Editorial commentary: the importance of staging hasn’t changed, but the procedure of choice has

Introduction

Current staging for non-small cell lung cancer (NSCLC) includes the utilization of computed tomography (CT) and 18F-flurodeoxygluocse positron emission tomography (FDG-PET) imaging to detail tumor size, density, and avidity. In addition, patients with a high suspicion of hilar or mediastinal lymph nodes on imaging (CN1–3), centrally located tumors, FDG-non-avid, or large (>3 cm) peripheral tumors are recommended to have mediastinal nodal staging obtained prior to proceeding with surgical resection (1,2). Although mediastinal lymph node staging has traditionally been performed by cervical mediastinoscopy, increased utilization of endosonographic-assisted endobronchial biopsies has become commonplace in 2023 (3). The ASTER trial, reported in 2010, provoked debate regarding the addition of confirmatory mediastinoscopy following negative endoscopy after results demonstrated a 79% sensitivity for mediastinoscopy to detect nodal metastases compared with 85% for endosonography alone (4). Since that time, other smaller trials have investigated the utility of confirmatory mediastinoscopy under circumstances where endosonographic staging is negative (5-9). Bousema and colleagues (10) have embraced this clinical question in the format of a trial, and in their manuscript entitled “Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial”, they have demonstrated that confirmatory mediastinoscopy can be omitted in patients with resectable NSCLC cN2–3 after negative endosonography.

This trial is timely, as clinical practice across the United States has significantly leveraged the less invasive nature of endosonographic hilar and mediastinal lymph node sampling for NSCLC, particularly in institutions that have dedicated proceduralists that perform these cases in high numbers. Therefore, not only publishing these results but also discussing their clinical application has significant value.

MEDIASTrial study

In their manuscript, Bousema and colleagues established a well-designed, comprehensive randomized clinical trial enrolling 360 patients with resectable NSCLC who underwent preoperative endosonographic mediastinal lymph node staging, and then either cervical mediastinoscopy to confirm node negativity or surgical resection (10). The rate of N2 upstaging by mediastinoscopy (7.7%) was found to be non-inferior in their intention to treatment analysis when compared to the direct surgical resection group (8.8%) and in doing so, Bousema demonstrated the non-inferiority of endosonography alone in the absence of nodal metastases for resectable NSCLC (10). This trial was appropriately conceived, had very few dropouts in each study group, and contained study participants that would be considered exchangeable to most NSCLC patients in the United States. In their conclusions, Bousema and colleagues described a non-inferior rate of unforeseen ‘upstaging’ of N2 disease for their endosonographic-only group. The methodology, statistical assessment, and selection of patients/sample size were appropriate given the results they have reported.

With this report, Bousema and colleagues challenge current National Comprehensive Cancer Network (NCCN) guidelines and conclude that omission of confirmatory mediastinoscopy is not associated with a significant risk for upstaging of patients, and therefore the performance of confirmatory mediastinoscopy is not necessary for appropriately selected patients and in centers were endosonographic biopsy is routinely performed. Bousema also reported comparable 30-day morbidity and mortality in both study groups, which are conclusions that support their prior work investigating the rate of incidental N2 disease after negative endosonography (11).

The analysis of Bousema and colleagues adds to a previous study by providing randomized data supporting the noninferiority of omitting mediastinoscopy (12). In addition, their manuscript serves as a guide for clinicians whose current practice might include mediastinoscopy to a more significant extent given preferences to follow NCCN guidelines which have not been updated to reflect these current trial results.

Discussion

The precedent for confirmatory mediastinoscopy has been established in previous studies which have suggested an increased sensitivity of 94% for detecting nodal metastases when performing mediastinoscopy following negative endosonography results (4). This emphasis is further represented in the 2022 NCCN Guidelines for NSCLC, which recommends confirmatory mediastinoscopy after cN0–1 endosonography in patients with cN1–3 disease (13). Thus, mediastinoscopy for staging has been widely considered particularly to confirm mediastinal disease in accessible lymph node stations. Although invasive, mediastinoscopy is associated with a low risk of associated complications which was demonstrated in this trial as well as in previous work (14).

Not unexpected, increased use of endosonography has led to significantly improved results, particularly when those procedures are performed with regularity by experts. In our institution, the percentage of patients staged endosonographically alone accounts for approximately 90% of NSCLC patients who meet NCCN guidelines, this is in sharp contrast to just 10 years ago when the opposite trend was observed. This is particularly relevant in an era of practice where increased utilization of neoadjuvant chemotherapy and immunotherapy, as well as the need for tumor genotyping, drives clinical decision-making. Foregoing mediastinoscopy can be considered as Bousema has suggested, however, we do recommend some caution in applying these study results to all patients. Consideration of invasive mediastinal staging may still be appropriate in select cases: (I) the results of endosonographic biopsy could represent a false negative based on clinical suspicion and confirmation may alter the treatment decision towards non-surgical management (particularly if institutional experience with endosonographic staging is not at the expert level); (II) lymph node stations are not accessible during surgery (e.g., paratracheal lymph node stations during left-sided resection); or (III) in cases where the use of neoadjuvant therapy might have a significant impact on the conduct of a subsequent surgical procedure.

Although the application of these study results will be far-reaching, it is always important to consider what is best on a case-by-case basis. Clinical suspicion for N2 disease is an important driver for staging regardless of pathology results obtained endosonographically, particularly if the results contradict what might be expected.

Conclusions

Updates to the imaging algorithm for lung cancer are constantly changing as improvements in technology expand and our understanding of clinical practice evolves. Bousema and colleagues should be recognized for their creativity and timeliness in publishing a clinically relevant study that adds substance to the debate on performing confirmatory invasive mediastinoscopy. Although the indications for mediastinal staging, including tumor size >3 cm, enlarged hilar or mediastinal lymph nodes >1 cm, or PET avid lymphadenopathy remain, the preferred technique for staging has evolved in many institutions in the United States (3). Increased comfort and experience with endosonographic hilar and mediastinal lymph node assessment have improved results such that confirmatory mediastinoscopy is no longer required for all patients. However, it is important to continue to use clinical judgement and to evaluate patients on a case-by-case basis to determine appropriateness for invasive mediastinal staging particularly when the results might impact clinical decision making.

Acknowledgments

Funding: None.

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-23-22/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-22/coif). The 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/.

References

1. Vilmann P, Frost Clementsen P, Colella S, et al. Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). Eur J Cardiothorac Surg 2015;48:1-15. [Crossref] [PubMed]
2. Detterbeck FC, Boffa DJ, Kim AW, et al. The Eighth Edition Lung Cancer Stage Classification. Chest 2017;151:193-203.
3. Wahidi MM, Lee S, Cramer GR, et al. Sampling of Thoracic Lymph Nodes and Lung Lesions: Trends in Procedural Utilization. Respiration 2023;102:495-502. [Crossref] [PubMed]
4. Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304:2245-52. [Crossref] [PubMed]
5. Al-Ibraheem A, Hirmas N, Fanti S, et al. Impact of (18)F-FDG PET/CT, CT and EBUS/TBNA on preoperative mediastinal nodal staging of NSCLC. BMC Med Imaging 2021;21:49. [Crossref] [PubMed]
6. Dunne EG, Fick CN, Jones DR. Mediastinal Staging in Non-Small-Cell Lung Cancer: Saying Goodbye to Mediastinoscopy. J Clin Oncol 2023;41:3785-90. [Crossref] [PubMed]
7. Sanz-Santos J, Almagro P, Malik K, et al. Confirmatory Mediastinoscopy after Negative Endobronchial Ultrasound-guided Transbronchial Needle Aspiration for Mediastinal Staging of Lung Cancer: Systematic Review and Meta-analysis. Ann Am Thorac Soc 2022;19:1581-90. [Crossref] [PubMed]
8. Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess 2012;16:1-75. iii-iv. [Crossref] [PubMed]
9. Visser MPJ, van Grimbergen I, Hölters J, et al. Performance insights of endobronchial ultrasonography (EBUS) and mediastinoscopy for mediastinal lymph node staging in lung cancer. Lung Cancer 2021;156:122-8. [Crossref] [PubMed]
10. Bousema JE, Dijkgraaf MGW, van der Heijden EHFM, et al. Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial. J Clin Oncol 2023;41:3805-15. [Crossref] [PubMed]
11. Bousema JE, van Dorp M, Hoeijmakers F, et al. Guideline adherence of mediastinal staging of non-small cell lung cancer: A multicentre retrospective analysis. Lung Cancer 2019;134:52-8. [Crossref] [PubMed]
12. Bousema JE, van Dorp M, Noyez VJJM, et al. Unforeseen N2 Disease after Negative Endosonography Findings with or without Confirmatory Mediastinoscopy in Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. J Thorac Oncol 2019;14:979-92. [Crossref] [PubMed]
13. Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022;20:497-530. [Crossref] [PubMed]
14. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e211S-50S.