The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer

Accepted Manuscript The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer Frank C. Detterbeck, MD, Vanessa Bolejack, MPH, Douglas A. Arenberg, MD, John Crowley, PhD, Jessica S. Donington, MD, Wilbur A. Franklin, MD, Nicolas Girard, MD, Edith M. Marom, MD, Peter J. Mazzone, MD, Andrew G. Nicholson, MD, Valerie W. Rusch, MD, Lynn T. Tanoue, MD, William D. Travis, MD, Hisao Asamura, MD, Ramon Rami-Porta, MD FETCS, on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup and Participating Institutions PII:

S1556-0864(16)00433-0

DOI:

10.1016/j.jtho.2015.12.114

Reference:

JTHO 123

To appear in:

Journal of Thoracic Oncology

Received Date: 24 September 2015 Revised Date:

1 December 2015

Accepted Date: 29 December 2015

Please cite this article as: Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, Girard N, Marom EM, Mazzone PJ, Nicholson AG, Rusch VW, Tanoue LT, Travis WD, Asamura H, Rami-Porta R, on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup and Participating Institutions, The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer, Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2015.12.114. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer

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Frank C. Detterbeck MD, 1 Vanessa Bolejack MPH, 2 Douglas A. Arenberg MD, 3 John Crowley PhD, 2 Jessica S. Donington MD, 4 Wilbur A. Franklin MD, 5 Nicolas Girard MD, 6 Edith M. Marom MD, 7 Peter J. Mazzone MD, 8 Andrew G. Nicholson MD, 9 Valerie W. Rusch MD, 10 Lynn T. Tanoue MD, 11 W illiam D. Travis MD, 12 Hisao Asamura MD, 13 and Ramon Rami-Porta MD FETCS, 14 on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup and Participating Institutions 1 5 1

Department of Surgery, Yale University, New Haven, CT, United States of America Cancer Research And Biostatistics, Seattle, WA, United States of America 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States of America 4 Department of Thoracic Surgery, New York University, New York, NY, United States of America 5 Department of Pathology, University of Colorado, Denver, CO, United States of America 6 Respiratory Medicine Service, Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France 7 Department of Diagnostic Imaging, Tel-Aviv University, Ramat Gan, Israel 8 Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, United States of America 9 Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, United Kingdom 10 Thoracic Surgery Service, Sloan-Kettering Cancer Center, New York, NY, United States of America 11 Department of Internal Medicine, Yale University, New Haven, CT, United States of America 12 Department of Pathology, Sloan-Kettering Cancer Center, New York, NY, United States of America 13 Division of Thoracic Surgery, Keio University, School of Medicine, Tokyo, Japan 14 Thoracic Surgery Service, Hospital Universitari Mutua Terrassa and CIBERES Lung Cancer Group, Terrassa, Barcelona, Spain 15 See Appendix

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Keywords: Lung cancer, Non-small cell lung cancer, TNM classification, Lung cancer staging, Multiple tumors Abstract: 242 words, Text: 2865 words, 5 figures (+ 5 online only), 4 Tables, 36 references Disclosure:

Support: Drs. William Travis and Valerie Rusch’s work is supported in part by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748

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Abstract

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Introduction: Separate tumor nodules with the same histology occur in the lungs in a small proportion of patients with primary lung cancer. This paper addresses how such tumors can be classified to inform the 8th edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors and pneumonic-type of lung cancer, which are addressed in separate analyses. Methods: Survival of patients with separate tumor nodules in the IASLC database were analyzed. This was compared with a systematic literature review. Results: Survival of clinical stage patients decreased according to the location of the separate tumor nodule relative to the index tumor (same-lobe > same-side > other-side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However there was also a decrease in the proportion of patients resected; among only surgically resected or among non-resected patients no survival differences were noted. There were no survival differences between same-lobe nodule patients and those with other T3 tumors, between same-side nodule patients and those with T4 tumors, and other-side nodule patients and those with other M1a tumors. The data correlated with that identified in a literature review. Conclusions: Tumors with same-lobe separate tumor nodules (of the same histology) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the 7th and 8th edition of TNM classification of lung cancer.

Introduction

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Patients with primary lung cancer sometimes present with separate solid pulmonary tumor nodules (called intrapulmonary metastases in the pathology community) that have the same or similar radiologic and histologic appearance, and are viewed as metastatic from one another as opposed to separate primary tumors. These may occur in the same lobe as the primary tumor site, or in a different lobe either on the same or the contralateral side. The presence of such separate nodules has implications in the tumor, node and metastasis (TNM) classification of the tumor. The stage classification system undergoes periodic updates to reflect new knowledge. This paper details analysis of available information in order to inform development of proposals for the forthcoming (8th) edition of the TNM classification of malignant tumors.

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A difficulty in addressing this topic is that the distinction of second primary lung cancers, separate tumor nodules, and multifocal ground glass/lepidic (GG/L) tumors and pneumonic-type of lung cancer has not been made very clearly in the past. As a result there has been ambiguity in the literature and confusion in how stage classification should be applied.1, 2 In conjunction with preparing this paper (on separate tumor nodules) this larger issue has also been addressed: details are provided in other articles3, 4 and summarized in a paper that outlines proposed TNM classification of all patients with multiple pulmonary sites of lung cancer.5 In the following text these definitions are applied as best as possible to the available data, thus reporting on outcomes specifically for separate tumor nodules as opposed to cohorts consisting largely of second primary cancers or multifocal cancers with ground glass features. Patients should be classified as having separate tumor nodule(s) when there is a dominant “classic” lung cancer (i.e. solid, spiculated) and one (or more) solid separate lung nodules, either presumed or proven to have the same histologic features (although sometimes the distinction between a dominant and an additional nodule may be subtle). These should be distinguished from synchronous 2nd primary cancers (which can often be of the same histotype, but are deemed to be independent cancers on review of all available clinical and histologic information), multifocal tumors that have a prominent ground glass or lepidic component, and pneumonic-type of adenocarcinoma which manifests as diffuse or

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multinodular areas of consolidation similar in appearance to a pneumonia.3, 4 Further descriptions of these types of tumors and criteria to identify them are provided in a summary paper.5

Methods

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Proposals for revisions of the TNM classification for lung cancer are developed under the auspices of the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) by the Staging and Prognostic Factors Committee (SPFC) of the International Association for the Study of Lung Cancer (IASLC), which provided funding for the project. The IASLC formed a subcommittee to address the definition and classification of multiple pulmonary sites of lung cancer (consisting of the authors on this paper). This subcommittee used a detailed analysis of the IASLC database as well as a systematic literature review to develop proposals. The paper was then sent for critical review to an extended workgroup of individuals with particular interest and expertise in this topic (appendix). This document was then further reviewed and eventually endorsed by the entire IASLC SPFC according to an established process.

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The IASLC has conducted an ongoing initiative to populate an international database of lung cancer patients. For revisions to the 8th edition, after exclusions, 77,156 cases diagnosed from 1999-2010 were available for analysis in this database (70,967 with non-small cell lung cancer and 6,189 with small cell lung cancer), as described in detail elsewhere.6 The analysis was carried out by Cancer Research And Biostatistics (CRAB). Overall survival (OS) was measured from the date of diagnosis for clinically staged (c-stage) patients, and date of surgery for pathologically staged (p-stage) patients using the Kaplan-Meier method. Prognostic groups were assessed using Cox proportional hazards regression analysis.7 SAS version 9.2 was used to perform the survival and regression analyses.

Results

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Additionally, the multiple lesions subcommittee carried out a systematic search for relevant literature from 1995-2015 with the help of a methodologist. The PICO questions, search, results, and inclusion and exclusion criteria are available on request. The search was structured to build on a prior systematic review of lung cancer patients with multiple tumor lesions conducted during development of the American College of Chest Physicians (ACCP) Lung Cancer Guidelines (3rd edition).8, 9 Reference lists of identified articles were also examined, and each paper in the ACCP review was revisited to ensure that definitions of patient categories were applied appropriately and abstracted correctly.

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IASLC Database Analysis

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Outcomes by Location of Separate Tumor Nodules (Intrapulmonary Metastases) Separate tumor nodules were reported in 1.7% of patients (505/29595) with clinical stage information and 3.5% of patients (1122/31537) with pathologic stage information (Supplementary Table 1, Supplemental Digital Content 1). There was no difference in the proportions of histologic type between cases with or without nodules (Supplementary Table 2, Supplemental Digital Content 1). The relationship of clinical to pathologic stage suggests that many of the same-lobe separate tumor nodules were discovered incidentally at resection (or at least not coded on clinical staging, perhaps due to uncertainty if the nodule was malignant). The number (and proportion) of cases recorded as having separate nodules (in any lobe) recorded rose in 2007 (Supplementary Figure 1A, B, Supplemental Digital Content 2). The percent of all c-stage patients with separate tumor nodules rose from <3% of cases from 1999-2005 to ~10% from 2007-2010; in pathologic stage (p-stage) patients with separate tumor nodules increased from ~3% in 1999-2005 to ~6% in 2007-2010 (Supplementary Figure 1A, B, Supplemental Digital Content 2). Outcomes for c-stage patients with separate solid tumor nodules are shown in (Figure 1A-D). There is a decrease in OS by location of the separate tumor nodule to the index tumor (same lobe > different ipsilateral lobe > different contralateral lobe). This is true in patients with either cN0 or cN-any tumors (all M0 except for possible contralateral nodules). However, the percent of patients with same-

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lobe tumor nodules that were resected varies markedly. Separate analysis of surgically and non-surgically treated patients shows no differences in outcomes relative to the tumor nodule location. (Figure 1C, D). This comparison is shown for cohorts who are cN0 M0 (except possible contralateral nodules), in order to compare groups that might be resectable. Thus, the data suggests a correlation of OS with the treatment modality, rather than the relative location of a separate tumor nodule.

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For p-stage cohorts, the impact of nodule location on OS is unclear (Figure 2A, B). A statistically significant difference is observed for same-lobe vs same-side tumors in the pN0 M0 R0 (p=0.032) and in the pN-any M0 R-any (p=0.024) cohorts but not for other comparisons; however there are more incidentally discovered separate tumor nodules in the same-lobe cohort. The OS by location is similar for pN-any R0 (data not shown) and pN-any, M0, R-any cohorts (all M0 except for possible contralateral nodules).

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Information on the size of separate tumor nodules was not available for most of the cases. There was little difference in the size of the primary tumor between same-lobe, same-side and other-side cases (Supplementary Figure 2, Supplemental Digital Content 2), although there was a slight shift toward smaller primary tumors in the p-stage other-side separate nodule group. A comparison of 1 vs. ≥2 nodules was limited due to a paucity of patients with ≥2 nodules. Among c-stage N0 M0 (except possible contralateral nodules) tumors there was a suggestion of worse survival for ≥2 nodules for same-lobe, same-side and other-side nodules; sample size did not permit statistical analysis. Among p-stage cases there is little suggestion of such a trend.

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The OS of p-stage patients with separate tumor nodules (in any lobe) increased over time (5-year OS of 19%, 43% and 71% for cohorts in 1999-2003, 2004-2006 and 2007-2010 of pN0 M0[except other nodules] R0 non-japanese cohorts [31, 52 and 95 patients]; patients from Japan were excluded because they are not represented in the 2007-2010 group and have generally better survival). For c-stage patients little change was observed but the number of patients was very limited (5-year OS of 50, 50 and 62% for cohorts in 1999-2003, 2004-2006 and 2007-2010 of cN0 M0[except other nodules] non-japanese patients [2, 4, and 26 patients]; this includes c-stage surgical and non-surgically treated patients).

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Comparison with Other T3, T4, M1a Descriptors A comparison of same-lobe separate tumor nodules and other T3 descriptors shows no clear difference in p-stage cohorts (pN0 M0 R0, pN-any M0 R0, pN0 M0 R-any) when stratified by a single vs. multiple T3 descriptors (Figure 3A, B, C). There is also no clear difference in OS in c-stage T3 patients (Supplementary Figure 3A, B, Supplemental Digital Content 2). A comparison of same-side (different lobe) separate tumor nodules and other T4 descriptors also reveals no clear difference (Figure 4A, B, C); this is also observed in c-stage cohorts (Supplementary Figure 4A, B, Supplemental Digital Content 2). The limited sample sizes preclude statistical analysis. Further details of other T descriptors is provided in another paper.10

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Among c-stage, non-surgically managed patients there is no clear difference in OS between patients with other-side separate tumor nodules and other M1a descriptors (Figure 5). There exists a small cohort of patients with other-side separate tumor nodules that were resected. The survival of these patients compared to other M1a surgically managed patients is shown in Figure S5; there are no statistically significant survival differences, but the limited sample size precludes a robust analysis.

Literature Review

The results of the systematic literature review for separate tumor nodules with the same histology involves primarily surgical series. When reported, it appears that the majority of same-lobe separate tumor nodules (Table 1) were discovered incidentally; no reports have contrasted the outcomes for incidental vs preoperatively detected nodules. The 5-year OS for all resected patients is approximately 40%, and for N0 patients approximately 50%. Typically, only 1 separate tumor nodule was reported; several studies found no difference in OS for 1 vs ≥2 nodules11, 12 but one found a trend for better OS with solitary nodules (5-year OS 62 vs 33%, p = 0.18).13 Several studies found significantly better OS for

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smaller vs larger primary tumors11, 14, 15 or a similar trend.16 OS in large registries is slightly lower; it is unclear how many of these patients were resected but it appears that the majority were.

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Less data is available for same-side (different lobe) separate tumor nodules (Table 2). The 5-year OS for all resected patients is approximately 30%, and for N0 patients approximately 40%. Little further detail has been reported. One study found a trend to better survival in smaller tumors.15 Registry studies appear to primarily involve non-operated patients and have provided no details. Very little data is available regarding outcomes of patients with contralateral separate tumor nodules (Tables 3). Registry studies report very poor survival, but the vast majority of patients were not treated with curative intent. Only one study has reported specific outcomes on >10 resected patients; the 5-year OS was 77%.17, 18

Discussion

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While some details were not captured in the IASLC database, so that we cannot be completely sure of the nature of the lesions in the database, it appears likely that the large majority were separate solid tumor nodules with the same histology. Nodules with different histologic features or synchronous primaries were specifically excluded. Furthermore, it is unlikely that many of the addtional nodules were GG/L tumors: the majority of the primary cancers were >3cm, the distribution of histotypes was similar to that of lung cancer in general, there was no obvious correlation with geographic regions (i.e. Asia which seems more recently to have a higher proportion of GG/L tumors), the incidence of separate tumor nodules prior to 2007 was similar to what was seen in the IASLC database from 1990-2000 (when GG/L tumors were seen rarely). Finally, the OS in the IASLC database is similar to that reported in papers focusing on separate solid tumor nodules of the same histology.

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An increase in the number and proportion of cases submitted with separate tumor nodules was observed starting in 2007. The IASLC database consists of data from a variety of sources, varying over time. However, such differences do not correlate with the increase in cases (Japan contributed in 1999, 2002 and 2004; the more detailed electronic data capture system accounted for the vast majority of clinical case entries after 2005). It is possible that the publication in 200719, 20 of the proposals for the 7th edition of TNM classification, which drew attention to separate tumor nodules because they changed classification, increased the recognition and reporting of such cases. However, the change in incidence did not correlate with a change in outcomes.

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Evaluation of patient outcomes is an important measure, but is determined by many factors: the inherent biologic impact of the tumor itself, competing risks (e.g. comorbidities), selection factors (e.g. discovered by symptoms, CXR, screening, risk factors), the type and effectiveness of treatment (e.g. curative-intent, palliative) etc. We must be careful not to attribute outcomes primarily to one factor when there is a disparity in other factors. For the purpose of stage classification, inherent biologic impact is the factor of greatest relevance. We have clear evidence that treatment varied according to the location of an separate tumor nodule (almost all same-lobe nodules were resected, whereas almost all other-side nodules were not). We have limited information on other factors in the IASLC database. Analysis of the IASLC database (Figure 1) shows stepwise decreasing OS in c-stage patients according to the location of separate tumor nodules (same-lobe > same-side > other-side). However, the outcomes specifcally in resected or in palliatively treated patients (Figure 1,2) suggests that treatment plays a major role. Furthermore, there are other factors to consider. Incidental nodules were much more common in same-lobe cases; these were presumably smaller and potentially of less biologic impact. The patients with other-side tumor nodules who underwent resection represent a highly selected group whose survival may not be representative of the larger cohort had they been resected as well. We are unable to evaluate the potential impact of such factors.

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Comparison of the results of the IASLC database with the results of a systematic literature review reveals similar outcomes in resected patients with same-lobe and same-side tumor nodules. However, for other-side separate tumor nodules the data is limited, as it is in the IASLC database.

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Based on the analysis above, the recommendation for TNM classification of separate solid tumor nodules (intrapulmonary metastases) is to maintain the classification of the 7th edition (Table 4). There are many reasons for this recommendation. There is a stepwise decrease in OS in c-stage patients. Data from the current IASLC database is similar to that of the previous (1990-2000) cohort. The survival of separate tumor nodule patients is not statistically different from that of corresponding T and M categories in the 7th edition. There is insufficient ability to account for multiple potential confounding factors to define further the inherent biologic impact of the separate nodule itself. A general principle of the SPFC is to not recommend changes unless there is sufficiently robust evidence to indicate that this is appropriate.

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However, the data does suggest that a separate tumor nodule (in any location, including the contralateral lung) with the same histologic features does not necessarily mean that cure is not possible. The data for resected patients, both from the IASLC database and the published literature, shows a substantial number of 5-year survivors, regardless of the location of the separate tumor nodule. Further exploration of this is warranted. At this point, however, the data, particularly for other-side separate tumor nodules, is too limited to be able to define how to select which patients might be appropriate for such an approach. The TNM designation described here is intended for separate solid tumor nodules with the same histologic features as that of the primary tumor. It is not to be applied to patients who are thought to have synchronous primary lung cancers or patient with mutliple foci of ground glass/lepidic adenocarcinoma. A better ability to distinguish these groups should help collection of data on specific patients to better define their outcomes going forward.

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Conclusion

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The IASLC database included a cohort (~3%) of patients with separate tumor nodules (intrapulmonary metastases). These appear to be mostly single nodules of the same histologic type with a histotype distribution similar to that of NSCLC in general. Survival decreases progressively by location relative to the primary tumor (same-lobe > same-side > other-side) for c-stage patients. However, the survival appears to correlate to the proportion of patients that underwent resection; there is no difference by location among either resected or non-resected cohorts. Other confounding factors, such as the size of separate nodules or whether clinically apparent or incidentally discovered cannot be fully assessed. Among p-stage patients, survival is similar for same-lobe nodules and other T3 tumors, for same-side (different lobe) nodules and other T4 patients, and for c-stage patients for other-side nodules and other M1a patients. Hence the 7th edition classification of same-lobe nodules as T3, same-side (different lobe) nodules as T4 and other-side nodules as M1a is proposed to be carried forward. The IASLC data is consistent with reported results garnered from a literature review.

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APPENDIX IASLC Staging and Prognostic Factors Committee

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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, Tokyo, Japan; David Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; David G. Beer, University of Michigan, Ann Arbor, MI, United States of America (USA); Ricardo Beyruti, University of Sao 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; Antoon 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 SloanKettering 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.

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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. Eugene Blackstone, Cleveland Clinic, OH, USA.

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Advisory Board of the IASLC Esophageal Cancer Domain Participating Institutions in the New IASLC Lung Cancer Staging Project

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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, M.D. Anderson Cancer Center (MDACC), Houston, USA; R. Terra, University of Sao Paulo Medical Center, Sao 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,

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Guangdong General Hospital, Guangzhou, China; K. Yokoi, Japanese Joint Committee for Lung Cancer Registry, Osaka, Japan.

Multiple Pulmonary Sites of Cancer Workgroup

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Jeremy Erasmus, MD Anderson Cancer Center, Houston, TX, USA; Douglas Flieder, Fox Chase Cancer Center, Philadelphia, PA, USA; Myrna Godoy, MD Anderson Cancer Center, Houston, TX, USA; Jin Mo Goo, Seoul National University College of Medicine, Seoul, South Korea; Lawrence R. Goodman, Medical College of Wisconsin, Milwaukee, WI, USA; Jim Jett, National Jewish Health System, Denver, CO, USA; Paul de Leyn, Catholic University, Leuven, Belgium; Alberto Marchevsky, Cedars Sinai Health System, Los Angeles, CA, USA; Heber MacMahon, University of Chicago, Chicago, IL, USA: David Naidich, New York University, New York, NY, USA; Morohito Okada, Hiroshima University, Hiroshima, Japan; Marina Perlman, Tel-Aviv University, Ramat Gan, Israel; Charles Powell, Mount Sinai School of Medicine, New York, NY, USA; Paul van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Arne Warth, University of Heidelberg, Germany.

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References

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1. Fonseca, A, Detterbeck, FC: How many names for a rose: Inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer, 85: 7-11, 2014. 2. Homer, R: Pathologists' staging of multiple foci of lung cancer. Am J Clin Pathol, 143: 701-706, 2015. 3. Detterbeck, F, Franklin W, Nicholson AG, Girard N, Arenberg D, Travis W, Mazzone P, Marom EM, Donington J, Tanoue L, Rusch V, Asamura H and Rami-Porta R, on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards and the Multiple Pulmonary Sites Workgroup. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol, in process, 2016. 4. Detterbeck, F, Marom EM, Arenberg D, Franklin W, Nicholson AG, Travis W, Girard N, Mazzone P, Donington J, Tanoue L, Rusch V, Asamura H and Rami-Porta R, on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards and the Multiple Pulmonary Sites Workgroup. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol, in process, 2016. 5. Detterbeck, F, Nicholson AG, Franklin W, Marom EM, Travis W, Girard N, Arenberg D, Bolejack V, Donington J, Mazzone P, Tanoue L, Rusch V, Crowley J, Asamura H and Rami-Porta R, on behalf of the IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup and Participating Institutions. The IASLC Lung Cancer Staging Project: Summary of Proposals for the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol, in process, 2016. 6. Rami-Porta, R, Bolejack, V, Giroux, DJ, Chansky, K, Crowley, J, Asamura, H, Goldstraw, P, on behalf of the International Association for the Study of Lung Cancer, S, Prognostic Factors Committee. The IASLC Lung Cancer Staging Project: The new database to inform the eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol, 9: 1618-1624, 2014. 7. Cox, D: Regression models and left tables (with discussion). J Royal Stat Soc, B34: 187-220, 1972. 8. Detterbeck, FC, Lewis, S, Diekemper, R, Addrizzo-Harris, D, Alberts, WM: Executive Summary: Diagnosis and Management of Lung Cancer 3 rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2013. Chest, 143: 7S-37S, 2013. 9. Kozower, B, Larner, JM, Detterbeck, FC, Jones, DR: Special Treatment Issues in Non-Small Cell Lung Cancer: Diagnosis and Management of Lung Cancer 3 rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest, 143: e369S-e399S, 2013. 10. Rami-Porta, R, Bolejack, V, Crowley, J, Ball, D, Kim, J, Lyons, G, Rice, TW, Suzuki, K, Thomas, C, Travis, W, Yi-Long, WobotISaPFC, Advisory Boards and participating Institutions: 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, 10: 990-1003, 2015. 11. Pennathur, A, Lindeman, B, Ferson, P, Ninan, M, Quershi, I, Gooding, WE, Schuchert, M, Christie, NA, Landreneau, RJ, Luketich, JD: Surgical Resection Is Justified in Non-Small Cell Lung Cancer Patients with Node Negative T4 Satellite Lesions. Ann Thorac Surg, 87: 893-899, 2009. 12. Port, JL, Korst, RJ, Lee, PC, Kansler, AL, Kerem, Y, Altorki, NK: Surgical Resection for Multifocal (T4) Non-Small Cell Lung Cancer: Is the T4 Designation Valid? Ann Thorac Surg, 83: 397-400, 2007. 13. Rao, J, Sayeed, RA, Tomaszek, S, Fischer, S, Keshavjee, S, Darling, GE: Prognostic Factors in Resected Satellite-Nodule T4 Non-Small Cell Lung Cancer. Ann Thorac Surg, 84: 934-939, 2007. 14. Terzi, A, Falezza, G, Benato, C, Genestreti, G, Santo, A, Furia, S, Feil, B, Calabrò, F: Survival Following Complete Resection of Multifocal T4 Node-Negative NSCLC: A Retrospective Study. Thorac cardiovasc Surg, 55: 44,47, 2007.

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15. Okamoto, T, Iwata, T, Mizobuchi, T, Hoshino, H, Moriya, Y, Yoshida, S, Yoshino, I: Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases. Surgery today, 43: 1123-1128, 2013. 16. Okumura, T, Asamura, H, Suzuki, K, Kondo, H, Tsuchiya, R: Intrapulmonary metastasis of non-small cell lung cancer: A prognostic assessment. J Thorac Cardiovasc Surg, 122: 24-28, 2001. 17. Tonnies, M, Koollmeier, J, Bauer, T, Griff, S, Kaiser, D: Curative surgical treatment options for patients with non-small cell lung cancer (NSCLC) and solitary pulmonary metastasis. Pneumologie, 66: 218-223, 2012. 18. Tönnies, M, Pfannschmidt, J, Bauer, TT, Kollmeier, J, Tönnies, S, Kaiser, D: Metastasectomy for Synchronous Solitary Non-Small Cell Lung Cancer Metastases. Ann Thorac Surg, 98: 249-256, 2014. 19. Postmus, P, Brambilla, E, Chansky, K, Crowley, J, Goldstraw, P, Patz, EJ, Yokomise, H: The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol, 2: 686-693, 2007. 20. Rami-Porta, R, Ball, D, Crowley, J, Giroux, DJ, Goldstraw, P, Jett, JR, Travis, WD, Tsuboi, M, Vallieres, E: The IASLC Lung Cancer Staging Project: Proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification of lung cancer. J Thorac Oncol, 2: 593-602, 2007. 21. Suzuki, M, Yoshida, S, Moriya, Y, Hoshino, H, Mizobuchi, T, Okamoto, T, Yoshino, I: Single T factors predict survival of patients with resected stage-IIB non-small-cell lung cancers. European Journal of Cardio-Thoracic Surgery, 39: 745-748, 2011. 22. Kocaturk, CI, Gunluoglu, MZ, Cansever, L, Dincer, IS, Bedirhan, MA: Prognosis in patients with non-small cell lung cancer and satellite tumors. Thoracic & Cardiovascular Surgeon, 59: 360-363, 2011. 23. Ruffini, E, Filosso, PL, Bruna, MC, Coni, F, Cristofori, RC, Mossetti, C, Solidoro, P, Oliaro, A: Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer — Lung Cancer Staging Project: a validation study from a single-centre experience. Eur J Cardiothorac Surg, 36: 1037-1044, 2009. 24. Trousse, D, D'Journo, XB, Avaro, J-P, Doddoli, C, Giudicelli, R, Fuentes, PA, Thomas, PA: Multifocal T4 non-small cell lung cancer: a subset with improved prognosis. Eur J Cardiothorac Surg, 33: 99-103, 2008. 25. Oliaro, A, Filosso, PL, Cavallo, A, Giobbe, R, Mossetti, C, Lyberis, P, Cristofori, RC, Ruffini, E: The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging system. Eur J Cardiothorac Surg, 34: 438-443; discussion 443, 2008. 26. Lee, JG, Lee, CY, Kim, DJ, Chung, KY, Park, IK: Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment. Eur J Cardiothorac Surg, 33: 480484, 2008. 27. Nagai, K, Sohara, Y, Tsuchiya, R, Goya, T, Miyaoka, E: Prognosis of Resected Non-Small Cell Lung Cancer Patients with Intrapulmonary Metastases. . J Thorac Oncol, 2: 282-286, 2007. 28. Bryant, AS, Pereira, SJ, Miller, DL, Cerfolio, RJ: Satellite Pulmonary Nodule in the Same Lobe (T4N0) Should Not Be Staged as IIIB Non-Small Cell Lung Cancer. Ann Thorac Surg, 82: 18081814, 2006. 29. Okada, M, Tsubota, N, Yoshimura, M, Miyamoto, Y, Nakai, R: Evaluation of TMN classification for lung carcinoma with ipsilateral intrapulmonary metastasis. Ann Thorac Surg, 68: 326-331, 1999. 30. Yano, M, Arai, T, Inagaki, K, Morita, T, Nomura, T, Ito, H: Intrapulmonary satellite nodule of lung cancer as a T factor. Chest, 114: 1305-1308, 1998. 31. Fukuse, T, Hirata, T, Tanaka, F, Yanagihara, K, Hitomi, S, Wada, H: Prognosis of ipsilateral intrapulmonary metastases in resected nonsmall cell lung cancer. Eur J Cardiothorac Surg, 12: 218223, 1997.

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32. Ou, SHI, Zell, JA: Validation study of the proposed IASLC staging revisions of the T4 and M nonsmall cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry. J Thor Oncol, 3: 216-227, 2008. 33. Zell, J, Ignatius Ou, S-H, Ziogas, A, Anton-Culver, H: Survival improvements for advanced stage nonbronchioloalveolar carcinoma-type nonsmall cell lung cancer cases with ipsilateral ntrapulmonary nodules. Cancer, 112: 136-143, 2008. 34. Williams Jr., W, Lin, H, Lee, J, Lippman, S, Roth, J, Kim, E: Revisiting stage IIIB and IV non-small cell lung cancer. Chest, 136: 701-709, 2009. 35. Watanabe, S, Asamura, H, Miyaoka, E, Okumura, M, Yoshino, I, Fujii, Y, Nakanishi, Y, Eguchi, K, Mori, M, Sawabata, N, Yokoi, K, Japanese Joint Committee of Lung Cancer, R: Results of T4 surgical cases in the Japanese Lung Cancer Registry Study: should mediastinal fat tissue invasion really be included in the T4 category? Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer, 8: 759-765, 2013. 36. Tung, Y-W, Hsu, C-P, Shai, S-E, Hsia, J-Y, Yang, S-S, Chen, C-Y: Surgical feasibility of ipsilateral multifocal non-small cell lung cancer in different lobes: excellent survival in node-negative subgroup. Eur J Cardiothorac Surg, 24: 1008-1012, 2003.

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Figures

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Figure 1: Overall Survival of Clinical-Stage Patients Overall survival of c-stage patients with separate solid tumor nodules (intrapulmonary metastases) by location. These patients had only the nodules account for the T3, T4 or M1a designation, but may have had lower T characteristics as well. The non-surgical c-stage patients had separate nodules which were suspected or proven to be the same as the primary lung cancer (i.e. this may or may not have been histologically confirmed). *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). A) cN0 cohort; p=0.051 for same-lobe vs same-side nodules, p=0.058 for same-side vs other-side nodules; B) cN-any cohort; p<0.0001 for same-lobe vs same-side nodules, p=0.055 for same-side vs other-side nodules; C) c-stage nodule cases that were surgically resected (and nodule pathologically confirmed), cN0, R-any cohort; p=not significant; D) c-stage nodule cases treated non-surgically, cN0 cohort; p=not significant.

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Figure 2: Overall Survival of Pathologic-Stage Patients Overall survival of pathologic-stage patients with separate solid tumor nodules (intrapulmonary metastases) by location. These patients had only the nodules account for the T3, T4 or M1a designation, but may have had lower T characteristics as well. Differences between same-lobe and same-side tumors are statistically significant; other comparisons are not significantly different. *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). A) pN0, R0 cohort; p=0.0024 for same-lobe vs same-side nodules, p=not significant for same-side vs other-side nodules; B) pN-any, R-any cohort; p=0.0032 for same-lobe vs same-side nodules, p=not significant for same-side vs other-side nodules.

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Figure 3: pT3 by Same-Lobe Tumor Nodule vs. Other T3 Descriptors Overall survival of p-stage patients with same-lobe separate nodule tumors vs. other T3 descriptors, stratified by a single vs. multiple T3 descriptors. For details of other T descriptors see the T descriptor paper.10 *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). A) pN0 M0 R0; B) pN-any M0 R0; C) pN0 M0 R-any

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Figure 4: pT4 by Same-Side Tumor Nodule vs. Other T4 Descriptors Overall survival of p-stage patients with same-side (different lobe) separate nodule only tumors vs. other T4 descriptors, stratified by a single vs. multiple T4 descriptors. For details of other T descriptors see the T descriptor paper.10 *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). A) pN0 M0 R0; B) pN-any M0 R0; C) pN0 M0 R-any Figure 5: Comparison of cM1a Descriptors in Non-Surgical Patients Overall survival of patients with other-side separate tumor nodule (intrapulmonary metastases) vs. other cM1a descriptors in c-stage (T-any N-any) tumors, not surgically treated (EDC cases only).

Supplemental Digital Content 2. Supplementary Figures Supplementary Figure S1: Percent of Cases with Separate Tumor Nodules by Year All tumors were M0 (except contralateral separate tumor nodule allowed); the separate tumor nodule patients may or may not have had tumors with other T characteristics, including higher T characteristics

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than the presence of the nodule itself (i.e. T-any, N-any, M0) Data for c-stage in 2000 and 2001 omitted due to limited numbers of patients (≤5). A) c-stage and B) p-stage cases

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Supplementary Figure S2: Primary Tumor Size by Separate Tumor Nodule Site Size of the primary tumor according to the location of a separate tumor nodule

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Supplementary Figure S3: cT3 by Same-Lobe Tumor Nodule vs. Other T3 Descriptors Overall survival of same-lobe separate tumor nodule(s) vs. other T3 descriptors in c-stage patients, stratified by a single vs. multiple T3 descriptors. For details of other T descriptors see the T descriptor paper.10 A) cN0 M0; B) cN-any M0

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Supplementary Figure S4: cT4 by Same-Side Tumor Nodule vs. Other T4 Descriptors Overall survival of c-stage patients with same-side (different lobe) separate tumor nodule only vs. other T4 descriptors, stratified by a single vs. multiple T4 descriptors. For details of other T descriptors see the T descriptor paper.10 A) cN0 M0; B) cN-any M0

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Supplementary Figure S5: Outcomes in Surgically Treated Patients with pM1a Descriptors Overall survival of surgically treated pM1a patients (pT-any N-any M1a, R-any cohort)

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Tables Table 1: Separate Tumor Nodules in the Same Lobe

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% N0 52 100 24 68 44 50 (49)b 38 64 51 100 100 30 <50 26 >50

% 5-year Survival All N0 54 69 78 52 26 40 28 48 52 20 33c 30 27 47 48 58 57 64 42 57 34 37 30 36 37 38 52

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% resected 100 100 100 100 100 100 (93)b 100 84 100 100 100 87 100 100 100 100

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First Author Okamoto15 Suziki21 Kocaturk22 Pennathur11 Ruffini23 Trousse24 Oliaro25 Lee26 Nagai27 Port12 Raod 13 Terzi14 Bryantd 28 Okumura16 Okada29 Yano30 Fukuse31 Average Registry/Database Studies e IASLC20 363 CCR32 422 SEER33 633 SEER34 2,285

% Incidental 90 53 100a 85 49 82 -

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% with No. of Multiple Patients Nodules 161 67 20 51 37 50 70 39 (49)b 23 316 53 19 35 9 32 33 26 105 51 39 20 12

28 23 35 24

54 -

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Inclusion criteria were studies of ≥ 20 patients with a separate tumor nodule in the same lobe as the dominant primary lung cancer from December 1995-April 2015. CCR = California Cancer Registry; IASLC = International Association for the Study of Lung Cancer; SEER = Surveillance, Epidemiology, and End Results. a data reported for N0 patients b data is for both same-lobe and ipsilateral different-lobe separate tumor nodule(s) c Four-year survival d included a minority of patients with adenocarcinoma with bronchioloalveolar carcinoma features e Majority of patients in each study underwent resection.

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Table 2: Separate Ipsilateral (Different Lobe) Tumor Nodules

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% 5-year Survival All N0 23 46 33 71 23 (28)b 10 16 31d 19 28 67 43 30

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First Author Nagai27 Watanabe35 Tönnies17,18 Okada29 Ruffini23 Oliaro25 Lee26 Okamoto15 Tung36 Averagee Registry/Database Studies IASLC 1990-9920 180 CCR32 745 SEER33 3,010 SEER34 3,019

% Inci% dental resected % N0 66 30 63 53 100 42a 89 100 <50 100 53 (93)c (49)c 100 100 48 100 100

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% with No. of Multiple Patients Nodules 129 85 38 38 36 35 (49)c 26 21 20 15

22 (9) f (7) a,f (8) f

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Inclusion criteria were studies of ≥ 20 patients with a separate tumor nodule in a different ipsilateral lobe as the dominant primary lung cancer from December 1995-April 2015. CCR = California Cancer Registry; IASLC = International Association for the Study of Lung Cancer; SEER = Surveillance, Epidemiology, and End Results. a includes both ipsilateral and contralateral different-lobe separate tumor nodule(s) b 3 year survival c data is for both same-lobe and ipsilateral different-lobe separate tumor nodule(s) dl 85% underwent pneumonectomy e Excluding values in parentheses. f The majority of patients did not undergo resection.

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Table 3: Separate Contralateral Tumor Nodules Study Tönnies17,18 SEER34 CCR32 IASLC 1990-199920

% pN2 24a 53 -

All 3 2-6b 3

Resected 80 -

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% 5-year Survival

No. of % patients Resected 12 100 5,382 6 1,148 8 362 2

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Inclusion criteria were studies of ≥ 20 patients with a primary lung cancer and a separate contralateral tumor nodule from December 1995-April 2015. CCR = California Cancer Registry; IASLC = International Association for the Study of Lung Cancer; SEER = Surveillance, Epidemiology, and End Results. a includes 43 patients with ipsilateral different-lobe separate tumor nodule(s) b Range of estimated 5-year survival for various histologic types.

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Table 4: TNM Classification of Separate Solid Tumor Nodules with the Same Histology*

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TNM Category Location of Nodule Relative to Primary Tumor T3 Same lobe T4 Same side, different lobe M1a Other side (different lobe) * This classification applies to separate solid tumor nodule(s) with the same histology as that of the primary tumor (either suspected or proven by biopsy/resection). This applies whether or not there are sites of extrathoracic metastases. However, if there are extrathoracic metastases, the tumor is classified as M1b (single site) or M1c (multiple sites). This classification does not apply to tumors judged to be synchronous primary lung cancers, or to multiple tumor nodules with ground glass or lepidic features.

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Clinical Stage – Separate Solid Tumor Nodules All c-Stage Cases, cN0 cM0*

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% Resected 94.6%

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Surgical c-Stage Cases, cN0 cM0*, R-any

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% Resected 86.6%

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All c-Stage Cases, N-any cM0*

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Non-Surgical c-Stage Cases, cN0 cM0*

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pT3 by Same-Lobe Nodule vs. Other T3 Cases

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pT4 by Same-Side Separate Nodule vs. Other T4 Cases

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Prognostic Impact of cM1a Descriptors

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Non-Surgical c-Stage Cases, T-any, N-any, M1a

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Additional slides (on-line only)

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% of Cases with Separate Tumor Nodules by Year Clinical Stage Cases

Pathologic Stage Cases

B 100%

80%

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1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

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>5cm 3-<5cm <3 cm

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AC C

S3

cT3 N-any M0*

ACCEPTED MANUSCRIPT

cT4 by Same-Side Separate Nodule vs. Other T4 Cases

B

M AN U

cT4 N0 M0*

EP

TE D

Same-Side Nodule Single Other Multiple Other

AC C

A

SC

RI PT

S4

cT4 N-any M0*

ACCEPTED MANUSCRIPT

RI PT

Prognostic Impact of M1a Descriptors in Resected Cases

M AN U

SC

pT-any N-any M1a, R-any

EP

TE D

Other-Side Nodule

AC C

S5