The IASLC Lung Cancer Staging Project: Proposals for the Revision of the T Descriptors in the Forthcoming (Seventh) Edition of the TNM Classification for Lung Cancer

To study the prognostic impact of the different descriptors that define the T component of the TNM classification in patients with N0M0 tumors, and to see whether they are useful in classifying non-small cell lung cancer (NSCLC), the T descriptors subcommittee established the following issues as priorities:

• •
  Clinical and pathologic tumor size in T1 and T2 tumors, excluding other T2 descriptors.
• •
  Clinical and pathologic T2 descriptors, in general and stratified by tumor size: atelectasis/pneumonitis of less than the whole lung, visceral pleural involvement, and endobronchial location.
• •
  Clinical and pathologic T3 descriptors: atelectasis/pneumonitis of the whole lung, parietal pleura invasion, chest wall invasion, diaphragmatic invasion, parietal pericardial invasion, mediastinal pleural invasion, endobronchial location, invasion of the phrenic nerve, and Pancoast tumor.
• •
  Clinical and pathologic T4 descriptors: carinal invasion, invasion of mediastinal tissue, invasion of the great vessels, invasion of the heart, invasion of the recurrent laryngeal nerve, invasion of the esophagus, invasion of the trachea, invasion of the vertebral body, additional nodules in the same lobe as the primary tumor, and malignant pleural and pericardial effusion.
• •
  Stratification of results by cell type.
• •
  Stratification of results by completeness of resection.

The total number of patients submitted to CRAB was 100,869, of whom 18,018 patients met the T descriptors subcommittee's initial analytic requirements of M0 NSCLC, a complete set of either cTNM or pTNM, and sufficient T descriptor details to support the assigned T stage (Table 1). On the basis of recommendations by the M descriptors subcommittee, 180 patients with tumors staged as M1 because of additional nodules in an ipsilateral different lobe from the primary tumor were added to the T component analysis, bringing the total analyzed to 18,198. These 18,198 patients originated from four geographical areas, including Europe, North America, Asia, and Australia, and from a variety of data sources (see Table 2).

The NSCLC M0 population with complete cTN included 38,162 patients (Table 1). There was sufficient clinical T descriptor information for 5760 patients, including 339 treated preoperatively, distributed as follows: 68% cN0, 5% cN1, 21% cN2, 4% cN3, and 3% cT4Nx. As for the analysis of the pathologic T, the population excluded neoadjuvant treatment and consisted of 26,177 M0 patients with complete pTN (substitutions of cM for pM were permitted). In 15,234 of these patients, the tumors had sufficient pT descriptors and were distributed as follows: 64% pN0, 19% pN1, 17% pN2, 0.5% pN3, and 0.3% pT4Nx. Table 3 summarizes the distribution of histologic types according to clinical and pathologic T factors. Complete resection (R0) was achieved in 85% of tumors with any pN, and this rate increased to 89% in those with no nodal involvement (pN0) (Table 4).

The approach to validation was suggested by the validation and methodology subcommittee and is described in more detail elsewhere. The validation analysis was performed in the general population and in the population of patients with no nodal disease. Complete and incomplete resections were included in the population for analysis of pathologic T.

Survival was measured from the date of entry (date of diagnosis for registries, date of registration for protocols) for clinically staged data and from the date of surgery for pathologically staged data; it was calculated by the Kaplan-Meier method. Prognostic groups were assessed by Cox regression analysis, using the SAS System for Windows version 9.0 PHREG procedure.

In the derivation of tumor size cutpoints, the running log-rank statistic produced by each hypothetical cutpoint in the pN0 R0 learning set was graphed against tumor size, and the tumor size that coincided with the highest log-rank statistic was chosen as the optimal cutpoint, after rounding to the nearest whole centimeter. The chosen cutpoint was then tested in the pN0 R0 validation set and explored in incompletely resected cases and in all the other nodal stage groups, and also in clinically obtained measurements of tumor size. S-Plus version 7.0 was the software used to generate the log-rank statistics.

When comparing overall survival between groups of patients defined by tumor size, we found that survival differences were optimized at size cutpoints of 2, 3, 5, and 7 cm. These tumor size cutpoints were chosen on the basis of pathologic measurements from completely resected cases in the learning set and were then tested in the remaining pathologic and clinical data. In the learning set of 2284 R0 patients with pT1 N0 tumors (two thirds of all such patients), the highest log-rank statistic coincided with a pathologic tumor measurement of 2.0 cm (Figure 1). For the learning set for 2607 R0 patients with pT2 N0 tumors, the highest log-rank statistic occurred at a pathologic tumor measurement of 7.3 cm, with the second-highest split at 5.0 cm (Figure 2). These four tumor size cutpoints were confirmed in the validation set of 2589 pT1- and pT2 N0 R0 cases with p values of 0.0017, <0.0001, <0.0001, and 0.0125 for each comparison between the resulting five adjacent tumor size groups, starting with the smallest tumors. In both the learning set and the validation set, tumor sizes were distributed as follows: 23% smaller than or equal to 2 cm; 23% larger than 2 cm but smaller than 3 cm; 37% larger than 3 cm but smaller than 5 cm; 11% larger than 5 cm but smaller than 7 cm; and 5% larger than 7 cm. Figure 3.

In all pathologically staged N0 R0 cases (learning and validation sets combined), for patients with tumors no larger than 2 cm (n = 1816), median survival was not reached. For those larger than 2 cm but smaller than 3 cm (n = 1653), survival was 113 months. For those with tumors larger than 3 cm but smaller than 5 cm (n = 2822), survival dropped to 81 months. For those with tumors larger than 5 cm but smaller than 7 cm (n = 825), survival was 56 months. For those with tumors larger than 7 cm (n =364), survival was 29 months. See FIGURE 1, FIGURE 2, FIGURE 3 and TABLE 5, TABLE 6 for details; the tables also summarize results for N0 cases irrespective of completeness of resection, and for any N status.

When clinically staged N0 cases were grouped into the five size categories as above, median survival was not significantly different between the smallest two size groups (68 vs 52 months, p = 0.09); nevertheless, comparisons between adjacent groups yielded significant survival differences at the 3-cm cutpoint (43 vs 30 months, p = 0.001) and at the 5-cm cutpoint (30 vs 17 months, p = 0.008). Survival for patients with tumors larger than 7 cm was not significantly different from cT3 tumors (17 versus 19 months, p = 0.61) (Table 6, Figure 4).

Subgroup analyses of these tumor size cutpoints within different histologic types of NSCLC yielded similar results. The differences between size categories diminished as nodal disease advanced.

In our analyses of overall survival among pathologically staged cases categorized by UICC sixth edition as T3, T4, and M1 by additional nodule (same side, different lobe), the following prognostic groups emerged: T3 (n = 1224), with median survival of 24 months; T4 exclusively by same-side nodules (n = 363), with survival of 21 months; T4 by pleural dissemination, including malignant pleural effusion or pleural nodules (n = 245), with survival of 18 months; other T4 (n = 340), with survival of 15 months; and M1 by same side/different lobe (n = 180), with survival of 18 months. In contrast to the analysis of tumor size, the primary comparisons of survival described below and shown in Figure 5 for these later-stage cases include all pathologically staged cases, irrespective of completeness of resection or nodal status. Comparisons are summarized in Table 7 for various populations (N0 R0; any R N0; and any R, any N).

In practice, the discovery of same-side and, especially, same-lobe nodules is primarily a surgical rather than a clinical finding; thus, there were few patients with tumors staged cT4 (n = 17) or cM1 (n = 24) on the basis of same-side pulmonary nodules. For this reason, comparisons involving same-side nodules were not explored in detail in the clinically staged data. Conversely, malignant pleural effusions are more commonly diagnosed clinically and preclude surgery as an option. Five-year and median survival rates for the 471 patients with pleural dissemination were 2% and 8 months versus 14% and 13 months for the 418 in the comparator cT4 group (excluding same-side nodules), and survival between these two groups was statistically significantly different (p < 0.0001) (Table 8, Figure 6).

Other T2 descriptors (visceral pleural invasion and partial atelectasis), and the different T3- and T4 descriptors (except for the additional pulmonary nodule(s) in the lobe of the primary tumor) could not be evaluated, either because of the small number of patients, the inconsistent clinical and pathologic results, or lack of validation.

Complete details of the internal and external validations of these findings are published elsewhere. In summary, the subclassification of T1 and T2 into T1a and T1b, and T2a and T2b, respectively, driven by Asian data for pathologic size and by European data for clinical size, showed distinct differences in survival for both clinical and pathologic subgroups. These findings were consistent in most databases and in the SEER external validation, both in the overall population and in the surgical subset.

The finding that T2 tumors larger than 7 cm were more like T3 than other T2 was observed to be both internally and externally valid. The population-based SEER data indicated more of a risk continuum by size than was seen in the project dataset, but the >7-cm group's prognosis was closer to the T3 group than it was to the rest of the T2 group.

The influence of histologic type on the prognostic impact of tumor size was also evaluated, and the cutpoints of 2, 3, 5, and 7 cm were valid within all major cell types.

Cases with additional nodules in the primary lobe consistently experienced better survival than other T4 cases. Nevertheless, we were not able to look at this issue using cTNM, because this T descriptor was generally only documented in the surgical data. When restricted to those treated with surgery in the SEER data, the additional nodule group's survival was better than those even with T3 disease.

The finding that additional nodules in a different lobe of the ipsilateral lung had better prognosis than the present classification (M1) would indicate (and similar to that of T4) was driven by consortia/surgical series pathologic data that were almost all from the Asia/Australia region. This finding was also supported by the European pathologic data and the SEER registry.

Data supporting the reclassification of pleural dissemination from T4 to M1 were driven by the European and North American series in the clinically staged analyses and by pathologic series from consortium/surgical series. These findings also were supported by the SEER data.

P. Goldstraw (chairperson), Royal Brompton Hospital, London, United Kingdom; D. Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; E. Brambilla, Laboratoire de Pathologie Cellulaire, Grenoble Cedex, France; P.A. Bunn, University of Colorado Health Sciences, Denver, CO, USA; D. Carney, Mater Misericordiae Hospital, Dublin, Ireland; T. Le Chevalier, Institute Gustave Roussy, Villejuif, France; J. Crowley, Cancer Research and Biostatistics, Seattle, WA, USA; R. Ginsberg (deceased), Memorial Sloan-Kettering Cancer Center, New York, NY, USA; P. Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; H.H. Hansen (retired), National University Hospital, Copenhagen, Denmark; P. Van Houtte, Institute Jules Bordet, Brussels, Belgium; J-G. Im, Seoul National University Hospital, Seoul, South Korea; J.R. Jett, Mayo Clinic, Rochester, MN, USA; H. Kato (retired), Tokyo Medical University, Tokyo, Japan; T. Naruke (deceased), Saiseikai Central Hospital, Tokyo, Japan; E.F. Patz, Duke University Medical Center, Durham, NC, USA; P.E. Postmus, Free University Hospital, Amsterdam, The Netherlands; R. Rami-Porta, Hospital Mutua de Terrassa, Terrassa, Spain; V. Rusch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; J.P. Sculier, Institute Jules Bordet, Brussels, Belgium; F.A. Shepherd, University of Toronto, Toronto, Ontario, Canada; Y. Shimosato (retired), Tokyo Medical College, Tokyo, Japan; L. Sobin, Armed Forces Institute of Pathology, Washington, DC, USA; W. Travis, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; M. Tsuboi, Tokyo Medical University, Tokyo, Japan; R. Tsuchiya, National Cancer Centre, Tokyo, Japan; E. Vallières, Swedish Cancer Institute, Seattle, WA, USA; Yoh Watanabe (deceased), Kanazawa Medical University, Uchinada, Japan; H. Yokomise, Kagawa University, Kagawa, Japan; and Z. Shaikh (research assistant), Royal Brompton Hospital, London, United Kingdom.

J.J. Crowley, K. Chansky, D. Giroux, and V. Bolejack, Seattle, WA, USA.

C. Kennedy, University of Sydney, Sydney, Australia; M. Krasnik, Gentofte Hospital, Copenhagen, Denmark; J.P. van Meerbeeck, University Hospital, Ghent, Belgium; J. Vansteenkiste, Leuven Lung Cancer Group, Leuven, Belgium.

O. Visser, Amsterdam Cancer Registry, Amsterdam, The Netherlands; R. Tsuchiya, T. Naruke (deceased), National Data from Japan; J.P. Van Meerbeeck, Flemish Lung Cancer Registry–VRGT, Brussels, Belgium; H. Bülzebruck, Thoraxklinik am Universitatsklinikum, Heidelberg, Germany; R. Allison and L. Tripcony, Queensland Radium Institute, Queensland, Australia; X. Wang, D. Watson, and J. Herndon, Cancer and Leukemia Group B (CALGB), USA; R.J. Stevens, Medical Research Council Clinical Trials Unit, London, United Kingdom; A. Depierre, E. Quoix, and Q. Tran, Intergroupe Francophone de Cancerologie Thoracique (IFCT), France; J.R. Jett and S. Mandrekar, North Central Cancer Treatment Group (NCCTG), USA; J.H. Schiller and R.J. Gray, Eastern Cooperative Oncology Group (ECOG), USA; J.L. Duque-Medina and A. Lopez-Encuentra, Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S), Spain; J.J. Crowley, Southwest Oncology Group (SWOG), USA; J.J. Crowley and K.M.W. Pisters, Bimodality Lung Oncology Team (BLOT), USA; T.E. Strand, Cancer Registry of Norway, Norway; S. Swann and H. Choy, Radiation Therapy Oncology Group (RTOG), USA; R. Damhuis, Rotterdam Cancer Registry, The Netherlands; R. Komaki and P. K. Allen, MD Anderson Cancer Center (MDACC-RT), USA; J.P. Sculier and M. Paesmans, European Lung Cancer Working Party (ELCWP); Y.L. Wu, Guangdong Provincial People’s Hospital, Peoples Republic of China; M. Pesek and H. Krosnarova, Faculty Hospital Plzen, Czech Republic; T. Le Chevalier and A. Dunant, International Adjuvant Lung Cancer Trial (IALT), France; B. McCaughan and C. Kennedy, University of Sydney, Sydney, Australia; F. Shepherd and M. Whitehead, National Cancer Institute of Canada (NCIC); J. Jassem and W.Ryzman, Medical University of Gdansk, Poland; G.V. Scagliotti and P. Borasio, Universita’ Degli Studi di Torino, S. Luigi Hospital, Orbassano, Italy; K.M. Fong and L. Passmore, Prince Charles Hospital, Australia; V.W. Rusch and B.J. Park, Memorial Sloan-Kettering Cancer Center, USA; H.J. Baek, Korea Cancer Centre Hospital, Seoul, South Korea; R.P. Perng, Taiwan Lung Cancer Society, Taiwan; R.C. Yung and A. Gramatikova, The Johns Hopkins University, USA; J. Vansteenkiste, Leuven Lung Cancer Group (LLCG), Belgium; C. Brambilla and M. Colonna, Grenoble University Hospital–Isere Cancer Registry, France; J. Hunt and A. Park, Western Hospital, Melbourne, Australia; J.P. Sculier and T. Berghmans, Institute of Jules Bordet, Brussels, Belgium; A.K. Cangir, Ankara University School of Medicine, Ankara, Turkey; D. Subotic, Clinical Centre of Serbia, Belgrade, Serbia; R. Rosell and V. Alberola, Spanish Lung Cancer Group (SLCG), Spain; A.A. Vaporciyan and A.M. Correa, MD Anderson Cancer Center–Thoracic and Cardiovascular Surgery (MDACC-TCVS), USA; J. P. Pignon, T. Le Chevalier, and R. Komaki, Institut Gustave Roussy (IGR), France; T. Orlowski, Institute of Lung Diseases, Warsaw, Poland; D. Ball and J. Matthews, Peter MacCallum Cancer Centre, Melbourne, Australia; M. Tsao, Princess Margaret Hospital, Toronto, Canada; S. Darwish, Policlinic of Perugia, Italy; H.I. Pass and T. Stevens, Karmanos Cancer Institute, Wayne State University, USA; G. Wright, St Vincent’s Hospital, Victoria, Australia; and C. Legrand and J.P. van Meerbeeck, European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.