Presurgical invasive mediastinal staging in lung cancer, unexpected N2 and long-term survival: a registry-based study with data from the Spanish group for video-assisted thoracic surgery

Introduction

Mediastinal lymph node staging is a key element in the diagnosis of lung cancer (1). The combination of computed tomography (CT) and positron emission tomography (PET) has improved staging (2,3). Some circumstances are known to influence their negative predictive value: tumour over 3 cm, centrally located or cN1 involvement (4-8). The 2014 clinical guidelines of the European Society of Thoracic Surgeons (ESTS) for the management of mediastinal staging recommend invasive staging in these circumstances (9). Other updated clinical guidelines still recommend this (10). Nonetheless, despite the multiple diagnostic procedures, it is not feasible to completely avoid unexpected mediastinal lymph node involvement (11,12). Further, there is a paucity of evidence on the long-term effect of not performing the recommended pre-surgical mediastinal staging (13).

We conducted a real-world study to assess the impact of avoiding the invasive procedures recommended by the guidelines on rates of unexpected pN2 and long-term survival in surgical lung cancer with data obtained from the prospective cohort of the Spanish Group for Video-Assisted Thoracic Surgery (GEVATS) of the Spanish Society of Thoracic Surgery (SECT) (14). This manuscript is written following the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1900/rc).

Methods

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research project was approved by all the ethics committees of the participant centres and patients recruited gave written informed consent to the use of the clinical data for scientific purposes. The name and registration number of each Institutional Review Board are available upon request.

Study design and patients

We conducted an observational study using data from a prospective registry. The GEVATS project of the SECT was launched in May 2015 to study the implementation of the video-assisted thoracic surgery (VATS) approach in Spain. A multicentre prospective cohort study was designed to include all anatomical lung resections performed in the 33 Spanish centres; which lasted for over a 15-month period (20 December 2016–20 March 2018). Further details of the database characteristics, auditing methods, and variables included are available elsewhere (14).

The follow-up was completed in 30 centres up to July 2022 (mean length of 51.4 months). We selected patients with a diagnosis of lung cancer and negative mediastinal CT and PET findings. Lymph nodes more than 1 cm in diameter were considered positive in CT, while PET findings were classified as positive by researchers based on the reference values used at their centre. We selected patients who had a tumour over 3 cm, centrally located or cN1. Tumour size was measured on CT images as the longest diameter. The tumour was considered peripheral if the centre of the tumour was in the outer third of the lung field considering the radial distance from the lung hilum to the periphery. If any N1-node was positive on CT or PET, the disease was classified as cN1.

Mediastinal staging

Patients were divided into two groups as a function of whether they had undergone any invasive procedure for mediastinal staging: endobronchial ultrasound (EBUS), mediastinoscopy or other. We compared the results of these invasive and non-invasive groups (IG and NIG respectively).

Outcomes

The rate of unexpected pN2 was compared between these two groups. For the NIG group the number of unexpected pN2 was based on the findings of the post-surgical pathological analysis. In the IG group, pN2 was considered unexpected if they had pathological N2 in the invasive test prior to surgery or in the post-surgical analysis. Additionally, we compared overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) between IG and NIG groups. We analysed OS in the subgroup of pN2 patients.

Variables

We included variables that might influence the rate of unexpected pN2 and/or survival.

The following variables were included:

• Patient-related variables: age, sex, body mass index, smoking habits, comorbidities, lung function parameters and previous lung cancer.
• Surgery-related variables: approach, type of resection, and total number of lymph nodes removed in the lymphadenectomy.
• Tumour-related variables: radiological tumour density, size in the CT, maximum standardized uptake value (SUVmax) on PET, histological type, synchronous tumour, pT and pN.

Statistical analysis

Quantitative variables were presented as mean and standard deviation and qualitative variables as absolute and relative frequencies expressed as percentages. Qualitative variables were compared with Chi-squared or Fisher’s exact tests as appropriate. Similarly, quantitative variables were compared with Student’s t- or Mann-Whiney U tests, or analysis of variance or Kruskal-Wallis tests, as appropriate.

For survival analysis, OS, CSS, and DFS were assessed using Kaplan-Meier curves and Log-rank tests. Univariable analysis was performed to identify variables related to OS. Any variables with a P value <0.20 were included in a Cox multivariable regression model. We used the pairwise deletion technique as a method of handling the missing data.

The statistical analysis was carried out using STATA version 16.1 (StataCorp, Texas, USA).

Results

Patients

We identified 2,826 patients who underwent lung cancer surgery, and of these, 2,132 had negative mediastinum in CT and PET. We selected those with tumour sizes >3 cm (769/36.1%), central tumours (789/37%), and/or cN1 (310/14.5%). The final sample was composed of 1,247 patients (Figure 1).

Figure 1 Flow chart of patients included in the study. GEVATS, Spanish Group for Video-Assisted Thoracic Surgery; CT, computed tomography; PET, positron emission tomography.

Mediastinal staging

Out of the 1,247 patients included in the analysis, 275 (22.1%) underwent invasive mediastinal staging. The criterion most commonly met for performing invasive procedures was the presence of cN1 and the method most commonly used was EBUS, especially in cases of cN1 (Table 1).

Patient characteristics

Table 2 shows the comparison of clinical characteristics between the two groups (IG and NIG). Significant differences in patient, tumour and surgical characteristics were detected.

Unexpected pN2

The overall rate of unexpected pN2 disease was 13.8% and 9.6% (P=0.04), in IG and NIG (Table 3). The factor most commonly associated with unexpected pN2 was cN1 (Table 3). The higher the number of these factors, the higher the risk of pN2 (Table 3). In the IG, 19 out of 38 (50%) unexpected N2 were discovered in the invasive staging test prior to surgery. Of these 19 patients, 10 received neoadjuvant treatment (6 chemotherapy and 4 chemo-radiotherapy).

Survival

Five-year OS was lower in the IG [52.4% (95% CI: 45.6–58.7%) vs. 64% (95% CI: 60.6–67.3%) in the NIG, P<0.001; Figure 2]. Similar results were observed for lung CSS and DFS.

Figure 2 Overall survival according to the mediastinal staging group. NIG, non-invasive group; IG, invasive group; CI, confidence interval.

In the multivariable model for OS, male sex, older age, diabetes mellitus, lower percentage of predicted diffusion capacity of the lung for carbon monoxide (DLCO), larger tumour size on CT, synchronous tumour, higher pathological N-stage, and IG status were significant independent predictors of death (Table 4).

In the subgroup of patients with unexpected pN2, there were no significant differences in 5-year OS between the IG and NIG (40.1% vs. 46%, P=0.56; Figure 3).

Figure 3 Overall survival according to the mediastinal staging group in the subgroup of patients with pN2. NIG, non-invasive group; IG, invasive group.

Discussion

In this real-world study, with a highly representative sample of major lung resections carried out in Spain for lung cancer (14), we have obtained evidence concerning the real management of mediastinal clinical staging and its long-term consequences. In a group of patients with a negative mediastinum in CT and PET, but with risk factors for unexpected pN2, and hence, in whom clinical guidelines recommend invasive staging, only 22% of operated patients actually underwent that mediastinal invasive staging. Nonetheless, the patients who had not undergone invasive staging were not more likely to have pN2 disease and nor did they have poorer long-term survival.

The rate of invasive staging was lower in patients with tumours measuring >3 cm or centrally located (around 23%), but significantly higher in those with cN1 disease compared to cN0 (41%). This can be attributed to their greater risk of pN2 (6,15), but is probably also related to the diagnosis of N1 lymph nodes. This is reflected in a wider use of EBUS in patients with cN1. The observed practice is not in line with the ESTS and other guidelines recommendations. According to some authors, this aspect of staging is the one with the greatest variability in lung cancer (16). Specifically, across five hospitals in the USA, Thornblade et al. observed that invasive staging rates ranged from 17% to 94%, differences that were not explained by clinical stage. In the Danish Lung Cancer Registry, 66% of stage I patients underwent invasive staging (17), while in more recent data from the Italian VATS registry, in which 2.6% of cases had cN1 disease, 22.1% cT2, and 1.8% cT3, only 3.5% of patients underwent invasive staging (18).

Not adhering to the recommendations on mediastinal staging and performing a less thorough work-up might lead to higher rates of unexpected pN2 disease. In our series, in the group without invasive testing the unexpected N2 was 9.6% while in the group with invasive testing with a 13.8% of unexpected N2, a half of them were discovered prior to surgery. These rates are similar to that in the Danish Registry (7.8%) with stage I and the Italian Registry (8.5%) with cN0 patients and tumour sizes >3 cm (17,19). Rates of unexpected pN2 tend to vary, ranging between 5% and 15% in the series published, and above all depend on patient selection (11-13,17,19-23).

Several risk factors for mediastinal lymph node involvement when CT and PET findings are negative have been studied. The key factors are the presence of a tumour size >3 cm (7,15,20,23,24), a centrally located tumour (4), and cN1 (6,15,25). Regarding the centrality criterion, there is no consensus and results may vary depending on the definition used (21,26). The strongest risk factor for pN2 is cN1 (6,15,25). In our study, we observed a significant difference in the rate of pN2 associated with cN1: 16.8% vs. 7.3% in patients with cN0. Nonetheless, there are other factors, such as histological type and SUVmax on PET, that have been shown to influence unexpected pN2 and should be taken into account (8,19,20). In a recent study based on the same GEVATS database, SUVmax on PET was an independent risk factor for unexpected lymph node involvement (27). It is also important to assess the combination of several factors. Including six factors, Farjah et al. obtained a negative predictive value of 100% (15). In our previous study using GEVATS data, considering the three factors proposed by the ESTS, the rate of unexpected pN2 increased from 4.5% with no risk factors to 18.8% in the presence of all three (28). Similar results were observed in the present study. In some studies, patients undergoing invasive staging have had higher rates of unexpected pN2 (12,13,17). This may be the result of tumour boards’ work to optimise the selection of patients for invasive mediastinal staging, focusing on those with a higher pretest probability of pN2 based on multiple risk factors (12).

Despite the numerous articles on risk factors for unexpected pN2 (7,9,12,15,19,21,23,24), there is a paucity of evidence concerning the consequences in terms of survival when clinical mediastinal staging is less exhaustive or guidelines are not followed (13,16). Thornblade et al. showed great variability in mediastinal staging between centres but did not provide data on long-term outcomes (16). In our study, we selected a group of patients for whom invasive mediastinal staging was recommended by the guidelines (9,10). And notably, the 5-year survival rate was higher in patients who did not undergo invasive procedures for staging (64% vs. 52.4%). Further, they did not show poorer cancer-specific or DFS. Results in other studies have been similar, with greater survival among patients not invasively staged (13,17). As can be observed in our data, this is achieved through the selection of patients for invasive staging, with a higher risk for mortality. Boada et al. also found a worse risk profile in patients with invasive staging (13). Nevertheless, after adjusting for other factors in the multivariable analysis, being in the invasively-staged group was still a risk factor.

Analysing the subgroup of patients with pN2, we also found longer survival in the non-invasively-staged group, although this difference did not reach statistical significance. Boada et al. reported non-significant poorer survival in their pN2 non-invasively-staged group. Probably, through invasive staging, a group of pN2 patients with a better prognosis could be selected. In our study, in patients with pN2, we observed 5-year survival rates of 40.1% vs. 46% in the IG and NIG, respectively. Similar survival rates have been found in other studies (11,20,29).

It is important to properly select patients for invasive mediastinal staging, but it is just as important to identify those in whom we could avoid unnecessary invasive procedures. In this way, we can optimise the use of resources, reduce the likelihood of complications associated with the diagnosis, and reduce patient time to referral for surgery. In our series, 78% of patients with surgical treatment did not undergo invasive mediastinal staging, despite the recommendations in the clinical guidelines. Likely thanks to rigorous selection, this has not resulted in either higher rates of unexpected pN2 or poorer long-term survival. As pointed out by other authors, increasing the rate of invasive staging does not avoid the occurrence of pN2, and therefore, thorough examination of the lymph nodes during surgery is still essential (12).

On the other hand, given that the main benefit of identifying N2 before surgery is to be able to provide neoadjuvant therapy, it would be interesting to have stronger evidence on its superiority over adjuvant therapy, to justify more invasive mediastinal staging. Based on data in the literature, Decaluwé and Dooms estimated that between 580 and 2,900 invasive procedures would be necessary to save one life after 5 years (30). There is still no consensus on the best time to give complementary chemotherapy (31). Fiorelli et al. compared 27 patients with confirmed cN2 given neoadjuvant chemotherapy with 61 patients with unexpected pN2, and after adjusting with propensity score matching, the latter group had a longer median survival (56 vs. 20 months) (20). Overall, in the presence of negative CT and PET mediastinal findings, it may not be justifiable to increase the use of invasive mediastinal staging procedures to achieve a relatively small reduction in the rate of pN2 without a clear benefit from providing therapies before surgery.

Limitations

The prospective database was not designed for the purposes of the study. Therefore, differences in survival observed between the study groups may be influenced by uncontrolled factors. Nonetheless, it does provide data on the main factors usually considered in survival studies for lung cancer.

We analysed survival of all patients with any of the risk factors for unexpected pN2 considered overall but have not examined each factor in isolation. Numerous patients have various risk factors simultaneously and we wanted to maximise the sample sizes in the comparison groups.

The type of lymphadenectomy performed and total number of lymph nodes removed may have an impact on upstaging (27). Given the multicentre nature of this study, there may be considerable variability in protocols for surgical lymph node staging. Fewer lymph nodes were removed in the invasively-staged group (a median of 7 vs. 8). Nevertheless, we included the number of lymph nodes in the multivariable analysis. In any case, this study provides real-world evidence on rates of unexpected pN2 and survival obtained with lymphadenectomy as currently performed in Spain.

Conclusions

Regarding the staging of surgical lung cancer, when CT and PET mediastinal results are negative, we believe that it is justifiable to use invasive staging procedures less often than recommended in the guidelines, as is already occurring in routine clinical practice. In a group of patients with risk factors for unexpected mediastinal lymph node involvement, we did not observe a higher rate of unexpected pN2 or poorer survival when the recommended invasive staging had not been performed.

Acknowledgments

We thank Johnson & Johnson for their collaboration in the development of the Spanish VATS Group. We also thank all those who are responsible for the clinical documentation services of each hospital for actively participating in the audit of the datasets. The GEVATS members are as follows: José Luis Recuero Díaz and Juan Diego Avilés Parra (University Hospital Miguel Servet and Lozano Blesa; IIS Aragón, Zaragoza); Julio Sesma Romero (University General Hospital of Alicante, Alicante); Sergio Amor-Alonso and Francisco Javier Moradiellos-Díez (Quironsalud Madrid University Hospital, Madrid); Miguel Jesús Arrarás (Valencian Oncology Institute Foundation, Valencia); Ana Isabel Blanco Orozco (University Hospital Virgen del Rocío, Sevilla); Marc Boada and David Sánchez (Hospital Clinic of Barcelona, Respiratory Institute, University of Barcelona, Barcelona); Alberto Cabañero Sánchez and Nicolás Moreno Mata (Ramón y Cajal University Hospital, Madrid); Isabel Cal Vázquez and Ramón Moreno-Balsalobre (University Hospital La Princesa, Madrid); Ángel Cilleruelo Ramos (University Clinical Hospital, Valladolid); Silvana Crowley Carrasco and David Gómez de Antonio (University Hospital Puerta de Hierro Majadahonda, Madrid); Elena Fernández-Martín and Florentino Hernando Trancho (Hospital Clínico San Carlos, Madrid); Santiago García-Barajas and Cipriano López García (University Hospital of Badajoz, Badajoz); Maria Dolores García-Jiménez (University Hospital of Albacete, Albacete); Jose María García-Prim and Eduardo Rivo (Santiago de Compostela University Hospital, Santiago de Compostela); Jose Alberto Garcia-Salcedo (12 de Octubre University Hospital, Madrid); Juan José Gelbenzu-Zazpe and María Elena Ramírez-Gil (Complejo Hospitalario of Navarre, Pamplona); Carlos Fernando Giraldo-Ospina and Roberto Mongil Poce (Hospital Regional Universitario, Málaga); María Teresa Gómez Hernández and Marcelo Jiménez López (Salamanca University Hospital, University of Salamanca, IBSAL, Salamanca); Jorge Henández and Juan José Fibla Alfara (Sagrat Cor University Hospital, Barcelona); Jennifer D. Illana Wolf (Puerta del Mar Hospital, Cádiz); Alberto Jauregui Abularach and Fernando Ascanio Gosling (Vall d´Hebron University Hospital, Barcelona); Unai Jiménez Maestre and Rafael Rojo Marcos (University Hospital Cruces, Bilbao); Néstor J. Martínez-Hernández (La Ribera University Hospital, Alcira, Valencia); Elisabeth Martínez-Téllez and Juan Carlos Trujillo Reyes (Santa Creu and Sant Pau Hospital, Autonomous University of Barcelona, Barcelona); Lucía Milla Collado and Mario Montesinos Escalada (Arnau de Vilanova Hospital, Lleida); Sergio B. Moreno Merino, Miguel Congregados Loscertales, Ana Isabel Triviño Ramírez and Marta López Porras (Virgen Macarena University Hospital, Sevilla); Carme Obiols Fornell and Sergi Call Caja (Mútua Terrassa University Hospital, University of Barcelona, Terrasa, Barcelona); Florencio Quero-Valenzuela (Virgen de las Nieves Hospital, Granada); Ricard Ramos-Izquierdo (University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona); Alberto Rodríguez-Fuster (Hospital del Mar, Hospital del Mar Medical Research Institute, Barcelona); and Carlos Simón (Gregorio Marañón University Hospital, Madrid).

Funding: The creation and maintenance of the database were supported by Ethicon, Johnson & Johnson. The authors had freedom of investigation and full control of the design of the study, methods used, outcome parameters and results, data analysis, and production of the written report.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1900/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1900/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1900/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1900/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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research project was approved by all the ethics committees of the participant centres and patients recruited gave written informed consent to the use of the clinical data for scientific purposes. The name and registration number of each Institutional Review Board are available upon request.

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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