The role of confirmatory mediastinoscopy after negative endosonography: is it truly necessary?

In light of the rapid evolution of lung cancer treatment, precise disease staging has become of paramount importance. The current staging methodologies encompass both non-invasive (e.g., computed tomography and positron emission tomography) and invasive approaches (e.g., mediastinoscopy and endosonography). Radiography is routinely employed as the initial step in the staging process; nevertheless, it is insufficient on its own, necessitating a confirmatory tissue diagnosis. Therefore, mediastinoscopy was formerly regarded as the gold standard for evaluating suspected mediastinal lymph nodes (1), until endosonography demonstrated its superiority over mediastinoscopy regarding sensitivity and specificity (2). Observations of trends in clinical practice for mediastinal nodal staging were evident both in Europe and the United States, aligning with the ongoing evolution in this field (3,4). Subsequently, following the outcomes of the ASTER trial (5), authoritative guidelines from the American College of Chest Physicians, the European Society of Thoracic Surgeons, and the National Comprehensive Cancer Network have recommended the incorporation of mediastinoscopy after negative endosonography in cases of suspected hilar or mediastinal metastasis (cN1–3) in non-small cell lung cancer (NSCLC) (6-8).

Nevertheless, the practice of performing confirmatory mediastinoscopy following negative endosonography continues to be a topic of debate, particularly concerning aspects such as nodal metastasis detection rates, surgical timing, cost implications, and morbidity and mortality (9,10). Furthermore, a national Dutch retrospective analysis revealed a frequent omission of confirmatory mediastinoscopy following negative endosonography, with a comparable rate of unforeseen N2 detection when compared to individuals who underwent staging without adherence to current guidelines (11). Similarly, in North America, the use of confirmatory mediastinoscopy is not commonly applied for patients with negative outcomes after endosonography (3).

Given the aforementioned considerations, the current phase prompts the following question: What is the role of confirmatory mediastinoscopy following negative endosonography?

In reference to the “Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial” (MEDIASTrial), which significantly contributes to this discussion, the authors displayed comprehensive preparation regarding fundamental rationales before its execution, including the potential targeted population (12), patients’ preferences (13), and the existing status of clinical practice and research (9), as well as a comprehensive protocol with a specifically statistical plan (14,15). This is a valuable example for future research endeavours.

In the formal publication of the main results, the authors of the MEDIASTrial mainly indicated that the omission of mediastinoscopy following a negative endosonography did not result in a significant increase in the detection of unforeseen N2 involvement, which was based on a rigorous evaluation against an evidence-based non-inferiority margin (immediate resection vs. mediastinoscopy first: 8.8% vs. 7.7%) (16). Moreover, there was no statistically significant difference in major morbidity and 30-day mortality between the immediate resection group and the confirmatory mediastinoscopy group following a negative result by endosonography. Regarding the patients who underwent mediastinoscopy, 11 patients experienced complications. Notably, one of these 11 patients suffered a severe hematoma, which regrettably precluded the opportunity for lobectomy and lymph node dissection. Furthermore, the interval between endosonography and pulmonary resection was around 28 days, with an additional 10-day waiting period introduced by confirmatory mediastinoscopy. Besides, several patients could not continue the trajectory due to various reasons during the staging period. In such instances, the treatment for NSCLC had to be postponed, and in some cases, it was even abandoned, potentially decreasing the survival rate.

Although the ASTER trial (5) and one systematic review with meta-analysis (10) found a higher N2–3 prevalence by endosonoscopy followed by confirmatory mediastinoscopy, the long-term survival was not impacted (17). This survival outcome perhaps had associations with a delay between diagnosis and surgery of lung cancer. Additionally, with the development of perioperative systematic therapy, adjuvant therapy for resectable lung cancer, such as radiotherapy, target therapy, and immunotherapy, may contribute to improving long-term outcomes from N upstaging. Hence, in situations where patients exhibit unforeseen N2 involvement following pulmonary resection without confirmatory mediastinoscopy, these subsequent treatments emerge as a viable alternative for enhancing prognosis, particularly in the context of the rapidly evolving landscape of immunotherapy.

Immunotherapy has been gradually submitted for early-stage and locally advanced NSCLC. Within the framework of CheckMate 816 (18), it is noteworthy that immunotherapy as neoadjuvant therapy presents potential benefits in terms of enhancing long-term survival without a concurrent increase in adverse events. Recent reports from KEYNOTE-671 (19) and NADIM II (20) have also yielded positive outcomes regarding perioperative immunotherapy. Thus, for the judicious utilization of immunotherapy or other strategies related to systemic therapy in the management of NSCLC, it is imperative to attain accurate pretreatment staging for suspected nodal metastasis, alongside the provision of comprehensive biomarkers. Especially, the latest revision of the TNM stage suggests stratifying N2 by single and multiple stations, which will lead to different oncological treatments perioperatively. It seems difficult to completely reject mediastinoscopy in clinical practice. Because there may be certain cases, such as the need for diagnosing occult N2–3, yet to be precisely defined, the recommendation for confirmatory mediastinoscopy could be considered.

Regarding mediastinoscopy, advancements in technology and techniques have been somewhat constrained. Compared to conventional mediastinoscopy, the application of video-assisted mediastinoscopy has improved lymph node yield with lower complication rates, though the negative predictive value was found higher (21). The surgical scar on the neck remains a challenge for patients and surgeons (13). Moreover, general anaesthesia with tracheal intubation is still employed for this surgical procedure as it requires hyperextension of the neck, and the trachea is manipulated and compressed (22). Emphasizing the optimization of anaesthesia and analgesics should be a priority, aiming to minimize surgical inflammation.

In the realm of endosonography, advanced technology has been employed, such as robotic procedures. The PRECISION-1 study concluded that robotic bronchoscopy can enhance the capability to localize and puncture small peripheral pulmonary nodules (23). The robotic navigation system may increase the detection of suspected mediastinal lymph nodes. However, robotic-assisted procedures typically incur substantial healthcare expenses.

In the healthcare economy, previous data has indicated that mediastinoscopy incurs a higher cost in comparison to endosonography (24,25). So, if the primary goal is to enhance sensitivity in cases of suspected invasive mediastinal nodal staging when there are no nodes or negative nodes at the first puncture, it is conceivable that a cost-effective strategy could involve the repetition of a second endosonographic examination. Indeed, if the lymph nodes fall within the range of mediastinoscopy and the second puncture through endosonography is negative, some surgeons may opt for mediastinoscopy to prevent a third endosonoscopy, possibly mitigating healthcare costs in consequence.

When revisiting the MEDIASTrial, it is not impeccable. It is important to acknowledge that it may have been underpowered to draw definitive conclusions, especially considering the presence of unbalanced groups. This limitation has the potential to impact the sample size and, consequently, the generalizability of the findings. Additionally, the primary outcome setting in the MEDIASTrial may have influenced the conclusion to omit mediastinoscopy following a negative endosonography. Plus, there is an absence of patient-reported outcomes in the MEDIASTrial, such as quality of life and psychological assessment, which can provide patient-centred evidence to strengthen current conclusions.

As a consequence, the omission of mediastinoscopy following negative endosonography can be considered a justifiable practice while awaiting the emergence of more robust evidence. In addition, it is essential to compile further arguments both supporting and opposing the performance of mediastinoscopy after endosonography. Apart from the aforementioned reasons in favour of mediastinoscopy, it could serve as an alternative if future preoperative predictions based on radiological scans accurately identify suspected lymph nodes within the mediastinoscopy area, rather than solely within the scope of endosonography. Last but not least, taking lessons from the MEDIASTrial, future research endeavours should be oriented towards optimizing pretreatment staging methods and formulating relevant treatment strategies.

Acknowledgments

Funding: This work was supported by Post doc grants from Rigshospitalet (No. R163-A7357-B5343 to L.H.) and Novo Nordisk Fonden (No. NNF220C0079013 to R.H.P.).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-57/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-57/coif). L.H. received Post doc grant from Rigshospitalet (No. R163-A7357-B5343). R.H.P. in this work was supported by Investigator Initiated Clinical Trials Grant from Novo Nordisk Fonden (No. NNF22OC0079013). Additionally, R.H.P. reports consulting fees from AstraZeneca, MSD, BMS, Roche; speaker fee from Medtronic, Medela, AstraZeneca and AMBU; and is advisory board member for AstraZeneca, MSD, BMS and Roche. The authors have no other 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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