uses high-frequency electrical currents to generate heat, which destroys tumor tissue through coagulation and necrosis. A probe is inserted via bronchoscopy into the tumor, where it delivers energy directly to the tumor mass (77). RFA is most commonly used for small tumors or peripheral lesions and can be especially effective in treating lesions that are not amenable to resection. RFA has been shown to have a minimal risk of significant adverse events (78). One innovation within this category is RFA with micro-perfusion, in which a conductive fluid such as saline is infused to enhance heat distribution, potentially improving ablation efficacy in larger or more complex tumors (77).

MWA generates electromagnetic waves that produce heat within the tumor, leading to coagulation necrosis. Similar to RFA, the applicator is delivered bronchoscopically to the targeted nodule (79). Microwave energy can achieve higher intratumoral temperatures over a shorter ablation time, making it suitable for lesions of various sizes. Recent studies highlight MWA’s efficacy in treating peripheral lung lesions with good local control rates and an acceptable safety profile (80).

Cryotherapy employs extremely low temperatures by Joule-Thompson principle to freeze and destroy tumor cells. A cryoprobe is advanced to the lesion through the bronchoscope, initiating a rapid freeze-thaw cycle that induces cellular damage. Notably, the freeze-thaw process can release tumor antigens, potentially eliciting an immune-mediated response against cancer cells (81). Cryotherapy shows particular promise for peripheral lesions, and its immunomodulatory effect is an area of active investigation (81).

PEF-based techniques, sometimes referred to as irreversible electroporation, use high-voltage electrical pulses to create nanopores in tumor cell membranes (82). This disrupts cellular homeostasis and leads to cell death, without significant heat generation (83), and alters the local (and possibly systemic) immune landscape. Although still emerging in the context of bronchoscopic interventions, PEF may offer an alternative local therapy for select pulmonary lesions, especially in patients with compromised lung function where minimizing thermal damage may be advantageous, where the lesion is close to important structures that can be damaged by heat, and additional immune stimulation may be advantageous.

Laser ablation uses high-intensity laser light to target and destroy tumor tissue. The laser fiber is passed through a bronchoscope to the tumor site, where it heats the tissue to a temperature that causes coagulation and necrosis (84). Although laser can debulk obstructive tumors in the central airways (85), data supporting its use for peripheral lung lesions are limited, and it may be less relevant for early-stage MFLCs in the periphery. Consequently, laser ablation is generally placed after other ablation modalities when considering treatment options for peripheral disease.

Procedure details

Prior to the procedure, a CT scan or positron emission tomography-computed tomography (PET-CT) is performed to map the tumor locations and plan the best approach for biopsy and ablation. In the case of ENB, the imaging data is integrated with the electromagnetic navigation system for precise localization. For RAB, the system’s 3D imaging is used to help identify the exact position of tumors in relation to the surrounding lung structures. Manufacturers recommend performing RAB under general anesthesia, while ENB may be done under either deep sedation or general anesthesia; once adequate anesthesia is achieved, the bronchoscope is introduced into the airways for navigation. With ENB, the electromagnetic navigation system provides real-time tracking, guiding the bronchoscope to the tumor site. Similarly, RAB uses robotic arms to maneuver the bronchoscope, offering greater stability and access to difficult-to-reach areas of the lungs. Once the target tumor is localized via either platform, a biopsy can be performed if needed. When ablation is indicated, the appropriate energy-based device such as a RFA catheter, MWA applicator (Figures 4,5), cryoprobe, or laser fiber, is inserted through the working channel of the bronchoscope to treat the lesion. After ablation, patients are monitored for complications such as bleeding, pneumothorax, or infection. In most cases, they can return home the same day or after a brief observation period.

Figure 4 RAB-guided MWA. (A,B) Robotic arm guided by the 3D navigation display positions the MWA probe through the working channel to the target lesion (yellow sphere). (C) Ablation power and time displayed on the console. (D) Intra-operative CBCT monitoring of the ablation zone. 3D, three-dimensional; CBCT, cone-beam computed tomography; MWA, microwave ablation; RAB, robotic-assisted bronchoscopy.

Figure 5 ENB-guided ablation. (A) ENB platform guiding the ablation probe through the working channel to the lesion (yellow), with predicted ablation zones (coloured ellipsoids). (B) Intra-operative CBCT assessment of the MWA zone (red outline as position of lesion). CBCT, cone-beam computed tomography; ENB, electromagnetic navigation bronchoscopy; MWA, microwave ablation.

Cone-beam CT (CBCT)-guided navigation enabled workflows

High-resolution CBCT has become integral to modern bronchoscopic navigation because it provides volumetric imaging in the procedural suite and allows immediate confirmation of catheter placement. Ceiling-mounted or robotic CBCT systems can be retracted away from the patient, facilitating patient access while limiting electromagnetic interference and allowing rapid transitions between fluoroscopy and three-dimensional imaging (86). By integrating with navigational bronchoscopy, these systems enable real-time verification of instrument-to-target alignment and dynamic updates for CT-to-body divergence, thereby increasing procedural confidence. Mobile C-arm CBCT units such as the Cios Spin offer a smaller footprint and lower cost but provide a more limited field of view and lower resolution due to power restrictions (87). Combining CBCT with shape-sensing or electromagnetic navigation therefore enhances lesion targeting, supports ablation trajectory planning and underpins the workflow for complex multi-lesion procedures.

Recent platform innovations now embed intraprocedural CBCT imaging directly into robotic bronchoscopy systems to facilitate divergence correction. The Ion Endoluminal System (Intuitive), for instance, integrates with CBCT such that intraoperative scans feed into its navigation software, allowing catheter repositioning and tool-in-lesion verification via fused 3D imaging during the procedure (88). More recently, Johnson & Johnson announced regulatory clearance for Monarch Quest, an enhanced iteration of the Monarch platform that supports AI-powered navigation and explicit compatibility with mobile CBCT systems such as OEC 3D (GE HealthCare, Chicago, USA), enabling real-time fusion of volumetric imaging and robotic guidance for improved targeting accuracy in lung nodule procedures (89). These developments illustrate a trend toward synergetic imaging-robotic systems, wherein robotic navigation and live volumetric imaging are not merely adjunctive but co-integrated to improve spatial precision, reduce repositioning, and increase confidence in multi-lesion bronchoscopic interventions.

Safety and efficacy

RFA and MWA are two widely studied thermal ablation techniques with proven safety and efficacy in the management of small peripheral lung tumors. One meta-analysis of ten studies comparing these methods found that RFA may offer slightly better overall survival (OS) and progression-free survival (PFS), whereas MWA had shorter ablation times (90). Both showed similar complication profiles, with pneumothorax, pleural effusion, and subcutaneous emphysema being among the most frequent adverse events. Another systematic review focusing on MWA reported local recurrence rates from 9% to 37%, primarily influenced by tumor size, especially lesions larger than 3–4 cm, and study era (91). Although pneumothorax remains the most common complication, severe adverse events are relatively rare, reinforcing the viability of thermal ablation in patients who cannot undergo surgical resection. Building on the success of RFA and MWA, bronchoscopic delivery of these techniques is increasingly explored, particularly through advanced navigation platforms such as RAB and ENB. Image-guided such as RFA and MWA have achieved low local recurrence rates for small peripheral tumors, highlighting their effectiveness (92). Overall, complication rates such as pneumothorax and bleeding are relatively low, highlighting the safety profile of these interventions (62,77). Moreover, a recent retrospective single center in Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital found technical success rates (93.3% vs. 97.0%, P=0.68), 6-month complete ablation rates, (96.7% vs. 95.5%, P>0.99), 12-month local control rates (95.0% vs. 95.5%, P=0.62), 12-month PFS rate (91.7% vs. 90.9%, P=0.62) were all high and similar between ENB MWA and CT-guided percutaneous transthoracic MWA, respectively. And the ENB MWA group had a significantly lower pneumothorax requiring thoracentesis rate (3.3% vs. 18.8%, P=0.006) (55). Collectively, these findings underscore the safety and efficacy of bronchoscopic ablation in the treatment of MFLCs, including both primary and metastatic tumors, particularly in patients who are poor surgical candidates. Furthermore, employing robotic or navigational platforms potentially expands the scope of ablation to more distal or anatomically complex lesions, thereby reducing the need for extensive surgery or systemic therapy in select cases.

Critical appraisal of RAB/ENB evidence

RAB and ENB biopsy against CT-TTNB/TTNA provide important insights but also illustrate the limitations of the evidence base. The VERITAS randomized trial is the only multicenter RCT directly comparing navigational bronchoscopy with CT-TTNA for indeterminate nodules, and it enrolled 234 patients (5 of whom were lost to follow-up) including 119 patients with navigational bronchoscopy and 110 patients with TTNB/TTNA. Despite its rigorous design, the study was industry-funded and excluded lesions located at the lung apex or arising within 1 cm of the pleura, limiting generalizability (53). Most other evidence derives from single-arm or retrospective cohorts. For example, the comparative cohort study by Low et al. used prospectively collected data from a single center including 143 RAB vs. 197 ENB biopsies, yet selection bias and reliance on operator experience are potential confounders (54). Similarly, the large retrospective study of 900 CT-TTNA vs. 106 ENB biopsies by Chaudry et al. acknowledged limitations including lack of standardized confirmation, high loss to follow-up and verification bias, absence of radial endobronchial ultrasound (EBUS) data and sedation differences, and the single-center nature of the dataset (52). Multicenter real-world evaluations of RAB reported by Khan et al. including 264 patients show diagnostic yields but are retrospective and subject to definition variability and absence of comparison groups (57). Moreover, meta-analyses provide pooled estimates but highlight heterogeneity and bias. A systematic review of 95 navigational bronchoscopy studies including 10,682 nodules reported diagnostic yields of different navigation technique including CBCT, ENB, RAB or virtual bronchoscopy, but 63 studies had high risk of bias or applicability concerns (58). Another meta-analysis restricted to RAB studies (25 studies, 1,779 lesions) also observed significant heterogeneity (I²=65.6%) and concluded that differences in study design, operator experience, adjunct imaging modalities, and definitions of diagnostic yield contributed to variability (59). Collectively, the predominance of retrospective, single-center studies, small sample sizes, and industry funding introduces selection and verification bias, limits external validity, and precludes robust head-to-head comparisons of RAB and ENB technologies. Uniform definitions of diagnostic yield and standardized protocols are needed, and future research should include randomized or well-designed prospective multicenter trials evaluating long-term outcomes and cost-effectiveness.

Evidence supporting bronchoscopic ablation using RAB or ENB platforms remains in early stages, comprising small non-comparative cohorts, retrospective case series, and pilot trials. The most rigorous prospective study to date is the multicenter single-arm trial of image-guided transbronchial MWA, and it enrolled 10 patients (11 tumors) and used CBCT and navigational bronchoscopy. Technical success and complete ablation were achieved in all cases, but the trial was halted after one unexpected death, and investigators acknowledged that the small cohort limited statistical analyses (93). Although this multicenter design provided standardized procedures and rigorous follow-up, the absence of a control group, short follow-up duration, and industry sponsorship raise concerns regarding generalizability and potential bias. A recent single-center retrospective study reviewing 26 cases of ENB-guided MWA compared three strategies including simultaneous video-assisted thoracic surgery (VATS) plus MWA, VATS followed by the second period ENB-guided MWA, and ENB-guided MWA alone, and found that ENB-guided MWA was feasible in patients with poor pulmonary reserve. However, the study acknowledged that the group receiving only ENB-guided MWA had worse baseline pulmonary function and a higher proportion of ground-glass opacities, introducing selection bias. With only 26 cases and no randomization, the study could not establish superiority or long-term efficacy, and heterogeneity between treatment groups limits interpretation (19).

Emerging ablation technologies are even more preliminary. The first-in-human study of endobronchial ultrasound-guided bipolar RFA ablated five tumors prior to surgical resection, demonstrating feasibility and no immediate complications but providing only histologic ablation zones and lacking long-term oncologic outcomes (94). A prospective pilot study of bronchoscopic MWA via a flexible catheter treated 13 patients, yet limitations included small sample size, lack of consistent real-time imaging, and the use of two different catheter designs (95). Meta-analyses of bronchoscopic ablation remain scarce; the evidence base is dominated by studies funded or supported by device manufacturers, which may introduce publication bias. Overall, these preliminary data suggest that bronchoscopic ablation using RAB or ENB platforms is technically feasible and associated with low immediate complication rates, but the paucity of randomized or controlled studies, small sample sizes, heterogeneity in patient selection and ablation protocols, and industry sponsorship limit confidence in long-term safety and efficacy. Robust prospective trials with standardized endpoints and longer follow-up are needed to determine whether bronchoscopic ablation offers durable oncologic control and meaningful quality-of-life benefits compared with established percutaneous or surgical approaches.

Challenges and limitations

Current bronchoscopic techniques face several limitations when addressing MFLCs. Lesions located near large blood vessels or the pleura present significant challenges due to the risk of bleeding and potential damage to adjacent structures. Additionally, the size of tumors can affect the feasibility of bronchoscopic ablation; larger tumors may require multiple sessions or alternative treatments to achieve adequate control (61). The accessibility of peripheral lesions is also a concern, as navigating the bronchoscope to these areas can be technically demanding. These factors necessitate careful patient selection and may limit the applicability of bronchoscopic techniques in certain cases.

Bronchoscopic ablation, while minimally invasive, carries potential risks. Common complications include pneumothorax, pleural effusion, and parenchymal hemorrhage. Although most complications can be treated conservatively or with minimal therapy, physicians should be aware of rare but serious complications. Potentially fatal complications include massive hemorrhage, intractable pneumothorax due to bronchopleural fistula, pulmonary artery pseudoaneurysm, systemic air embolism, and pneumonitis (77,90). Other serious complications include injury to nearby tissues such as brachial nerve plexus, phrenic nerve, diaphragm, and chest wall; and infective complications including lung abscess, and empyema can rarely occur (59,91,92). Precautions to minimize risk should be taken whenever possible.

Currently, bronchoscopic ablation is not used for treatment of mediastinal or pulmonary lymph nodes as these tend to be centrally located and thermal ablation could cause collateral injury and severe complications. In addition, the tumors typically targeted are less than 3 cm in size, limited in part by ablation size of available technology. Studies on bronchoscopic ablation primarily include patients without lymph node or distant metastasis, as confirmed by CT or PET-CT, ensuring that the eligible nodules are effectively classified as T1N0M0. A small number of institutions, including our center, have started exploring bronchoscopic ablation in patients with multi-focal primary lung cancers and oligo metastases, with promising results demonstrating its safety and effectiveness (66,96). While bronchoscopic ablation is suitable for diagnosing and treating MFLCs patients, it is essential to rule out lymph node or distant metastasis through additional imaging tests to confirm limited disease to minimize the risk of future recurrence.

Although our center’s data showed that the 79 patients who underwent ENB MWA had a 100% OS rate at a median follow-up of 18.5 months, ablation site recurrence occurred in only 5 patients, 2 of whom also had widespread distant metastases (61). While bronchoscopic ablation techniques have shown promise in the short term, there is a need for further research to establish long-term outcomes and safety. Current studies often have limited follow-up periods, making it challenging to assess the durability of treatment effects and the incidence of late-onset complications. Long-term data are essential to determine the efficacy of bronchoscopic ablation compared to traditional surgical approaches and to understand its role in the overall management of MFLCs.

Future directions

Combining bronchoscopic techniques with other treatment modalities holds promise for improving outcomes in lung cancer management. For instance, integrating SBRT with immunotherapy has been recognized as a promising treatment option, especially in the metastatic setting (97). SBRT delivers high doses of radiation to tumors with precision, while immunotherapy enhances the body’s immune response against cancer cells. Early clinical evidence suggests that this combination can lead to improved tumor control and survival rates (98). Similarly, a study published by our center demonstrated that combining bronchoscopic ablation with surgical wedge resection or radiotherapy may offer synergistic effects, potentially leading to better local and systemic control of the disease (99). There is growing evidence that a combination of cryoablation and other treatments, including gefitinib or nivolumab, could enhance treatment efficacy and improve the prognosis of patients with advanced NSCLC (100,101). Ongoing research is exploring these combination approaches to establish optimal treatment regimens for patients with MFLCs.

Evidence from pilot studies has laid the foundation for several prospective trials evaluating navigation-guided ablation. Early single-centre reports of navigation bronchoscopy-guided MWA demonstrated 100 % technical success with minor complications and a 2-year local control rate of about 71 % (95), while CBCT-augmented flexible-probe ablation maintained pulmonary function and quality of life (93). Building on these findings, ongoing studies are assessing ENB-guided MWA combined VATS for synchronous bilateral multiple primary lung nodules [National Clinical Trial (NCT) 05662553] (102), and exploring flexible transbronchial microwave probe (NCT05786625, NCT06158971) (103,104). PEF ablation programmes are also progressing. The AFFINITY trial (NCT05890872) has completed enrollment and is assessing Galvanize Aliya System (Redwood City, California) PEF delivered bronchoscopically or percutaneously in 30 patients with stage IV NSCLC or lung metastases (105). And early reports note that high-voltage, short-duration pulses achieve non-thermal tumor cell death with minimal adjacent tissue injury and may stimulate systemic immunity (106). In a neoadjuvant two-arm study, PEF energy was delivered bronchoscopically to 36 early-stage NSCLC patients about 20 days before resection without any device-related adverse events (107), and additional early- and late-stage trials (NCT06739031, NCT05583188, NCT05987345) are underway or recently completed (108-110). Platform maturation is underscored by the randomized VERITAS trial, where contemporary navigation bronchoscopy achieved a 76 % diagnostic yield, equivalent to CT-guided biopsy, but with markedly fewer pneumothoraces and hemorrhagic complications (111). Collectively, these studies will clarify the role of platform-enabled ablation in MFLCs management and guide the integration of bronchoscopic therapies with systemic and surgical treatments.

Advancements in molecular biology and genomics are paving the way for personalized treatment strategies in lung cancer. By analyzing the genetic and molecular characteristics of individual tumors, clinicians can tailor bronchoscopic interventions to the specific needs of each patient. This personalized approach may involve selecting the most appropriate bronchoscopic platforms, such as RAB or ENB, based on tumor location and accessibility. Additionally, integrating molecular profiling with treatment planning can help identify patients who are likely to benefit from combination therapies, including targeted therapies and immunotherapy. Implementing personalized treatment plans is expected to enhance treatment efficacy, minimize unnecessary procedures, and improve overall patient outcomes. The concise, bullet-point summary of the core management principles for MFLCs was shown in Table 3.

Clinical integration and practical algorithms

In managing MFLCs, RAB and ENB platforms are best viewed not as standalone tools but as integral components within a multidisciplinary decision pathway (Figure 6). Before outlining the practical algorithm, two working concepts should be defined: the dominant lesion and the other lesions. The dominant lesion denotes the nodule most likely to drive management decisions, typically characterized by a greater solid component, more rapid interval growth, and higher FDG uptake on PET-CT; importantly, it is not necessarily the largest nodule. Other lesions generally correspond to subsolid, GGO-predominant nodules with low or absent FDG avidity and slow growth. Final categorization should integrate pulmonary reserve, the cumulative risk associated with multiple resections, age and comorbidities, and patient preference (112-114). After initial review at a tumor board, patients undergo thin-cut chest CT with or without PET-CT and formal assessment of pulmonary function. Tissue diagnosis and staging are performed before treatment selection, typically with navigational bronchoscopy (± EBUS) to distinguish multiple primary tumors from IPM based on histology and, where feasible, molecular profiling; when safely achievable, biopsy of at least two lesions with next-generation sequencing is preferred to maximize discriminatory power and inform individualized planning (115,116). For good surgical-risk patients with single-lobe, peripheral tumors ≤2 cm, contemporary randomized trials support anatomic segmentectomy as an oncologically sound option (117,118); for lesions >2 cm or central disease, lobectomy remains preferred when pulmonary reserve permits. For moderate/poor surgical-risk patients, parenchymal-sparing strategies are prioritized: peripheral lesions ≤3 cm are candidates for bronchoscopic ablation, whereas larger or central lesions often favor SBRT with surgery reserved for carefully selected cases. When disease spans multiple lobes, a hybrid strategy is considered: surgical management of the dominant lesion according to the above size/location criteria, with bronchoscopic ablation and/or SBRT for additional nodules to preserve lung parenchyma. Importantly, RAB/ENB platforms facilitate sequential access to multiple lesion in the one anesthetic when pre-planned by the tumor board, enabling biopsy of several nodules and, in selected cases meeting predefined criteria, immediate local therapy in that same sitting; this approach has shown technical feasibility and workflow efficiency in series of concomitant transbronchial ablation (18,66). This integrated algorithm centers RAB/ENB as enablers of precise diagnosis, pathologic/molecular triage, and parenchymal-sparing local therapy selection across the spectrum of MFLC presentations.

Figure 6 The flowchart of clinical integration of RAB and ENB in the management of MFLCs. CT, computed tomography; EBUS, endobronchial ultrasound; ENB, electromagnetic navigation bronchoscopy; MDT, multidisciplinary tumor; MFLCs, multi-focal lung cancers; PET-CT, positron emission tomography-computed tomography; RAB, robotic-assisted bronchoscopy; SBRT, stereotactic body radiation therapy.

Conclusions

In summary, the management of MFLCs requires a delicate balance between effective local control and preservation of pulmonary function. Traditional surgery and radiotherapy remain important pillars of treatment, yet their applicability is often limited in patients with multiple lesions, unfavorable anatomy, or impaired lung reserve. In this context, RAB and ENB have emerged as enabling technologies that extend diagnostic and therapeutic options. By integrating high-precision navigation, real-time imaging, and compatibility with ablative instruments, these platforms permit tissue diagnosis, molecular profiling, and targeted ablation within a single workflow. Their incorporation into multidisciplinary treatment algorithms facilitates hybrid strategies that combine resection, bronchoscopic ablation, SBRT, and systemic therapy according to lesion size, location, and individual surgical risk, thereby expanding therapeutic eligibility while preserving lung parenchyma. Looking ahead, ongoing research and clinical trials are essential to validate the long-term efficacy and safety of bronchoscopic ablation techniques, optimize procedural protocols, and define patient selection criteria. The continued evolution of bronchoscopic navigation technologies holds great promise for expanding treatment options and integrating these approaches into personalized management strategies for patients with complex pulmonary conditions. Nevertheless, this review is limited by its narrative design and restriction to English-language publications, which may introduce bias and exclude relevant evidence available in other languages.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-943/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-943/prf

Funding: This study was supported by the Research Grant Council (RGC), Hong Kong (grant 2022/23, ref No. 14111222).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-943/coif). R.L. reports receiving consulting fees from Medtronic and Siemens Healthineer. C.N. reports receiving consulting fees from Johnson and Johnson, Medtronic, Olympus and Siemens Healthineer. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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