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Effect of Tumor Size on Prognosis in Patients Treated with Radical Radiotherapy or Chemoradiotherapy for Non–Small Cell Lung Cancer: An Analysis of the Staging Project Database of the International Association for the Study of Lung Cancer

      Background

      Analysis of the International Association for the Study of Lung Cancer database revealed that for patients with completely resected, node-negative, non–small-cell lung cancer (NSCLC), increasing tumor size was associated with worsening survival. This analysis was performed to determine the effect of size on prognosis in patients in the same database but who were treated with radiotherapy or chemoradiotherapy.

      Methods

      Patients were eligible if they had pathologically confirmed NSCLC, no evidence of distant metastases, intended treatment was radical radiotherapy (minimum 50 Gy) or combined chemotherapy and radiotherapy, no surgery, and tumor diameter was available.

      Results

      Eight hundred and sixty-eight patients were available for analysis. Patient characteristics were: sex (men) 65.3%; median age 64 years (range, 32–88); Eastern Cooperative Oncology Group performance status 0: 55%, 1: 33%, 2 or more: 5%; chemotherapy 74%; no chemotherapy 18%; weight loss less than 5 %: 70%, and more than 5%: 25%. Primary tumor size was categorized according to tumor, node, metastasis 7th edition. On univariate analysis, the following factors were prognostic for survival: age (continuous) (p = 0.0035); performance status of 1 or more (p = 0.0021); weight loss less than 5% (p < 0.0001); chemotherapy (p = 0.0189); and primary tumor size (continuous) (p = 0.0002). Sex and clinical nodal stage were not significant. On multivariate analysis, age and weight loss remained significant factors for survival, as was tumor size less than 3 cm.

      Conclusions

      In patients treated with radiotherapy with or without chemotherapy, tumor size less than 3 cm was associated with longer survival than larger tumors. Evidence of the effect of size on prognosis above this was weak. Five-year survival of more than 10% was observed in all four size categories.

      Key Words

      The 7th edition of the tumor, node, metastasis (TNM) staging system for lung cancer has five T categories for size: T1a, which is 2 cm or less; T1b, greater than 2 cm and up to and including 3 cm; T2a, greater than 3 cm and up to and including 5 cm; T2b, greater than 5 cm and up to and including 7 cm; and T3, tumors greater than 7 cm. These T categories are derived from an analysis of the staging database of the International Association for the Study of Lung Cancer (IASLC), which showed worsening prognosis for increasing tumor size.
      • Rami-Porta R
      • Ball D
      • Crowley J
      • International Staging Committee
      • Cancer Research and Biostatistics
      • Observers to the Committee
      • Participating Institutions
      • et al.
      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.
      That analysis was restricted to 8099 patients who had complete surgical resection of their disease, and who were node-negative, to avoid confounding the effect of size with the effect of lymph node involvement.
      However, further analyses on 9007 patients who had undergone any type of resection (complete and incomplete) but whose tumors had no nodal involvement, and on 1,3742 patients with complete and incomplete resections and with tumors including any type of nodal involvement, showed that the tumor-size groups were consistent in all these populations.
      • Rami-Porta R
      • Ball D
      • Crowley J
      • International Staging Committee
      • Cancer Research and Biostatistics
      • Observers to the Committee
      • Participating Institutions
      • et al.
      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.
      In theory, size should also be important in patients who are treated for cure with radiotherapy or chemoradiotherapy. Size may be even more directly relevant for local control (without which cure cannot be achieved), because the surgeon who achieves an R0 resection is able to eradicate all clonogenic cells, regardless of the primary tumor size. However, in the case of radiotherapy, cell killing is proportional to dose, and therefore, local control is dependent on both the number of clonogenic cells and the dose that can be safely administered. Indeed, a number of retrospective studies have suggested that tumor size is an important prognostic factor in lung cancer patients treated by nonsurgical means, particularly radiotherapy.
      • Basaki K
      • Abe Y
      • Aoki M
      • Kondo H
      • Hatayama Y
      • Nakaji S
      Prognostic factors for survival in stage III non-small-cell lung cancer treated with definitive radiation therapy: impact of tumor volume.
      • Bradley JD
      • Ieumwananonthachai N
      • Purdy JA
      • et al.
      Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma.
      • Dehing-Oberije C
      • De Ruysscher D
      • van der Weide H
      • et al.
      Tumor volume combined with number of positive lymph node stations is a more important prognostic factor than TNM stage for survival of non-small-cell lung cancer patients treated with (chemo)radiotherapy.
      • Etiz D
      • Marks LB
      • Zhou S-M
      • et al.
      Influence of tumor volume on survival in patients irradiated for non–small-cell lung cancer.
      • Stinchcombe TE
      • Morris DE
      • Moore DT
      • et al.
      Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy.
      This is consistent with the hypothesis that larger tumors are likely to contain more clonogenic cells, and it fits with clinical observations of tumor size and local control using radiotherapy in other cancer sites.
      • Dubben HH
      • Thames HD
      • Beck-Bornholdt HP
      Tumor volume: a basic and specific response predictor in radiotherapy.
      We therefore, undertook this study to see whether the T stage size categories derived from the surgical population for the 7th edition had a similar prognostic effect in patients from the same database but who were treated with radiotherapy with or without chemotherapy.

      PATIENTS AND METHODS

      The IASLC Staging Project was established in 1998 to inform the 7th edition of the TNM classification. A description of the project and the resulting database has been published previously.
      • Goldstraw P
      • Crowley J
      The International Association for the Study of Lung Cancer International Staging Project on Lung Cancer.
      More than 100,000 cases were accrued to the database and included patients treated by surgery, radiotherapy and chemotherapy, or combinations of these. To be eligible for the current analysis, patients on the database had to have a histologically confirmed diagnosis of NSCLC, no evidence of distant metastases, an intended treatment of radical radiotherapy (minimum 50 Gy) or combined chemotherapy and radiotherapy, no surgery, and an available tumor diameter. Other prognostic factor data including patient age, sex, performance status (ECOG), and weight loss were also drawn from the database. Unlike the initial analysis of the surgical patients, which was restricted to pathologically staged N0 cases, this analysis included patients with and without clinical lymph node involvement. Because the database was restricted to the era before fludeoxyglucose positron emission tomography became widely available, clinical diagnosis of lymph node involvement was unreliable. Further, the patients referred for radiotherapy were much more likely to have had lymph node involvement than surgical patients, and it would have been impractical to perform an analysis restricted to radiotherapy patients with negative nodes. However, it was intended that an adjustment for any effect of lymph node involvement would be undertaken through multivariate analysis, as it would be for other potential prognostic factors.

      Statistical Analysis

      The Kaplan–Meier estimator was used for survival curves. Survival was measured from the start of radiotherapy. Survival distributions were compared using the log-rank test. Univariate and multivariate Cox regression was used to model the effect of primary tumor size and other prognostic factors on survival. Stepwise variable selection was used to determine significant prognostic factors for the final multivariate model.

      RESULTS

      There were 868 patients from five separate sources available for analysis (Table 1). Patient characteristics are listed in Table 2. Survival of patients grouped according to size (T1, T2a, T2b, and T3) is shown in Figure 1. Patients with tumors less than or equal to 3 cm had significantly longer survival than patients with tumors larger than 3 cm but smaller than or equal to 7 cm. Patients with the largest tumors, that is, larger than 7 cm, had the worst survival, but this did not achieve statistical significance compared with T2b tumors (p = 0.11). Five-year survival above 10% was observed in all the four size categories. The influence of other prognostic factors is shown in Table 3. On univariate analysis, age, performance status, weight loss, chemotherapy, T category, and tumor size were all significant prognostic factors, but sex and clinical node status were not (Table 4). On multivariate analysis, age, weight loss, and tumor size equal to or less than 3 cm remained significant prognostic factors, but there was little evidence that size beyond this was prognostic (Table 5).
      TABLE 5Multivariate Analysis of Effect of Size and Other Prognostic Factors on Survival
      95% Hazard Ratio CI
      FactorReference Level for Hazard RatioHazard RatioLower LimitUpper Limitp
      Age (continuous) yrs1-yr increase in age1.0141.0061.0220.0007
      Weight loss ≥ 5%Weight loss < 5%1.4921.2591.769<.0001
      Weight loss not availableWeight loss < 5%1.3320.9721.8250.0744
      PT size > 3 cm and ≤ 5 cmPT size ≤ 3 cm1.2491.0321.5110.0223
      PT size > 5 cm and ≤ 7 cmPT size > 3 cm and ≤ 5 cm0.9730.7911.1970.9333
      PT size > 7 cmPT size > 5 cm and ≤ 7 cm1.1780.9271.4970.1681
      PT, primary tumor; CI, confidence interval.
      TABLE 4Univariate Analysis of Effect of Size and Other Prognostic Factors on Survival
      Factorχ2Degrees of Freedomp
      p Value from likelihood ratio test.
      Age (continuous)8.541310.0035
      Age (quartiles)11.499030.0093
      Sex2.210810.137
      PS≥19.457910.0021
      Weight loss < 5%26.64172<.0001
      Chemotherapy7.941920.0189
      Clinical T17.576450.0035
      Clinical N1.572730.6656
      7th edition TNM stage8.464250.1324
      PT size (continuous)13.646410.0002
      PT size (grouped)18.868030.0003
      PT, primary tumor; TNM stage, tumor, node, metastasis stage; PS, performance status.
      a p Value from likelihood ratio test.
      Figure thumbnail gr2
      FIGURE 1Survival according to PT size (cm). PT, primary tumor.
      TABLE 3Survival According to Primary Tumor Size and Other Prognostic Factors
      FactorLevelMedian SurvivalMedian 95% CI5-Year Survival Estimate (%)5-Yr. Survival 95% CI
      LowerUpperLower (%)Upper(%)
      Tumor size, cmPT size ≤ 31.81.52.116.912.122.4
      PT size > 3 and ≤ 51.31.21.512.99.217.3
      PT size > 5 and ≤ 71.41.21.616.311.022.5
      PT size > 71.10.91.310.25.815.9
      Age, yrs< 561.41.31.717.212.123.1
      < 641.51.31.714.09.619.2
      < 701.51.31.814.29.419.9
      ≥ 701.20.91.310.76.815.5
      No data0.70.41.928.64.161.2
      SexWomen1.61.31.716.211.921.0
      Men1.31.21.413.110.316.3
      Performance status01.41.31.717.313.921.0
      11.31.21.410.06.614.2
      ≥21.20.91.69.63.120.6
      No data1.61.12.14.60.418.5
      Weight loss< 5%1.61.41.716.613.519.9
      ≥ 5%1.00.81.28.75.313.1
      No data1.20.91.67.82.118.4
      ChemotherapyChemotherapy1.41.31.616.313.319.6
      No chemotherapy1.21.01.410.36.115.7
      No data1.41.11.85.81.912.8
      Clinical TT1a1.61.32.115.57.725.7
      T1b2.62.13.222.613.033.8
      T2a1.31.21.512.18.216.7
      T2b1.30.91.916.98.428.0
      T31.31.11.413.38.918.6
      T41.31.21.414.09.219.9
      Clinical NN01.61.31.812.27.618.0
      N11.41.12.18.42.220.0
      N21.41.21.515.712.519.2
      N31.31.01.412.87.419.9
      7th editionIA2.01.52.916.26.629.6
      TNM stageIB1.30.81.82.60.211.8
      IIA2.30.93.215.83.934.9
      IIB1.71.32.015.25.529.2
      IIIA1.41.21.615.612.419.2
      IIIB1.31.21.413.08.718.1
      PT, primary tumor; CI, confidence interval; TNM stage, tumor, node, metastasis stage; PS, performance status.
      TABLE 2Patient Characteristics
      FactorLeveln%
      Tumor size, cmPT size ≤ 323326.8
      PT size > 3 and ≤ 529734.2
      PT size > 5 and ≤ 717520.2
      PT size > 716318.8
      Age, yrs< 5621324.5
      < 6422325.6
      < 7020423.5
      ≥ 7022125.5
      No data70.8
      SexWomen30134.6
      Men56765.3
      Performance status047855.1
      128733.1
      2445.1
      No data596.8
      Weight loss< 5%60970.2
      ≥ 5%21424.7
      No data455.2
      ChemotherapyChemotherapy63873.5
      No chemotherapy15317.6
      No data778.9
      Clinical TT1a698.0
      T1b657.5
      T2a27131.2
      T2b606.9
      T320523.6
      T419822.8
      Clinical NN015818.2
      N1435.0
      N254562.8
      N312214.1
      7th editionTNM stageIA374.3
      IB384.4
      IIA192.0
      IIB333.8
      IIIA51459.2
      IIIB22726.2
      PT, primary tumor; TNM, tumor, node, metastasis; PS, performance status.
      TABLE 1Patient Data Sources
      Data Sourcen%
      M.D. Anderson Cancer Center24127.8
      National Cancer Institute of Canada141.6
      Peter MacCallum Cancer Center13015.0
      Queensland Radium Institute212.4
      Radiotherapy Oncology Group (RTOG)46253.2
      Total868100.0

      DISCUSSION

      This analysis of the IASLC staging database is the first to study the relationship between survival and the tumor-size groupings of the TNM 7th edition in patients with NSCLC treated with radiotherapy instead of surgery. It reveals that patients with T1 tumors (7th edition) have longer survival than patients with T2 and T3 tumors categorized according to size, but it failed to provide evidence that there was a prognostic effect of size within the T2a and T2b categories. The survival of T3 tumor patients was shorter than for T2 tumor patients, but this did not achieve statistical significance. Five-year survival from the beginning of radiotherapy was similar for all four size groups, within the range of 10% to17% and all with overlapping 95% confidence intervals.
      Several reasons can be advanced for the failure of this study to detect a convincing prognostic effect of tumor size beyond the T1 category. First, the population studied was different because unlike the surgical population, cases with involved nodes were eligible, and the effect of node involvement may have partly masked the effect of primary tumor size. That is, the worse prognosis conferred by node involvement and associated risk of distant metastasis overrode any adverse influence of increasing tumor size on local control as a competing risk for death. However, clinical N status overall was not in itself prognostic in this study, so this is unlikely to be the explanation for the absence of a prognostic effect of increasing tumor size beyond T1. In a previous publication based on the IASLC database, clinical N status was strongly prognostic, but this was driven mostly by the outcomes in patients who underwent surgical treatment.
      • Rusch VW
      • Crowley J
      • Giroux DJ
      • International Staging Committee
      • Cancer Research and Biostatistics
      • Observers to the Committee
      • Participating Institutions
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer.
      The authors were unable to determine why clinical nodal status had little prognostic effect in nonsurgical patients, but suggested less effective treatment or the presence of comorbidities as possible explanations.
      Second, it is possible that the prognostic effect of size varies according to the treatment given, that is, it is predictive rather than prognostic. As mentioned earlier, the size of the primary tumor may have different implications based on whether the cancer was removed surgically, or treated with (chemo)radiation. In the case of the surgically treated patient, increasing size (and with it the number of clonogenic cells) may be associated with increasing risk of distant metastasis, but may have little influence on technical resectability and local control. However, tumor size may be a major determinant of local control in the radiotherapy patient, if size is a surrogate for the number of clonogenic cells, and there is a limit to the dose of radiotherapy that can be given. It has been estimated that a 1-cm tumor contains 109 cells, a 3-cm tumor somewhere between 1010 and 1011 cells, and a 5-cm tumor a little over 1011 cells.
      • James K
      • Eisenhauer E
      • Christian M
      • et al.
      Measuring response in solid tumors: unidimensional versus bidimensional measurement.
      A 7-cm tumor contains approximately 1011.5 cells. Because cell killing by radiation is exponential, there should be a size–response effect for a fixed dose of radiation over the range of sizes represented by the T categories (assuming all the cells are clonogenic). The size of the effect should progressively diminish with increasing T size. The tumor may also be made up of stroma, inflammatory cells, and necrotic material as well as clonogenic cells, and intertumor variation in the proportions of these components may account for differences in response between tumors of similar size. Tumors also vary in their radiosensitivity, either an intrinsic genetically determined characteristic, or as a result of the presence or absence of tumor hypoxia. These factors, alone or in combination, may affect the probability of local control independently of the tumor size in an irradiated tumor, but not in one that has been resected. Finally, in this analysis no adjustment has been made for the prognostic effect of comorbidities, which are likely to be more important in a radiotherapy population compared with patients who are fit enough to undergo surgical resection.
      A number of retrospective studies have analyzed the relationship between tumor size and survival in patients with nonmetastatic NSCLC treated with radiotherapy, with and without chemotherapy.
      • Basaki K
      • Abe Y
      • Aoki M
      • Kondo H
      • Hatayama Y
      • Nakaji S
      Prognostic factors for survival in stage III non-small-cell lung cancer treated with definitive radiation therapy: impact of tumor volume.
      • Bradley JD
      • Ieumwananonthachai N
      • Purdy JA
      • et al.
      Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma.
      • Dehing-Oberije C
      • De Ruysscher D
      • van der Weide H
      • et al.
      Tumor volume combined with number of positive lymph node stations is a more important prognostic factor than TNM stage for survival of non-small-cell lung cancer patients treated with (chemo)radiotherapy.
      • Etiz D
      • Marks LB
      • Zhou S-M
      • et al.
      Influence of tumor volume on survival in patients irradiated for non–small-cell lung cancer.
      • Stinchcombe TE
      • Morris DE
      • Moore DT
      • et al.
      Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy.
      ,
      • Werner-Wasik M
      • Swann RS
      • Bradley J
      • et al.
      Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer.
      ,12 The largest study had 270 patients. All these studies demonstrated worse survival associated with increasing tumor size, but methodologic differences limit comparison with the present report. In none of the studies were the data analyzed according to the size groupings of the TNM 7th edition. Tumor size was sometimes treated as a continuous variable and sometimes as a dichotomous variable divided by the median value. In three studies, tumor size was calculated by adding the sizes of the primary tumor and the lymph nodes together.
      • Dehing-Oberije C
      • De Ruysscher D
      • van der Weide H
      • et al.
      Tumor volume combined with number of positive lymph node stations is a more important prognostic factor than TNM stage for survival of non-small-cell lung cancer patients treated with (chemo)radiotherapy.
      ,
      • Etiz D
      • Marks LB
      • Zhou S-M
      • et al.
      Influence of tumor volume on survival in patients irradiated for non–small-cell lung cancer.
      ,
      • Werner-Wasik M
      • Swann RS
      • Bradley J
      • et al.
      Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer.
      Seven studies allowed the use of induction chemotherapy, and it is not always clear whether size was measured before chemotherapy, or after chemotherapy but before radiotherapy.
      • Basaki K
      • Abe Y
      • Aoki M
      • Kondo H
      • Hatayama Y
      • Nakaji S
      Prognostic factors for survival in stage III non-small-cell lung cancer treated with definitive radiation therapy: impact of tumor volume.
      • Bradley JD
      • Ieumwananonthachai N
      • Purdy JA
      • et al.
      Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma.
      • Dehing-Oberije C
      • De Ruysscher D
      • van der Weide H
      • et al.
      Tumor volume combined with number of positive lymph node stations is a more important prognostic factor than TNM stage for survival of non-small-cell lung cancer patients treated with (chemo)radiotherapy.
      • Etiz D
      • Marks LB
      • Zhou S-M
      • et al.
      Influence of tumor volume on survival in patients irradiated for non–small-cell lung cancer.
      • Stinchcombe TE
      • Morris DE
      • Moore DT
      • et al.
      Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy.
      ,
      • Werner-Wasik M
      • Swann RS
      • Bradley J
      • et al.
      Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer.
      ,12 In the present study tumor size was measured before any treatment was given.
      One prospective study of 509 patients treated with radiotherapy, with or without chemotherapy, assessed the effect of tumor volume on survival.

      Ball D, Fisher R, Burmeister B, et al. The complex relationship of lung tumour volume to survival in patients with non-small cell lung cancer treated by definitive radiotherapy; Trans Tasman Radiation Oncology Group study 9905 (abstract). Radiother Oncol.

      Size was analyzed both as a continuous variable and grouped by quartiles, and before any treatment was given. There were some similarities in the findings in that study and the present report. The smallest tumors in the lowest quartile had the best prognosis, but beyond that, the impact of size was less evident, as seen in the IASLC patients. Tumor size also had little effect on 5-year survival in both studies. The clinical implication of this last observation is that tumor size alone should not influence the decision to give radiotherapy with curative intent.
      In summary, the effect of increasing tumor size on prognosis was less evident in patients treated with (chemo)radiotherapy (except for T1 patients) than for patients treated with surgery, or in most of the existing radiotherapy literature. This finding has been independently supported by the results of a prospective and methodologically rigorous cooperative group trial,

      Ball D, Fisher R, Burmeister B, et al. The complex relationship of lung tumour volume to survival in patients with non-small cell lung cancer treated by definitive radiotherapy; Trans Tasman Radiation Oncology Group study 9905 (abstract). Radiother Oncol.

      indicating that it is unlikely to be a chance finding. Therefore, this study alerts us to the possibility that the tumor size descriptors may not have the same applicability to patients treated by (chemo)radiotherapy as they do for patients treated surgically, at least, in terms of prognosis. Future editions of TNM will be informed by a prospective database that is actively accruing at the time of writing.
      • Giroux DJ
      • Rami-Porta R
      • Chansky K
      • et al.
      International Association for the Study of Lung Cancer International Staging Committee. The IASLC Lung Cancer Staging Project: data elements for the prospective project.
      We hope the cases added to the database will provide sufficient numbers of patients in all treatment groups so that a broadly relevant staging system can be developed and used, regardless of which treatment is applied.

      ACKNOWLEDGMENTS

      The International Association for the Study of Lung Cancer Staging Project was funded by a restricted educational grant from Eli Lilly and Company. No individual from the company had any role in evaluating the data or in preparing the article. The project was also supported by the American Joint Committee on Cancer grant Improving American Joint Committee on Cancer/UICC tumor, node, metastasis cancer staging.

      APPENDIX. INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER INTERNATIONAL STAGING 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, National Cancer Center, Tokyo, Japan; David Ball, Peter MacCallum Cancer Institute, Melbourne, Australia; David Beer, University of Michigan, Ann Arbor, MI; Elisabeth Brambilla, Centre Hospitalier Universitaire Albert Michallon, Grenoble, France; Vanessa Bolejack, Cancer Research And Biostatistics, Seattle, WA; Paul Bunn, Ex Office, University of Colorado Cancer Center, Aurora, CO; Kari Chansky, Cancer Research And Biostatistics, Seattle, WA; John Crowley, Cancer Research And Biostatistics, Seattle, WA; Frank Detterbeck, Yale University, New Haven, CT; Wilfried Eberhardt, University of Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Françoise Galateau-Sallé, Centre Hospitalier Universitaire, Caen, France; David Gandara, Ex Office, University of California Davis Cancer Center, Sacramento, CA; Dorothy Giroux, Cancer Research And Biostatistics, Seattle, WA; 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; James Jett, Ex Office, National Jewish Health, Denver, CO; Catherine Kennedy, University of Sydney, Sydney, Australia; Jhingook Kim, Samsung Medical Center, Seoul, Korea; Haruhiko Kondo, Shizuoka Cancer Center, Shizuoka, Japan; Mark Krasnik, Gentofte Hospital, Copenhagen, Denmark; Diana Lowry, Cancer Research And Biostatistics, Seattle, WA; Jan van Meerbeeck, University Hospital, Ghent, Belgium; Takashi Nakano, Hyogo College of Medicine, Hyogo, Japan; Andrew Nicholson, Royal Brompton Hospital, London, United Kingdom; Anna Nowak, University of Western Australia, Subiaco, Australia; Harvey Pass, Board Liaison, New York University, New York, NY; Michael Peake, Glenfield Hospital, Leicester, United Kingdom; Pieter Postmus, Free University Medical Center, Amsterdam, The Netherlands; Thomas Rice, Cleveland Clinic, Cleveland, OH; Kenneth Rosenzweig, Mount Sinai Hospital, New York, NY; Valerie Rusch, Memorial Sloan-Kettering Cancer Center, New York, NY; 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; Leslie Sobin, Armed Forces Institute of Pathology, Washington, DC; Charles Thomas, Oregon Health & Science University, Portland, OR; Charles F. Thomas Jr, Mayo Clinic, Rochester, MN; William Travis, Memorial Sloan-Kettering Cancer Center, New York, NY; Ming Tsao, The Princess Margaret Hospital, Toronto, Ontario, Canada; Masahiro Tsuboi, Board Liaison, Kanagawa Cancer Center, Yokohama, Japan; Andrew Turrisi, Sinai Grace Hospital, Detroit, MI; Eric Valliéres, Swedish Cancer Institute, Seattle, WA; Johan Vansteenkiste, University Hospitals, Leuven, Belgium; Hirokazu Watanabe, National Cancer Center Hospital, Tokyo, Japan; Yi-Iong 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, M.D. Anderson Cancer Center, Houston, TX; Seiki Hasegawa, Hyogo College of Medicine, Hyogo, Japan; Kouki Inai, Hiroshima University Postgraduate School, Hiroshima, Japan; Kemp Kernstine, City of Hope, Duarte, CA; Hedy Kindler, The University of Chicago Medical Center, Chicago, IL; Lee Krug, Memorial Sloan-Kettering Cancer Center, New York, NY; Kristiaan Nackaerts, University Hospitals, Leuven, Belgium; David Rice, M.D. Anderson Cancer Center, Houston, TX.

      ADVISORY BOARD OF THE IASLC THYMIC MALIGNANCIES DOMAIN

      Conrad Falkson, Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, Ontario, Canada; Giuseppe Giaccone, National Cancer Institute, Bethesda, Maryland; Kazuya Kondo, Institute of Health Biosciences, Tokushima, Japan; Mario Lucchi, University of Pisa, Pisa, Italy; Cesar Moran, M.D. Anderson Cancer Center, Houston, TX; Meinoshin Okumura, Osaka University Graduate School of Medicine, Osaka, Japan.

      ADVISORY BOARD OF THE IASLC OESOPHAGEAL CANCER DOMAIN

      Eugene Blackstone, Cleveland Clinic, Cleveland, OH.

      PARTICIPATING INSTITUTIONS

      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, 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, M.D. 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, M.D. 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.

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