The Accuracy of Clinical Staging of Stage I-IIIa Non-Small Cell Lung Cancer

An Analysis Based on Individual Participant Data
Open AccessPublished:October 26, 2018DOI:https://doi.org/10.1016/j.chest.2018.10.020

      Background

      Clinical staging of non-small cell lung cancer (NSCLC) helps determine the prognosis and treatment of patients; few data exist on the accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival.

      Methods

      We used individual participant data from randomized controlled trials (RCTs), supplied for a meta-analysis of preoperative chemotherapy (± radiotherapy) vs surgery alone (± radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathologic TNM (pTNM) stage, for participants in the control group.

      Results

      Results are based on 698 patients who received surgery alone (± radiotherapy) with data for cTNM and pTNM stage. Forty-six percent of cases were cTNM stage I, 23% were cTNM stage II, and 31% were cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically overstaged. Agreement was not associated with age (P = .12), sex (P = .62), histology (P = .82), staging method (P = .32), or year of randomization (P = .98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%.

      Conclusions

      This study demonstrates suboptimal agreement between clinical and pathologic staging. Discrepancies between clinical and pathologic T and N staging could have led to different treatment decisions in 10% and 38% of cases, respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC.

      Key Words

      Abbreviations:

      IPD (individual participant data), NSCLC (non-small cell lung cancer), PET-CT (positron emission tomography-computed tomography), RCT (randomized controlled trial), SABR (stereotactic body radiotherapy)
      FOR EDITORIAL COMMENT, SEE PAGE 456
      The clinical staging of non-small cell lung cancer (NSCLC) is of paramount importance in determining a patient’s prognosis, guiding treatment decisions, and defining clinical trial eligibility, as well as allowing comparison between clinical trials. Incorrect staging of NSCLC may result in inaccurate prognostic information for patients and errors in patient treatment. After extrathoracic metastases have been excluded, tumor and nodal staging are critical in making treatment decisions, as patients with N0 and N1 involvement are generally candidates for surgery. Patients with ipsilateral mediastinal disease (N2) are a heterogeneous group and may be offered chemoradiation therapy or surgery (with preoperative or postoperative chemotherapy). Patients with contralateral (N3) mediastinal (or supraclavicular) nodal disease are offered chemoradiation therapy or palliative treatment options. Therefore, clinical understaging, that is, staging that misses mediastinal metastases or mediastinal invasion of the primary lesion, may risk the patient undergoing radical treatment of the primary lesion for no benefit. Conversely, incorrect clinical overstaging of mediastinal disease may result in surgery being denied to an otherwise operable patient. The current guidance from the Union for International Cancer Control
      • Brierley J.D.
      • Gospodarowicz M.K.
      • Wittekind C.
      TNM Classification of Malignant Tumours.
      suggests that when there is doubt about stage, the less advanced, or lower category should be chosen.
      The emergence of techniques such as stereotactic body radiotherapy
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      (SABR) and radiofrequency ablation
      • Lencioni R.
      • Crocetti L.
      • Cioni R.
      • et al.
      Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study).
      to treat early-stage NSCLC in medically inoperable patients has further highlighted the importance of accurate clinical staging. Applying local nonsurgical treatments without the benefit of systematic lymph node dissection runs the risk of being futile if there is clinical understaging with unrecognized mediastinal or systemic disease.
      Although the importance of accurate clinical staging is clear and the performance characteristics of individual tests in lung cancer staging are known, fewer data exist on the accuracy of clinical staging of NSCLC and how this relates to the staging techniques employed. Three studies that have been reported all show high levels of inaccurate clinical staging; however, none have demonstrated the impact of erroneous staging on clinical outcome. A prospective study of 383 patients with potentially resectable NSCLC demonstrated that clinically unsuspected N2 disease was found in 14% of patients. Despite routine use of positron emission tomography-computed tomography (PET-CT) scanning,
      • Cerfolio R.J.
      • Bryant A.S.
      • Ojha B.
      • Eloubeidi M.
      Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial.
      a post-hoc analysis of 67 patients from the control arm of the Medical Research Council LU225 trial of preoperative chemotherapy suggested that nodal staging was inaccurate in 25% (95% CI, 15%-36%) of patients who underwent PET-CT scanning and mediastinoscopy.
      • Navani N.
      • Nankivell M.
      • Stephens R.J.
      • et al.
      Inaccurate clinical nodal staging of non-small cell lung cancer: evidence from the MRC LU22 multicentre randomised trial.
      A study comparing clinical and pathologic TNM data, collected for 2,336 patients included in the Dutch Lung Surgery Audit,
      • Heineman D.J.
      • Geert ten Berge M.
      • Daniels J.M.
      • et al.
      The quality of staging non-small cell lung cancer in the Netherlands: data from the Dutch Lung Surgery Audit.
      showed that only 54% of patients were clinically staged accurately, and no comment could be made on whether this impacted on patient survival outcomes. Thus, to investigate further, we used individual participant data (IPD) from trials supplied for a systematic review and meta-analysis of preoperative chemotherapy in non-small cell lung cancer to assess the accuracy of clinical staging, factors that may affect inaccuracy, and how inaccuracy might impact on treatment decisions and survival.

      Methods

      To be eligible for inclusion in the original IPD meta-analysis,
      NSCLC Meta-analysis Collaborative Group
      Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data.
      trials should have randomized patients with NSCLC to preoperative chemotherapy followed by surgery (± postoperative radiotherapy) vs surgery (± postoperative radiotherapy). Full details of the methods are presented elsewhere.
      NSCLC Meta-analysis Collaborative Group
      Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data.
      IPD were collected for 15 eligible randomized controlled trials and included 2,385 patients with non-small cell lung cancer.
      NSCLC Meta-analysis Collaborative Group
      Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data.
      However, only data from patients from the control arm in these trials were used in this analysis, to ensure that any difference between clinical and pathologic staging could not have been influenced by preoperative chemotherapy. Included randomized controlled trials (RCTs) used different editions of TNM staging, and these changes over time were taken into account (e-Table 1).
      Data on age, sex, clinical staging techniques, clinical TNM stage, extent of resection, pathologic TNM stage, histology, performance status, treatment group and dates of randomization, last follow-up, and death were collected. We approached study investigators for permission to use these data for these analyses and for clarification where staging methods were unclear in the original trial protocol or manuscript.

       Statistical Analysis

      To assess agreement between clinical TNM stage (cTNM) and pathologic TNM stage (pTNM), a simple percentage agreement was calculated. Agreement between clinical and pathologic stage was also calculated using a weighted Cohen’s κ, which takes into account both agreement by chance and the degree of disagreement. κ statistics were categorized, as < 66% = low agreement, ≥ 66% = fair agreement, and ≥ 90% = good agreement.
      • McMinn A.M.
      • van Sluijs E.M.F.
      • Harvey N.C.
      • et al.
      Validation of a maternal questionnaire on correlates of physical activity in preschool children.
      • Portney L.G.
      • Watkins M.P.
      Foundations of Clinical Research: Applications to Practice.
      To assess whether or not patient and trial characteristics might be associated with any cTNM staging inaccuracy age, sex, histology, year of randomization, and staging method were included in a multivariate logistic regression model. Histology was classified into adenocarcinoma, squamous, and other/unknown. Staging methods were classified as CT scan with or without a chest radiograph or CT scan plus any other staging method, as there were insufficient data to do this in more detail. Staging method correlated strongly with year of randomization, so we included only the former in our primary analysis. However, a sensitivity analysis was also performed, where staging method was replaced with year of randomization. We generated Kaplan-Meier curves for overall survival based on patients who were clinically understaged, clinically overstaged, and for those whose cTNM and pTNM agreed, and compared these using a log-rank test, stratified by trial and subsequently also pathologic stage. The accuracy of clinical T stage and nodal status were considered separately to help pinpoint which disagreements could have influenced treatment decisions.

      Results

      Fifteen RCTs were included in the original IPD systematic review and meta-analysis of preoperative chemotherapy followed by surgery vs surgery alone. Nine trials
      • Gilligan D.
      • Nicolson M.
      • Smith I.
      • et al.
      Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT2/EORTC 08012 multicentre randomised trial and update of systematic review.
      • Roth J.A.
      • Fosella F.
      • Komaki R.
      • et al.
      A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIa non-small cell lung cancer.
      • Depierre A.
      • Milleron B.
      • Moro-Sibilot D.
      • et al.
      Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II and IIIa non-small cell lung cancer.
      • Splinter T.A.
      • van Putten J.W.
      • Meuzalaar J.
      • Smit E.F.
      • Kho G.S.
      • Groen H.J.
      Randomized multicentre phase II study of chemotherapy followed by surgery versus surgery alone in stage I and II non-small cell lung cancer (NSCLC).
      • Nagai K.
      • Tsuchiya R.
      • Mori T.
      • et al.
      A randomised trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIa N2 non-small cell lung cancer.
      • Mattson K.V.
      • Abratt R.P.
      • ten Velde G.
      • Krofta K.
      Docetaxel as neoadjuvant therapy for radically treatable stage III non-small cell lung cancer: a multinational randomised phase III study.
      • Pisters K.M.
      • Vallieres E.
      • Crowley J.J.
      • et al.
      Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.
      • Wu Y.-L.
      • Gu L.-J.
      • Weng Y.-M.
      • Feng W.-N.
      • Cheng C.
      Neo-adjuvant chemotherapy with docetaxel plus carboplatin for non-small cell lung cancer.
      • Yang X.
      • Wu Y.
      • Gu L.
      • et al.
      A randomized trial comparing neoadjuvant gemcitabine plus carboplatin or cisplatin followed by surgery with surgery alone in clinical stage IIIA non-small-cell lung cancer (NSCLC).
      (randomizing 1,586 patients in total) included data on both cTNM and pTNM stage, providing 698 control-arm patients for analysis (Table 1). These RCTs accrued patients between 1987 and 2005.
      Table 1Characteristics of Included Trials
      TrialTotal Patients RandomizedPatients Randomized to Control ArmPatients Who Provided Clinical and Pathologic DataAccrual PeriodStaging System (TNM)
      a For details of TNM staging systems, see e-Figure.
      Staging MethodSurgical Protocol
      M.D. Anderson (USA); Roth et al
      • Roth J.A.
      • Fosella F.
      • Komaki R.
      • et al.
      A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIa non-small cell lung cancer.
      /1994
      6032321987-19934Chest radiographyOne or more positive nodal stations allowed. Patients with left lung tumors and paratracheal lymph node metastases excluded
      MIP-91 (France); Depierre et al
      • Depierre A.
      • Milleron B.
      • Moro-Sibilot D.
      • et al.
      Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II and IIIa non-small cell lung cancer.
      /2002 (12, 29)
      3551761701991-19974Chest radiography, CT imagingMediastinal node dissection and node sampling were left to the discretion of the surgeon
      Netherlands; Splinter et al
      • Splinter T.A.
      • van Putten J.W.
      • Meuzalaar J.
      • Smit E.F.
      • Kho G.S.
      • Groen H.J.
      Randomized multicentre phase II study of chemotherapy followed by surgery versus surgery alone in stage I and II non-small cell lung cancer (NSCLC).
      /2000
      7940371991-19994CT imaging and mediastinoscopyMediastinal lymph node exploration was encouraged: for right-sided lesions, this included 2R, 4R, 7, 8, 9. For left-sided lesions, this included 4L, 5, 6, 7, 8, 9
      JCOG 9209 (Japan); Nagai et al
      • Nagai K.
      • Tsuchiya R.
      • Mori T.
      • et al.
      A randomised trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIa N2 non-small cell lung cancer.
      /2003
      6231311993-19984CT imagingSurgery was either lobectomy, bilobectomy, or pneumonectomy along with systematic mediastinal lymph node dissection
      Finland; Mattson et al
      • Mattson K.V.
      • Abratt R.P.
      • ten Velde G.
      • Krofta K.
      Docetaxel as neoadjuvant therapy for radically treatable stage III non-small cell lung cancer: a multinational randomised phase III study.
      /2003
      6232231995-19994CT imaging“Local surgery”
      MRC LU22 (UK); Gilligan et al
      • Gilligan D.
      • Nicolson M.
      • Smith I.
      • et al.
      Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT2/EORTC 08012 multicentre randomised trial and update of systematic review.
      /2007
      5192611941997-20055/6Bronchoscopy, mediastinoscopy, and CT imaging, PETAt cervical mediastinoscopy, the following lymph node stations will, wherever possible, be sampled: 2R, 2L, 4R, 4L, 7
      SWOG S9900 (USA); Pisters et al
      • Pisters K.M.
      • Vallieres E.
      • Crowley J.J.
      • et al.
      Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.
      /2010
      3541741701999-20045/6Chest radiography and CT imagingAll accessible hilar (level 10) lymph nodes must be dissected …A complete mediastinal lymph node sampling should be performed…for right-sided lesions, this includes 2R, 4R, 7, 8, and 9. For left-sided lesions, this includes 4L, 5, 6, 7, 8, and 9
      China; Wu et al
      • Wu Y.-L.
      • Gu L.-J.
      • Weng Y.-M.
      • Feng W.-N.
      • Cheng C.
      Neo-adjuvant chemotherapy with docetaxel plus carboplatin for non-small cell lung cancer.
      /2002
      5523201999-20045/6Chest radiography, CT imaging, bronchoscopy and abdominal ultrasoundSurgery consisted of radical lung resection and systematic mediastinal lymph node dissection
      China; Yang et al
      • Yang X.
      • Wu Y.
      • Gu L.
      • et al.
      A randomized trial comparing neoadjuvant gemcitabine plus carboplatin or cisplatin followed by surgery with surgery alone in clinical stage IIIA non-small-cell lung cancer (NSCLC).
      /2005
      4021211999-20045/6Chest radiography, CT imaging, bronchoscopy and abdominal ultrasoundLobectomy or pneumonectomy with systematic lymph node dissection
      a For details of TNM staging systems, see e-Figure.
      Clinical staging protocols varied among the trials (Table 1). One trial
      • Roth J.A.
      • Fosella F.
      • Komaki R.
      • et al.
      A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIa non-small cell lung cancer.
      (which recruited patients between 1987 and 1993) used chest radiography and mediastinoscopy only. More recent trials used CT scans and PET-CT imaging, but no trial utilized PET-CT scanning routinely, such that only 67 patients included in the analysis underwent PET-CT imaging. There was also variation among trials in the surgical methods used (Table 1).
      Of the 698 patients included, 318 (46%) were cTNM stage I (83% of which were Ia), 160 (23%) were cTNM stage II (91% of which were IIa), and 218 (31%) were cTNM stage IIIa (Table 2). Only two patients were classed as cTNM stage IIIB, and were therefore not included in the regression or survival analyses. A more detailed breakdown is given in e-Figure 1.
      Table 2Agreement Between Clinical and Pathologic TNM Stage Data
      TNM StageTNM StageTotal
      pIpIIpIIIapIIIbpIV
      cI177 (25.4%)72 (10.3%)
      a Clinically understaged.
      44 (6.3%)
      a Clinically understaged.
      22 (3.2%)
      a Clinically understaged.
      3 (0.4%)
      a Clinically understaged.
      318 (45.6%)
      cII40 (5.7%)
      b Clinically overstaged.
      67 (9.6%)32 (4.6%)
      a Clinically understaged.
      16 (2.3%)
      a Clinically understaged.
      5 (0.7%)
      a Clinically understaged.
      160 (22.9%)
      cIIIa32 (4.6%)
      b Clinically overstaged.
      28 (4.0%)
      b Clinically overstaged.
      116 (16.6%)30 (4.3%)
      a Clinically understaged.
      12 (1.7%)
      a Clinically understaged.
      218 (31.2%)
      cIIIb0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      2 (0.3%)0
      a Clinically understaged.
      2 (0.3%)
      cIV0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      00
      Total249 (35.7%)167 (23.9%)192 (27.5%)70 (10.0%)20 (2.9%)698 (100%)
      a Clinically understaged.
      b Clinically overstaged.
      Agreement between cTNM and pTNM staging was low (52%; weighted Cohen’s κ = 0.35; 95% CI, 0.30-0.40) (Table 2). In 34% of cases, patients were clinically understaged, and in 14% of cases, patients were clinically overstaged (Table 2). In the main regression analysis, age (P = .12), sex (P = .62), histology (P = .82), and the staging method (P = .32) were not significantly associated with the accuracy of cTNM staging, and in a sensitivity analysis there was no association with year of randomization (P = .98; e-Table 2).
      Survival varied with the accuracy of cTNM staging. In particular, patients who were clinically understaged appeared to have poorer survival than those who were clinically overstaged or those for whom cTNM and pTNM staging agreed (log-rank test stratified by trial P < .0001) (Fig 1). However, this is driven by the underlying pTNM stage (log-rank test stratified by trial and pathologic stage P = .54), which is more clearly illustrated in Figure 2. In particular, 44% of patients classed as cTNM stage I were pTNM stage II-IV, and 33% of patients classed as cTNM stage II were pTNM stage III-IV, explaining their lower survival (Fig 2).
      Figure thumbnail gr1
      Figure 1Kaplan-Meier curves for overall survival for all trial data combined, by agreement of clinical TNM staging with pathologic TNM staging.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier curves for overall survival in clinically staged I, II, and III patients, by agreement of clinical TNM staging with pathologic TNM staging.
      Agreement was low between clinical and pathologic T stage (65%; weighted Cohen’s κ = 0.33; 95% CI, 0.27-0.39) (Table 3) and N stage (62%, weighted Cohen’s κ = 0.42; 95% CI, 0.37-0.48) (Table 4). Specifically, clinical staging failed to detect T4 disease in 10% of patients (Table 3), and nodal disease in 19% of patients. In addition, 12% were judged erroneously to have node-positive disease (Table 4).
      Table 3Agreement Between Clinical and Pathologic T Stage Data
      T StageT StageTotal
      pT1pT2pT3pT4
      cT134 (4.9%)16 (2.3%)
      a Clinically understaged.
      3 (0.4%)
      a Clinically understaged.
      7 (1.0%)
      a Clinically understaged.
      60 (8.6%)
      cT235 (5.0%)
      b Clinically overstaged.
      360 (51.6%)69 (9.9%)
      a Clinically understaged.
      40 (5.7%)
      a Clinically understaged.
      504 (72.2%)
      cT37 (1.0%)
      b Clinically overstaged.
      42 (6.0%)
      b Clinically overstaged.
      60 (8.6%)23 (3.3%)
      a Clinically understaged.
      132 (18.9%)
      cT40
      b Clinically overstaged.
      0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      2 (0.3%)2 (0.3%)
      Total76 (10.9%)418 (59.9%)132 (18.9%)72 (10.3%)698 (100%)
      a Clinically understaged.
      b Clinically overstaged.
      Table 4Agreement Between Clinical and Pathologic Nodal Status Data
      Nodal StatusNodal StatusTotal
      pN0pN1pN2pN3
      cN0259 (37.1%)74 (10.6%)
      a Clinically understaged.
      57 (8.2%)
      a Clinically understaged.
      1 (0.1%)
      a Clinically understaged.
      391 (56.0%)
      cN156 (8.0%)
      b Clinically overstaged.
      67 (9.6%)29 (4.2%)
      a Clinically understaged.
      0
      a Clinically understaged.
      152 (21.8%)
      cN228 (4.0%)
      b Clinically overstaged.
      19 (2.7%)
      b Clinically overstaged.
      104 (14.9%)4 (0.6%)
      a Clinically understaged.
      155 (22.2%)
      cN30
      b Clinically overstaged.
      0
      b Clinically overstaged.
      0
      b Clinically overstaged.
      00
      Total343 (49.1%)160 (22.9%)190 (27.2%)5 (0.7%)698 (100%)
      a Clinically understaged.
      b Clinically overstaged.

      Discussion

       Results Summary

      We found that cTNM stage disagreed with pTNM stage in about one-half of patients, and was not clearly associated with age, sex, histology, the staging method used, or year of randomization. The discrepancies between clinical and pathologic T staging and N staging could have led to different treatment decisions in 10% and 38% of cases, respectively.

       Strengths

      To our knowledge, this is the first time IPD from major RCTs have been combined to assess the accuracy of staging in stage I-III NSCLC. While the randomized controlled trials included did not intend to evaluate staging, with the agreement of those who provided the data, this novel methodology provided us with a valuable opportunity to investigate more reliably the accuracy of clinical TNM staging. We could take advantage of per-protocol clinical staging and surgery and rigorous documentation of clinical and pathologic TNM stage for each patient. Also, data from randomized trials are less susceptible to the selection biases that can affect cohort studies.
      • Lopez-Encuentra A.
      • Garcia-Lujan R.
      • Rivas J.J.
      • Rodriguez-Rodriguez J.
      • Torres-Lanza J.
      • Varela-Simo G.
      Comparison between clinical and pathologic staging in 2994 cases of lung cancer.
      • Stiles B.M.
      • Servais E.L.
      • Lee P.C.
      • Port J.L.
      • Paul S.
      • Altorki N.K.
      Point: Clinical stage IA non-small cell lung cancer determined by computed tomography and positron emission tomography is frequently not pathologic IA non-small cell lung cancer: the problem of understaging.
      Using IPD has enabled us to restrict the analysis to the control arms of these trials, thus avoiding confounding by treatment received and, in particular, potential downstaging from use of preoperative chemotherapy.
      For the first time, to our knowledge, this study also demonstrates the impact of the inaccuracy of clinical staging on patient survival outcomes. Importantly, the impact of staging accuracy on clinical decision making is also demonstrated using unselected data. The poorer survival seen in clinically understaged patients was explained by the underlying pTNM stage.

       Limitations

      Over time the trials included here used increasingly sophisticated staging methods, but surprisingly, a significant improvement in accuracy was not seen. However, many of the staging methods utilized in the included trials may now be considered suboptimal.
      • Postmus P.E.
      • Kerr K.M.
      • Oudkerk M.
      • et al.
      Early and locally advanced non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      Earlier studies employed CT scanning and mediastinoscopy while the most recent trial used additional PET-CT imaging, but none used endosonography. Despite this, our staging accuracy results are remarkably similar to those from the audit of the quality of staging in Dutch patients,
      • Heineman D.J.
      • Geert ten Berge M.
      • Daniels J.M.
      • et al.
      The quality of staging non-small cell lung cancer in the Netherlands: data from the Dutch Lung Surgery Audit.
      which included routine use of PET-CT imaging and endosonography and included patients from January 2013 to December 2014. Indeed, of the patients included in our analysis that did undergo PET-CT imaging, one-quarter of patients were still understaged and this is discussed elsewhere.
      • Navani N.
      • Nankivell M.
      • Stephens R.J.
      • et al.
      Inaccurate clinical nodal staging of non-small cell lung cancer: evidence from the MRC LU22 multicentre randomised trial.
      While PET-CT imaging or endosonography was not routinely utilized in the trials included in this meta-analysis, this practice reflects current American College of Chest Physicians guidance
      • Silvestri G.A.
      • Gonzalez A.V.
      • Jantz M.A.
      • 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.
      for patients with stage IA disease, which does not recommend the use of PET imaging or endosonography. Although it is difficult to generalize, assuming the trial population reflects routine practice, the data here suggest that 44% of patients with clinical stage I disease might have more advanced disease diagnosed postoperatively. A further limitation is that intraoperative pathologic staging protocols may have varied and are unlikely to be as comprehensive as currently recommended.
      • Lardinois D.
      • De Leyn P.
      • Van Schil P.
      • et al.
      ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer.
      However, incomplete pathologic staging would only serve to reduce the extent of nodal staging inaccuracy.

       Context

      The advent of stereotactic radiotherapy and radiofrequency ablation for the treatment of early-stage NSCLC has highlighted the importance of accurate nodal staging. These newer techniques are used for the treatment of early-stage lung cancer but, in contrast to surgery, do not provide pathologic staging information. In a study of relapse of NSCLC following stereotactic radiotherapy or surgery, there were twice as many recurrences in local lymph nodes in patients undergoing stereotactic radiotherapy compared with surgery,
      • van den Berg L.L.
      • Klinkenberg T.J.
      • Groen H.J.
      • Widder J.
      Patterns of recurrence and survival after surgery or stereotactic radiotherapy for early stage NSCLC.
      emphasizing the importance of accurate nodal staging prior to SABR.
      When surgery is undertaken and pathologic staging is available, prior invasive mediastinal sampling may take on less significance if we assume that surgery followed by adjuvant chemotherapy is at least as effective as chemoradiation. When considering stage II and III disease, inaccurate clinical staging may reduce the efficacy of surgery by failing to detect multistation N2 or N3 disease. For patients undergoing radical radiotherapy, imprecise clinical staging can result in an incorrect radiation field.
      The most likely explanation for the low level of accuracy of clinical staging for patients with operable NSCLC is the sensitivity of the diagnostic tools employed. Patients being considered for treatment with curative intent typically undergo CT and PET-CT imaging as well as mediastinal sampling when required. Using a 10-mm short-axis cutoff for significance of mediastinal nodes, the sensitivity of CT scanning in detecting mediastinal metastases is 55%.
      • Silvestri G.A.
      • Gonzalez A.V.
      • Jantz M.A.
      • 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.
      PET-CT imaging has a sensitivity of 77% to 81%
      • Schmidt-Hansen M.
      • Baldwin D.R.
      • Zamora J.
      FDG-PET/CT imaging for mediastinal staging in patients with potentially resectable non-small cell lung cancer.
      and may vary according to brand of scanner and histology. In a systematic pooled analysis of 9,267 patients, mediastinoscopy had a sensitivity of 78%.
      • Silvestri G.A.
      • Gonzalez A.V.
      • Jantz M.A.
      • 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.
      Overstaging may occur with PET-CT imaging unless current guidelines
      • Silvestri G.A.
      • Gonzalez A.V.
      • Jantz M.A.
      • 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.
      are adhered to and PET-positive findings are clarified by invasive sampling. More recently the introduction of endobronchial and endoscopic ultrasound has improved the clinical staging of patients with NSCLC, resulting in a reduction in futile surgery
      • Annema J.T.
      • van Meerbeeck J.P.
      • Rintoul R.C.
      • et al.
      Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.
      • Korevaar D.A.
      • Crombag L.M.
      • Cohen J.F.
      • Spijker R.
      • Bossuyt P.M.
      • Annema J.T.
      Added value of combined endobronchial and oesophageal endosonography for mediastinal nodal staging in lung cancer: a systematic review and meta-analysis.
      and potentially increased survival
      • Navani N.
      • Nankivell M.
      • Lawrence D.R.
      • et al.
      Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial.
      when employed routinely for patients with stage I-III disease.

       Implications

      These findings have implications for the care of patients with NSCLC, as well as appropriate selection of suitable patients for inclusion in clinical trials. Understaging the T stage may mean that the patient undergoes surgery without the surgeon knowing the full extent of the primary disease, which may result in an incomplete resection. Ten percent of patients in our analysis were found to have previously unexpected T4 disease. Erroneous nodal staging in patients without metastatic disease can similarly result in inappropriate treatment decisions, which can significantly impact on patient outcomes. Patients with nodal disease undetected by clinical staging methods may undergo futile surgery (or SABR) whereas chemoradiotherapy may have been the preferred initial treatment of clinicians and patients with full knowledge of nodal involvement. Conversely, if clinical staging overestimates the extent of nodal disease (114 patients [15%] in this meta-analysis), then this may mean patients are denied potentially curative surgery. The data for this analysis were obtained from patients in controlled clinical trials, generally from centers with lung cancer expertise. Therefore, clinical staging accuracy in the wider population could well be worse.

      Conclusions

      The results of this analysis highlight some flaws in the clinical care of patients with NSCLC and emphasize the need for further research into techniques for improving staging accuracy for patients with stage I-III NSCLC.

      Acknowledgments

      Author contributions: S. B. and D. F. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. S. B., D. F., J. F. T., R. J. S., and N. N. contributed substantially to the study design, data analysis and interpretation, and writing of the manuscript.
      Financial/nonfinancial disclosures: None declared.
      *NSCLC Meta-analysis Collaborative Group: Project Management Group: Sarah Burdett, Larysa H. M. Rydzewska, and Jayne F. Tierney (MRC Clinical Trials Unit at UCL, London, UK); Anne Auperin, Thierry Le Chevalier, Cécile Le Pechoux, and Jean-Pierre Pignon (Gustave-Roussy, Villejuif, France). International Advisory Group: Rodrigo Arriagada (Karolinska Institutet, Stockholm, Sweden), (Gustave-Roussy, Villejuif, France), David H. Johnson (Southwestern Medical Center, University of Texas, Dallas, TX), Jan van Meerbeeck (MOCA-Thoracic Oncology, University Hospital Antwerp, Antwerp, Belgium), Mahesh K. B. Parmar (MRC Clinical Trials Unit at UCL, London, UK); Richard J. Stephens (MRC Clinical Trials Unit at UCL, London, UK [retired]); and Lesley A. Stewart (Centre for Reviews and Dissemination, York, UK). Collaborators who supplied individual participant data: Paul A. Bunn (University of Colorado Cancer Center, Aurora, CO); Bertrand Dautzenberg (Service de Pneumologie et Réanimation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France); David Gilligan (Addenbrooke’s Hospital, Cambridge, UK); Harry Groen (Universitair Medisch Centrum Groningen, Groningen, The Netherlands); Aija Knuuttila (Helsinki University Central Hospital, Helsinki, Finland); Eric Vallieres (Swedish Cancer Institute, Seattle, WA); Rafael Rosell (Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain); Jack Roth (University of Texas M.D. Anderson Cancer Center, Houston, TX); Giorgio Scagliotti (University of Turin, San Luigi Hospital, Turin, Italy); Masahiro Tsuboi (National Cancer Center Hospital East, Kashiwanoha, Kashiwa-shi, Japan); David Waller (Glenfield Hospital, Leicester, UK); Virginie Westeel (Centre Hospitalier Universitaire, Besançon, France); and Yi-Long Wu and Xue-Ning Yang (Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China).
      Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
      Other contributions: The authors thank all the patients who took part in all the trials included in these analyses. Publication is on behalf of the Non-Small Cell Lung Cancer Collaborative Group.
      Additional information: The e-Figure and e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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      Linked Article

      • Setting the Stage
        CHESTVol. 156Issue 3
        • In Brief
          In a previous issue of CHEST (March 2019), Navani and colleagues1 presented results of a meta-analysis focused on the accuracy of clinical staging of non-small cell lung cancer (NSCLC) in clinical trial patients. In their analysis, clinical staging was accurate in just 52% of cases, with 34% of patients clinically understaged based on the pathologic TNM stage. This effect was seen across all subgroups stratified by stage. However, the meta-analysis did not take into account the important potential confounder of elapsed time between clinical staging and pathologic staging, which may contribute to understaging and progression of disease.
        • Full-Text
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      • Response
        CHESTVol. 156Issue 3
        • In Brief
          We thank Dr Gard and Dr Voskoboynik for their interest in our article1 and for their thoughtful comments. We agree that timeliness of care appears to be important for patients undergoing lung cancer diagnosis and treatment and is the subject of an ongoing systematic review.2 A previous randomized trial of endobronchial ultrasound by our group3 resulted in faster diagnosis and was also associated with improved survival. Reduced time to treatment may also improve patient experience and result in fewer patients reporting a drop in performance status.
        • Full-Text
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