Advertisement

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer

Open ArchivePublished:December 24, 2015DOI:https://doi.org/10.1016/j.jtho.2015.10.008

      Abstract

      Introduction

      Small cell lung cancer (SCLC) is commonly classified as either limited or extensive, but the Union for International Cancer Control TNM Classification of Malignant Tumours seventh edition (2009) recommended tumor, node, and metastasis (TNM) staging based on analysis of the International Association for the Study of Lung Cancer (IASLC) database.

      Methods

      Survival analyses were performed for clinically and pathologically staged patients presenting with SCLC from 1999 through 2010. Prognosis was compared in relation to the TNM seventh edition staging to serve as validation and analyzed in relation to proposed changes to the T descriptors found in the eighth edition.

      Results

      There were 5002 patients: 4848 patients with clinical and 582 with pathological stages. Among these, 428 had both. Survival differences were confirmed for T and N categories and maintained in relation to proposed revisions to T descriptors for seventh edition TNM categories and proposed changes in the eighth edition. There were also survival differences, notably at 12 months, in patients with brain-only single-site metastasis (SSM) compared to SSM at other sites, and SSM without a pleural effusion showed a better prognosis than other patients in the M1b category.

      Conclusion

      We confirm the prognostic value of clinical and pathological TNM staging in patients with SCLC, and recommend continued usage for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. However, for M descriptors, it remains uncertain whether survival differences in patients with SSM in the brain simply reflect better treatment options rather than better survival based on anatomic extent of disease.

      Keywords

      Introduction

      Lung cancer remains the leading cause of cancer related mortality in the Western world.
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      Small cell lung cancer (SCLC) continues to represent around 15% of lung cancers, with the incidence declining in men but continuing to rise in women.
      Despite recent advances in patient management for non–small cell carcinomas, management has remained largely unchanged in the past decade for SCLC, and survival rates for both localized and advanced disease have also remained relatively constant.
      Staging remains a key factor in both the prognostication and management of patients with lung cancer, both for non–small cell and small cell types. Early staging systems for SCLC divided cases into two subgroups: limited and extensive.
      • Stahel R.A.
      • Ginsberg R.
      • Havemann K.
      • et al.
      Staging and prognostic factors in small cell lung cancer: a consensus report.
      • Zelen M.
      Keynote address on biostatistics and data retrieval.
      Limited disease was characterized by tumors confined to one hemithorax, although local extension and ipsilateral or supraclavicular nodes could also be present if they could be encompassed in the same radiation portal as the primary tumor. All other cases were classified as extensive disease. This remained the predominant method of staging, independent of the rare cases when surgical resection could be undertaken, although the tumor, node, and metastasis (TNM) classification was also applicable to SCLC. However, when the seventh edition of the TNM classification was published in 2009, it was recommended to favor the TNM classification for staging of patients with SCLC, and to stratify by stages I, II, and III when designing clinical trials of early stage disease.
      • Shepherd F.A.
      • Crowley J.
      • Van Houtte P.
      • et al.
      The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.
      This was based on a cohort of 12,620 eligible cases with small cell histology, of whom 8088 had TNM staging available for analysis, and of whom there were 3215 with full clinical staging and 128 with pathological staging.
      • Shepherd F.A.
      • Crowley J.
      • Van Houtte P.
      • et al.
      The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.
      This cohort was a subset of an overall database created by the International Association to the Study of Lung Cancer (IASLC) that contained 100,869 patients.
      • Goldstraw P.
      • Crowley J.
      • Chansky K.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.
      Despite the magnitude of the database, not all descriptors could be validated.
      • Rami-Porta R.
      • Goldstraw P.
      Strength and weakness of the new TNM classification for lung cancer.
      The limitations of the retrospective database prompted the IASLC to launch a call for the collection of new data.
      • Giroux D.J.
      • Rami-Porta R.
      • Chansky K.
      • et al.
      The IASLC Lung Cancer Staging Project: data elements for the prospective project.
      The call resulted in a new database of 77,156 evaluable patients diagnosed with lung cancer between 1999 and 2010.
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC Lung Cancer Staging Project: the new database to inform the 8th edition of the TNM classification of lung cancer.
      This new database is being used to inform the eighth edition of the TNM classification of lung cancer, which is scheduled to be published in 2016, and the purpose of this paper is to report on the analysis of the clinical and pathological TNM staging for SCLC and propose refinements for the upcoming eighth revision of the TNM staging system in relation to this particular subgroup of tumors.
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC Lung Cancer Staging Project: the new database to inform the 8th edition of the TNM classification of lung cancer.
      • Asamura H.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      • Eberherdt W.
      • Mitchell A.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming (8th) edition of the TNM classification for lung cancer.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.

      Methods

      The database upon which analyses herein are based was originally created by the IASLC to inform revisions for the Union for International Cancer Control TNM Classification of Malignant Tumours seventh edition staging manual for lung cancer, with additional cases that had an initial presentation between 1999 and the end of 2010. These latter cases form the basis of this study. Cases analyzed for survival according to seventh edition stage categories were required to have adequate TNM staging information at baseline and adequate follow-up for survival. Analyses focusing on proposed changes for the eighth edition were applied to the subset of SCLC cases that had sufficient descriptors to reclassify according to the proposed eighth edition T categories. This required, at minimum, detail on the size of the primary tumor (for cases T1–T3) and the anatomical basis for classification of T2 to T4 cases.
      Overall survival was defined as the time between date of entry (e.g., date of diagnosis for clinically staged cases, date of surgery for pathologically staged cases) and the date of death. Patients alive at last contact were censored at the last contact date. Survival was estimated using the Kaplan–Meier method, with an overall p value based on the log-rank test. Formal comparisons between adjacent stage categories were generated via Cox proportional hazards regression. An ordered log-rank test was applied to proposed eighth edition overall stage categories.
      • Liu P.Y.
      • Tsai W.Y.
      A modified logrank test for censored survival data under order restrictions.
      This is a global test to evaluate against the possibility that categories are ordered differently than expected. All analyses were performed using SAS software (version 9.4; SAS Institute, Inc, Cary, NC).

      Results

      Population

      In total, there were 5002 retrospective cases, of which 4848 were clinically staged, 582 were pathologically staged, and 428 both clinically and pathologically staged (Table 1). All patients presented between 1999 and 2010; there was no overlap with the database collected to inform the recommendations for the seventh edition. The majority of cases were from multiple-site consortia and registry databases, primarily from Asia and Europe. Among the 4848 patients considered in the analyses of clinical stage, 577 (12%) were surgically managed, and the majority of nonsurgically managed patients (among those for whom there was adequate information on both systemic and radiation therapy) received chemotherapy with or without radiation therapy (Table 2). A small minority (1%) received best supportive care only. Among 2931 nonsurgical patients known to have received systemic therapy or radiation, the details of therapy were obtainable in just 309 records. Among the 309, 103 patients received both systemic and radiation therapy, 205 patients received systemic therapy only, and one received radiation only.
      Table 1Source of Staging and Type of Database Submission for the 5002 Cases in the Small Cell Lung Cancer Database
      Type of Database SubmissionAvailable TNM StagingGeographic RegionTotal
      Clinical TNMPathological TNMClinical and Pathological TNMAsiaAustraliaEuropeNorth/South America
      Consortium1688974171400080202202
      Registry2645467015268302698
      Series871143193131102
      Total44201544281431243516315002
      TNM, tumor, node, and metastasis.
      Table 2Type of Management by Clinical Stage, from the Small Cell Lung Cancer Clinically Staged Database
      Clinical Stage (7th ed)TreatmentTotal
      Surgery (%)Chemotherapy/Radiotherapy, Nonsurgical (%)No Treatment (%)Missing Rx Data, Nonsurgical (%)
      IA273 (100)000273
      IB81 (93)5 (6)1 (1)087
      IIA60 (95)2 (3)01 (2)63
      IIB35 (32)48 (44)027 (25)110
      IIIA84 (17)290 (57)2 (<1)128 (26)504
      IIIB14 (2)602 (70)5 (<1)245 (28)866
      IV30 (1)1984 (67)38 (1)893 (31)2945
      Total577 (12)2931 (60)46 (1)1294 (27)4848
      Rx, prescription.
      Cases originating from the electronic data capture database included information regarding the staging method used to obtain clinical stage. Among 380 clinically staged cases with this information, 376 were staged using standard radiology along with at least one other method. One hundred fifty-eight patients (41%) received a bone scan, 373 patients (98%) received a computed tomography scan of the upper chest or abdomen along with other methods, 89 patients (23%) received a positron emission tomography or computed tomography scan, 357 patients (94%) underwent bronchoscopy, and 30 patients (8%) underwent mediastinoscopy. One hundred six patients (26%) underwent all of these except for a positron emission tomography scan and mediastinoscopy.
      The median follow-up time for patients that were alive at last contact was 27 months for the clinically staged group and 61 months for the pathologically staged group.

      T Component

      Application of the T component categories from the seventh edition, independent of nodal status, showed significantly better survival for clinical T1 compared to T2, T2 to T3, and T3 to T4 (Table 3). The significance of these comparisons persisted after adjusting for surgical management versus not adjusting for surgical management. There seemed to be little difference between T1a and T1b and T2a and T2b (Fig. 1). Similar trends were seen in cases clinically staged but without resection (data not shown), as well as in pathological staging, though there was no difference between pT3 and pT2 (Supplementary Fig. 1).
      Table 3Formal Comparisons between T and N Anatomical Categories, Seventh Edition and Proposed Eighth Edition
      ComparisonUnadjusted HRp ValueAdjusted HR
      Adjusted for surgery.
      p Value
      Clinical T categories
       T2 vs. T11.640.00021.530.0016
       T3 vs. T22.25<0.00011.510.0046
       T4 vs. T31.290.00011.210.0049
      Pathological T categories
       T2 vs. T11.400.0159
       T3 vs. T21.160.4541
       T4 vs. T32.590.0012
      Clinical N categories
       N1 vs. N01.55<0.00011.130.27
       N2 vs. N11.480.00031.150.20
       N3 vs. N21.240.00131.110.12
      Clinical N categories, nonsurgical cases only
       N1 vs. N00.890.39
       N2 vs. N11.210.13
       N3 vs. N21.140.06
      Clinical N categories, surgical cases only
       N1 vs. N01.760.0031
       N2 vs. N11.340.19
       N3 vs. N21.080.88
      Proposed 8th edition
       cT categories
      T2 vs. T11.510.051.350.16
      T3 vs. T21.620.071.430.18
      T4 vs. T32.010.00051.540.04
       pT categories
      T2 vs. T11.480.0061
      T3 vs. T20.780.2431
      T4 vs. T33.18<0.0001
      HR, hazard ratio.
      a Adjusted for surgery.
      Figure thumbnail gr1
      Figure 1Survival according to clinical T categories, seventh edition. c, clinical; N, number of cases; MST, median survival time.

      N Component

      Application of the N component categories from the seventh edition, independent of T category, showed better survival trends for clinical N0 through to N3 (Table 3; Fig. 2); however, the differences were not statistically significant after adjusting for surgical management. There was evidence of an interaction between treatment (surgery versus no surgery) and clinical N categories, for its impact on survival. In cases that underwent surgery, independent of T category, there was a significant difference between N0 patients and those with node-positive disease for both clinical and pathological staging (Fig. 3; Supplementary Fig. 2). However, in cases that were nonsurgically managed, these survival trends were not apparent (Supplementary Fig. 3). There were insufficient data to subdivide N descriptors further in relation to, for example, the relevance of ipsilateral supraclavicular versus contralateral mediastinal nodal involvement in N3 disease.
      Figure thumbnail gr2
      Figure 2Survival according to clinical N categories, seventh edition. c, clinical; N, number of cases; MST, median survival time.
      Figure thumbnail gr3
      Figure 3Survival according to clinical N categories, surgically resected cases. Note that six cases with N3 disease were omitted. c, clinical; N, number of cases; MST, median survival time.

      Assessment of Proposed Changes to T Categories for NSCLC

      Analyses for the eighth edition of cases with NSCLC have proposed changes to criteria for various T categories,
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      these being endobronchial location regardless of distance from carina becoming uniformly T2, with size >4 cm being T2b and with size >5 cm becoming T3. Those with size >7 cm become T4. Tumors with diaphragmatic involvement also become T4. There is additional subdivision within the T1 according to size, with cut points at 1-cm increments (1 and 2 cm), resulting in three groups within the T1. Comparison between T categories in the seventh edition compared to proposed changes in the eighth revision show similar discrimination between categories, although greater discrimination between T3 and T4 (Fig. 4A and B).
      Figure thumbnail gr4
      Figure 4Survival according to (A) seventh edition clinical T categories and (B) proposed eighth edition clinical T categories in the subset of cases where tumor descriptor data were sufficient to classify according to the proposed eighth edition. c, clinical; N, number of cases; MST, median survival time.

      Assessment of Proposed Changes to TNM Stage

      Revisions to TNM stage categories have been proposed based on the proposed revisions to T, N, and M categories.
      • Asamura H.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      • Eberherdt W.
      • Mitchell A.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming (8th) edition of the TNM classification for lung cancer.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      For M0 cases, stage I is subdivided into three categories based on the 1-cm size increments of the T1N0 category. Cases in T1 and T2 categories with N1 disease are amalgamated into IIB. The T3N2 move to IIIB, and a new category, IIIC, contains the N3 cases with T3 or T4 disease. Stage IV is subdivided based upon whether or not there is distant disease at multiple sites. Figure 5 shows the proposed stage groupings applied to the subset of the SCLC database that had adequate information to stage according to this proposal. A difference in prognosis is apparent between stages II and III, which is not seen in the analysis of the same dataset by seventh edition staging (Table 4). In this database, some stage categories are underrepresented in SCLC. It is unclear whether the subdivisions of stages I and II would result in different prognoses in a larger database. Differences between stage groupings were significant between IIIA and IIB and between IIIB and IIIA (Table 4). After adjusting for surgical resection versus no surgical resection, these differences were no longer significant. However, the ordered log-rank test was significant for the trend of decreasing survival with higher stage (p < 0.0001).
      Figure thumbnail gr5
      Figure 5Survival according to (A) seventh edition clinical TNM stages and (B) proposed eighth edition clinical TNM stages in cases where tumor descriptor data were sufficient to classify according to the proposed eighth edition. ed., edition; N, number of cases; MST, median survival time.
      Table 4Formal Comparisons between Clinical TNM Stages (Seventh Edition and Proposed Eighth Edition)
      ComparisonUnadjusted HRp ValueAdjusted HR
      Adjusted for surgery.
      Adjusted p Value
      Clinical TNM stages (7th ed)
       IB vs. IA1.670.051.490.13
       IIA vs. IB0.820.600.870.70
       IIB vs. IIA2.300.062.170.08
       IIIA vs. IIB1.220.540.750.40
       IIIB vs. IIIA1.36<0.00011.230.01
       IV vs. IIIB1.68<0.00011.68<0.0001
      Clinical TNM stages (proposed 8th ed)
       IA2 vs. IA12.330.162.330.16
       IA3 vs. IA20.750.360.750.36
       IB vs. IA31.730.131.550.22
       IIA vs. IB1.360.521.300.59
       IIB vs. IIA0.870.770.930.88
       IIIA vs. IIB2.11<0.00011.240.42
       IIIB vs. IIIA1.260.011.170.09
       IIIC vs. IIIB1.120.161.080.30
       IV vs. IIIC1.61<0.00011.62<0.0001
      HR, hazard ratio; TNM, tumor, node, metastasis.
      a Adjusted for surgery.

      Assessment of Pathological T2 Descriptors—Visceral Pleural Invasion

      The seventh edition of the TNM classification recommended assessment of the depth of visceral pleural invasion. Cases were categorized as PL0 (i.e., no invasion or invasion beneath the elastic layer), PL1 (i.e., invasion of the visceral pleura beyond the elastic layer), and PL2 (i.e., invasion through the visceral pleura with extension to the visceral pleural surface), with a view to informing the eighth revision. Data show no significant difference between PL0, PL1, or PL2, independent of T category (Supplementary Fig. 4).

      M Component

      Analyses of patients with clinical stage M1b showed no significant difference between patients who had either a SSM or multiple site disease (Fig. 6A). However, when SSMs were subdivided into those with brain involvement only, there was an apparent difference between this group and other sites of SSM and multiple site disease at 12 months (36% versus 23% and 20%, respectively; Fig. 6B). However, this reduced at 24 months and the difference did not reach significance at either time point (p = 0.13, with a hazard ratio of 0.78), likely because of the small number of cases. In addition, patients with a SSM and no pleural effusion showed an improved survival when compared with patients who had either pleural effusions or multiple metastatic sites or both (p = 0.02, with a hazard ratio of 0.71; Fig. 6C). There were insufficient data to assess the prognostic significance of the presence or absence of tumor cells within pleural and pericardial effusions (N = 59 and N = 2, respectively). There were also insufficient data to assess specific sites of N3 nodal involvement (n = 34 clinical N3 cases with N3 supraclavicular versus contralateral location).
      Figure thumbnail gr6
      Figure 6Evaluation of metastatic sites. (A) Single site metastases versus multiple sites, M1 cases. (B) Single-site metastases to the brain versus other sites. (C) Single versus multiple site metastases with or without pleural effusion. N, number of cases; MST, median survival time; PE, pleural effusion; SSM, single-site metastasis.

      Discussion

      The management of SCLC differs significantly from that of NSCLC, in that nearly all patients will not be amenable to complete resection and surgery will seldom be offered. Instead, patients are typically treated with systemic chemotherapy with or without radiation, a treatment strategy that has remained essentially unchanged over the past decade, despite the era of targeted therapy for some NSCLC subgroups. However, a significant minority of patients with SCLC are amenable to surgical resection, as evidenced by the numbers collected within this database. In this study, there were a total of 5002 patients, of whom 4848 were clinically staged, 582 were pathologically staged, and 428 both clinically and pathologically staged. This compares to numbers originally analyzed in 2007 of 3215 patients with clinical TNM staging and 128 patients with pathological TNM staging.
      • Shepherd F.A.
      • Crowley J.
      • Van Houtte P.
      • et al.
      The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.
      These numbers validate the earlier IASLC publication proposing the uptake of TNM staging for patients with early SCLC
      • Shepherd F.A.
      • Crowley J.
      • Van Houtte P.
      • et al.
      The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.
      and show that further proposed revisions to T categories for NSCLC in the eighth edition of the TNM classification can equally be applied to patients with SCLC. However, our data showed no significant survival difference in relation to visceral pleural invasion. Numbers were too small to compare the effect of visceral pleural invasion in individual T categories where significant prognostic differences between categories (i.e., PL0, PL1, and PL2) were seen in patients with NSCLC.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      In addition, these greater numbers showed refinements in the survival data for patients with M1b disease, with SSM patients without pleural effusions, and those with brain metastases only having a better prognosis than patients with either multiple site disease or SSM with a pleural effusion. This may reflect the ability to undertake more localized radiotherapy, not least of all because the survival difference in patients with brain-only SSM is reduced at 24 months (when compared to 12 months). It remains uncertain if this should warrant a separate M1b category; this may reflect a treatment effect rather than a true survival difference based on extent of anatomic spread of disease. Nevertheless, for future revisions of the TNM staging system we recommend documenting prospectively for patients with metastases: (1) the number of extrathoracic metastatic sites; (2) the exact number and locations of metastatic organs involved; (3) the diameter as surrogate for volume of individual metastatic sites, including involved lymph nodes beyond the nodal stations shown in the IASLC lymph node map; (4) investigations performed to undertake staging; and (5) whether presentation with brain metastases was symptomatic or asymptomatic. With higher patient numbers within individual subgroups and available longer follow-up of patients, a more valid evaluation of these important questions might be possible.
      In relation to the N component, data again confirm the seventh edition recommendation for determining the N category in patients with limited disease, in particular highlighting the prognostic significance of N0 disease independent of the T component. This finding, together with the fact that survival differences in relation to the N categories were lost in nonsurgical cases independent of the T component (Supplementary Figs. 2 and 3; Supplementary Digital Content 1) highlights the importance of systematic nodal dissection in resected cases. Indeed, patients with pN2 disease have a 2-year survival rate of 37%. It also highlights the importance of confirmation of nodal disease in inoperable patients when appropriate, in order to obtain the most accurate staging data. This is emphasized by reviewing the agreement between clinical and pathological staging (Table 5, Table 6, Table 7), with N category agreement being 73% and overall agreement being 57%, and a greater extent of clinical under- rather than overstaging. These data have not shown improvement when compared to data from the seventh TNM staging cohort,
      • Vallieres E.
      • Shepherd F.A.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer.
      and it was not possible to assess any further subdivision based on the advent of the bronchoscopic ultrasound-guided fine-needle aspiration biopsy. However, with the advent of this practice, there should be greater facility for assessment of mediastinal nodal involvement, and it will be interesting to see if agreement improves in future cohorts.
      Table 5Concordance between Clinical and Pathological T Categories
      T Category Concordance (M0 Cases)Pathological T CategoryPercent Agreement
      T1AT1BT2AT2BT3T4
      cT1A1215220817769
      cT1B5593009156
      cT2A03821828582
      cT2B002124067
      cT301831535050
      cT40200166767
      Seventy-one percent of cases (295/414) show agreement; 6% (25/414) are overstaged and 23% (94/414) are understaged clinically.
      Table 6Concordance between Clinical and Pathological N Categories
      N Category Concordance (M0 Cases)Pathological N CategoryPercent Agreement
      N0N1N2N3
      cN02533732079
      cN114248052
      cN216323055
      cN3012125
      Seventy-three percent of cases (301/414) show agreement; 9% (36/414) are overstaged and 18% (77/414) are understaged clinically.
      Table 7Concordance between Clinical and Pathological TNM Stage, in Cases where Both Clinical and Pathological Stage Data were Available
      Stage ConcordancePathological TNM StagePercent Agreement
      IAIBIIAIIBIIIAIIIBIV
      cIA129342610181159
      cIB14953120169
      cIIA6524571050
      cIIB047850132
      cIIIA6416282158
      cIIIB101032125
      cIV111020444
      Fifty-seven percent of cases (244/428) show agreement; 12% (50/428) are overstaged and 31% (134/428) understaged clinically.
      In the paper discussing proposals for the seventh revision of the TNM staging system, comments were made on the need for additional studies in relation to the importance of M1a disease—in particular, whether there was prognostic significance to the presence or absence of tumor cells within pleural effusions, and the relevance of ipsilateral supraclavicular versus contralateral mediastinal nodal involvement in patients with N3 disease. Unfortunately, there were not enough data within the cohort, even with the additional patients, to assess these areas, and there is a need for specific targeting of these pathological and clinical parameters in any future collection, especially in relation to SCLC.
      We acknowledge that there are limitations to this analysis in that there are sources of bias to interpretation of these analyses. For example, 12% of patients were surgically managed—a much higher proportion than routinely seen—and only 1% of patients received best supportive care, while this is closer to 40% in routine care. Outcomes will have been biased by therapy received, and treatment administered data were available for only 11% of the nonsurgical patients. Nevertheless, we believe that the analyses herein are robust in terms of forming the basis for a TNM staging system for SCLC. As above, refinements in future data collection will hopefully obviate some of these limitations.
      In conclusion, this study confirms the prognostic value of both clinical and pathologic TNM staging in patients with SCLC who have limited disease. It also supports its continued usage for SCLC in relation to proposed changes to T categories for NSCLC in the eighth edition. These data also show survival differences in patients with SSM, in that those with brain involvement only or with SSM without pleural effusion have a better prognosis than other patients in the M1b category. Although it remains uncertain whether this reflects ability to treat rather than true survival differences based on disease extent, we recommend that M categories for SCLC are the same as those for NSCLC: namely, M1a, M1b (single metastatic lesions in a single distant organ), and M1c (multiple lesions in a single organ or multiple lesions in multiple organs).
      • Eberherdt W.
      • Mitchell A.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming (8th) edition of the TNM classification for lung cancer.
      This will allow both consistency in future data collection and specific data collection that may provide greater details for patients with metastatic disease.

      Appendix 1

      IASLC Staging and Prognostic Factors Committee

      Peter Goldstraw, Past Chair, Royal Brompton Hospital and Imperial College, London, United Kingdom; Ramón Rami-Porta, Chair, Hospital Universitari Mutua Terrassa, Terrassa, Spain; Hisao Asamura, Chair Elect, Keio University School of Medicine, Tokyo, Japan; David Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; David G. Beer, University of Michigan, Ann Arbor, MI, USA; Ricardo Beyruti, University of São Paulo, Brazil; Vanessa Bolejack, Cancer Research and Biostatistics, Seattle, WA, USA; Kari Chansky, Cancer Research and Biostatistics, Seattle, WA, USA; John Crowley, Cancer Research and Biostatistics, Seattle, WA, USA; Frank Detterbeck, Yale University, New Haven, CT, USA; Wilfried Ernst Erich Eberhardt, West German Cancer Centre, University Hospital, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Françoise Galateau-Sallé, Centre Hospitalier Universitaire, Caen, France; Dorothy Giroux, Cancer Research and Biostatistics, Seattle, WA, USA; Fergus Gleeson, Churchill Hospital, Oxford, United Kingdom; Patti Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; James Huang, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Catherine Kennedy, University of Sydney, Sydney, Australia; Jhingook Kim, Samsung Medical Center, Seoul, Korea; Young Tae Kim, Seoul National University, Seoul, South Korea; Laura Kingsbury, Cancer Research And Biostatistics, Seattle, WA, USA; Haruhiko Kondo, Kyorin University Hospital, Tokyo, Japan; Mark Krasnik, Gentofte Hospital, Copenhagen, Denmark; Kaoru Kubota, Nippon Medical School Hospital, Tokyo, Japan; Toni Lerut, University Hospitals, Leuven, Belgium; Gustavo Lyons, British Hospital, Buenos Aires, Argentina; Mirella Marino, Regina Elena National Cancer Institute, Rome, Italy; Edith M. Marom, MD Anderson Cancer Center, Houston, TX, USA; Jan van Meerbeeck, Antwerp University Hospital, Edegem (Antwerp), Belgium; Alan Mitchell, Cancer Research and Biostatistics, Seattle, WA, USA; Takashi Nakano, Hyogo College of Medicine, Hyogo, Japan; Andrew G. Nicholson, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, United Kingdom; Anna Nowak, University of Western Australia, Perth, Australia; Michael Peake, Glenfield Hospital, Leicester, United Kingdom; Thomas Rice, Cleveland Clinic, Cleveland, OH, USA; Kenneth Rosenzweig, Mount Sinai Hospital, New York, NY, USA; Enrico Ruffini, University of Torino, Torino, Italy; Valerie Rusch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Nagahiro Saijo, National Cancer Center Hospital East, Chiba, Japan; Paul Van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; Jean-Paul Sculier, Institut Jules Bordet, Brussels, Belgium; Lynn Shemanski, Cancer Research and Biostatistics, Seattle, WA, USA; Kelly Stratton, Cancer Research and Biostatistics, Seattle, WA, USA; Kenji Suzuki, Juntendo University, Tokyo, Japan; Yuji Tachimori, National Cancer Center, Tokyo, Japan; Charles F. Thomas, Jr, Mayo Clinic, Rochester, MN, USA; William Travis, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Andrew Turrisi, Sinai Grace Hospital, Detroit, MI, USA; Johan Vansteenkiste, University Hospitals, Leuven, Belgium; Hirokazu Watanabe, National Cancer Center Hospital, Tokyo, Japan; Yi-Long Wu, Guangdong Provincial Peoples Hospital, Guangzhou, People’s Republic of China.

      Advisory Board of the IASLC Mesothelioma Domain

      Paul Baas, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Jeremy Erasmus, MD Anderson Cancer Center, Houston, TX, USA; Seiki Hasegawa, Hyogo College of Medicine, Hyogo, Japan; Kouki Inai, Hiroshima University Postgraduate School, Hiroshima, Japan; Kemp Kernstine, City of Hope, Duarte, CA, USA; Hedy Kindler, The University of Chicago Medical Center, Chicago, IL, USA; Lee Krug, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Kristiaan Nackaerts, University Hospitals, Leuven, Belgium; Harvey Pass, New York University, NY, USA; David Rice, MD Anderson Cancer Center, Houston, TX, USA.

      Advisory Board of the IASLC Thymic Malignancies Domain

      Conrad Falkson, Queen’s University, Ontario, Canada; Pier Luigi Filosso, University of Torino, Italy; Giuseppe Giaccone, Georgetown University, Washington, DC, USA; Kazuya Kondo, University of Tokushima, Tokushima, Japan; Marco Lucchi, University of Pisa, Pisa, Italy; Meinoshin Okumura, Osaka University, Osaka, Japan.

      Advisory Board of the IASLC Esophageal Cancer Domain

      Eugene Blackstone, Cleveland Clinic, OH, USA.

      Participating Institutions in the New IASLC Lung Cancer Staging Project

      F. Abad Cavaco and E. Ansótegui Barrera, Hospital La Fe, Valencia, Spain; J. Abal Arca and I. Parente Lamelas, Complejo Hospitalario de Ourense, Ourense, Spain; A. Arnau Obrer and R. Guijarro Jorge, Hospital General Universitario de Valencia, Valencia, Spain; D. Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; G. K. Bascom, Good Samaritan Hospital, Kearney, NE, USA; A. I. Blanco Orozco and M. A. González Castro, Hospital Virgen del Rocío, Sevilla, Spain; M. G. Blum, Penrose Cancer Center, Colorado Springs, USA; D. Chimondeguy, Hospital Universitario Austral, Argentina; V. Cvijanovic, Military Medical Academy, Belgrade, Serbia; S. Defranchi, Hospital Universitario-Fundacion Favaloro, Buenos Aires, Argentina; B. de Olaiz Navarro, Hospital de Getafe, Getafe, Spain; I. Escobar Campuzano and I. Macía Vidueira, Hospital de Bellvitge, L’Hospitalet de Llobregat, Spain; E. Fernández Araujo and F. Andreo García, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; K. M. Fong, Prince Charles Hospital, Brisbane, Australia; G. Francisco Corral and S. Cerezo González, Hospital La Mancha Centro, Ciudad Real, Spain; J. Freixinet Gilart, Hospital Universitario ‘Dr. Negrín,’ Las Palmas de Gran Canaria, Spain; L. García Arangüena, Hospital Sierrallana, Torrelavega, Spain; S. García Barajas, Hospital Infanta Cristina, Badajoz, Spain; P. Girard, L’Institut Mutualiste Montsouris, Paris, France; T. Goksel, Turkish Thoracic Society, Turkey; M. T. González Budiño, Hospital General Universitario de Oviedo, Oviedo, Spain; G. González Casaurrán, Hospital Gregorio Marañón, Madrid, Spain; J. A. Gullón Blanco, Hospital San Agustín, Avilés, Spain; J. Hernández Hernández, Hospital de Ávila, Avila, Spain; H. Hernández Rodríguez, Hospital Universitario de Tenerife, Santa Cruz de Tenerife, Spain; J. Herrero Collantes, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain; M. Iglesias Heras, Hospital de Ávila, Ávila, Spain; J. M. Izquierdo Elena, Hospital Nuestra Señora de Aránzazu, Donostia, Spain; E. Jakobsen, Danish Lung Cancer Registry, Denmark; S. Kostas, Athens School of Medicine, Athens, Greece; P. León Atance and A. Núñez Ares, Complejo Hospitalario de Albacete, Albacete, Spain; M. Liao, Shanghai Lung Tumor Clinical Medical Center, Shanghai, China; M. Losanovscky, Clinica y Maternidad Suizo Argentina, Buenos Aires, Argentina; G. Lyons, Hospital Britanico de Buenos Aires, Buenos Aires, Argentina; R. Magaroles and L. De Esteban Júlvez, Hospital Joan XXIII, Tarragona. Spain; M. Mariñán Gorospe, Hospital de San Pedro de Logroño, Logroño, Spain; B. McCaughan and C. Kennedy, University of Sydney, Sydney, Australia; R. Melchor Íñiguez, Fundación Jiménez Díaz, Madrid, Spain; L. Miravet Sorribes, Hospital La Plana, Castellón, Spain; S. Naranjo Gozalo and C. Álvarez de Arriba, Hospital Universitario Marqués de Valdecilla, Santander, Spain; M. Núñez Delgado, Hospital de Meixoeiro, Vigo, Spain; J. Padilla Alarcón and J. C. Peñalver Cuesta, Instituto Valenciano de Oncología, Valencia, Spain; J. S. Park, Samsung Medical Center, Seoul, South Korea; H. Pass, New York University Langone Medical Center and Cancer Center, New York, USA; M. J. Pavón Fernández, Hospital ‘Severo Ochoa,’ Leganés, Spain; M. Rosenberg, Alexander Fleming Institute and Hospital de Rehabilitación Respiratoria, Buenos Aires, Argentina; E. Ruffini, University of Torino, Torino , Italy; V. Rusch, Memorial Sloan-Kettering Cancer Center, New York, USA; J. Sánchez de Cos Escuín, Hospital de Cáceres, Cáceres, Spain; A. Saura Vinuesa, Hospital de Sagunto, Sagunto, Spain; M. Serra Mitjans, Hospital Universitari Mutua Terrassa, Terrassa, Spain; T.E. Strand, Cancer Registry of Norway, Norway; D. Subotic, Clinical Centre of Serbia, Belgrade, Serbia; S. Swisher, MD Anderson Cancer Center, Houston, TX, USA; R. Terra, University of São Paulo Medical Center, São Paulo, Brazil; C. Thomas, Mayo Clinic Rochester, Rochester, MN, USA; K. Tournoy, University Hospital Ghent, Belgium; P. Van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; M. Velasquez, Fundacion Clinica Valle del Lili, Cali, Colombia; Y. L. Wu, Guangdong General Hospital, Guangzhou, China; K. Yokoi, Japanese Joint Committee for Lung Cancer Registry, Osaka, Japan.

      Supplementary Data

      References

        • Lozano R.
        • Naghavi M.
        • Foreman K.
        • et al.
        Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380: 2095-2128
      1. Howlader N. Noone A.M. Krapcho M. SEER Cancer Statistics Review, 1975–2010. National Cancer Institute, Bethesda, MD2013
        • Stahel R.A.
        • Ginsberg R.
        • Havemann K.
        • et al.
        Staging and prognostic factors in small cell lung cancer: a consensus report.
        Lung Cancer. 1989; 5: 119-126
        • Zelen M.
        Keynote address on biostatistics and data retrieval.
        Cancer Chemother Rep 3. 1973; 4: 31-42
        • Shepherd F.A.
        • Crowley J.
        • Van Houtte P.
        • et al.
        The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer.
        J Thorac Oncol. 2007; 2: 1067-1077
        • Goldstraw P.
        • Crowley J.
        • Chansky K.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.
        J Thorac Oncol. 2007; 2: 706-714
        • Rami-Porta R.
        • Goldstraw P.
        Strength and weakness of the new TNM classification for lung cancer.
        Eur Respir J. 2010; 36: 237-239
        • Giroux D.J.
        • Rami-Porta R.
        • Chansky K.
        • et al.
        The IASLC Lung Cancer Staging Project: data elements for the prospective project.
        J Thorac Oncol. 2009; 4: 679-683
        • Rami-Porta R.
        • Bolejack V.
        • Giroux D.J.
        • et al.
        The IASLC Lung Cancer Staging Project: the new database to inform the 8th edition of the TNM classification of lung cancer.
        J Thorac Oncol. 2014; 9: 1618-1624
        • Asamura H.
        • Chansky K.
        • Crowley J.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
        J Thorac Oncol. 2015; 10: 1675-1684
        • Eberherdt W.
        • Mitchell A.
        • Crowley J.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming (8th) edition of the TNM classification for lung cancer.
        J Thorac Oncol. 2015; 10: 1515-1522
        • Rami-Porta R.
        • Bolejack V.
        • Crowley J.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
        J Thorac Oncol. 2015; 10: 990-1003
        • Liu P.Y.
        • Tsai W.Y.
        A modified logrank test for censored survival data under order restrictions.
        Stastistics and Probability Letters. 1999; 41: 57-63
        • Vallieres E.
        • Shepherd F.A.
        • Crowley J.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer.
        J Thorac Oncol. 2009; 4: 1049-1059