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• W2051200533 abstract "In this issue of the Journal of Thoracic Oncology, Asamura et al. provocatively suggest that the number of metastatic lymph nodes (LNs) provides more accurate pathologic nodal (pN) staging in lung cancer than the current method of considering anatomical location of involved nodes. They analyzed retrospectively 1659 patients who underwent resection for non-small cell lung cancer from 2000 to 2006 and classified LN involvement according to whether metastases were seen in one to two nodes (nN1), three to six nodes (nN2), or seven or more nodes (nN3). There was no significant difference in overall survival between pN1 and pN2 according to the current method of N staging based on whether metastases were identified in peribronchial, interlobar, or hilar LN (pN1) versus ipsilateral mediastinal LN (pN2). However, multivariate analysis showed that the nN category was an independent prognostic factor for overall survival. This study benefits from the inclusion of a relatively large number of patients over a recent time frame and from an uniform approach to staging by experienced surgeons, although the analyses raise a few methodological issues. The authors use a “lobe-specific” approach to N staging, removing and examining by frozen section mediastinal LN known anatomically to be the first site of drainage for each lobe and only proceeding to removing additional groups of mediastinal LN if the first one shows metastases. Although this approach is increasingly accepted in many centers, controversy exists as to whether it yields equivalent staging to a systematic nodal dissection in all patients. In addition, tumors were staged according the sixth edition of the tumor-node-metastasis (TNM) classification for lung cancer, which potentially leads to the inclusion of some patients who would be excluded if the seventh edition definitions were used (e.g., patients with pleural metastases who would now be considered to have M1a rather than T4 disease).1American Joint Committee on Cancer AJCC Cancer Staging Manual. 7th Ed. Springer, New York, NY2010Crossref Google Scholar, 2International Union Against Cancer TNM Classification of Malignant Tumours. 7th ed. Wiley-Blackwell, Oxford, UK2009Google Scholar The authors also report that analyses of each nN stage in terms of overall survival across each pT stage did not uniformly reach statistical significance. This may reflect the very small numbers of patients available for analysis in the higher stage T subsets. Given the substantial changes in T stage descriptors from the sixth to the seventh editions, it is difficult to know whether the analyses of nN stages across individual T stage would be different had the authors used the current staging system. In addition, the authors do not explain how their nN split points were selected. Finally, the lack of difference in overall survival in this study based on the current approach of LN location (i.e., nepN1 versus pN2) is troubling, as virtually every major analysis during the past three decades has shown this to be statistically significant, including the very large database of the International Association for the Study of Lung Cancer (IASLC).3Rusch VW Crowley J Giroux DJ 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.J Thorac Oncol. 2007; 2: 603-612Crossref PubMed Scopus (419) Google Scholar The lack of prognostic significance in the current study is potentially explained by the exclusion of worse prognosis N2 disease, specifically patients known to have “bulky” or “clinical” mediastinal nodal metastases. Only patients who had “minimal” N2 disease underwent resection and were analyzed for overall survival. Thus, it is impossible to know how the proposed nN classification extrapolates to the larger population of patients with N2 disease. Moreover, no attempt is made to apply thisproposed classification to clinical staging.Validity in both clinical and pathologic staging has been one of the cardinal principles for acceptance of changes to the TNM staging system. N staging according to LN anatomical location is known to yield heterogeneous prognostic groups and has consistently been a source of dissatisfaction for lung cancer investigators. As well discussed by Asamura et al., several alternative approaches to N staging have been proposed, either the number of involved LN or LN stations. In other malignancies such as breast, colon, and gastric cancer, the absolute number of metastatic LNs has long been the accepted parameter of N staging. For cancers of the esophagus and gastroesophageal junction, a major shift occurred from the sixth to the seventh editions of the TNM classification with the number of metastatic LNs rather than LN anatomical location now being the basis for N staging. This change occurred as the result of the analysis of a large international database.4Rice TW Rusch VW Apperson-Hansen C et al.Worldwide esophageal cancer collaboration.Dis Esophagus. 2009; 22: 1-8Crossref PubMed Scopus (286) Google Scholar, 5Rice TW Rusch VW Ishwaran H et al.Cancer of the esophagus and esophagogastric junction: data-driven staging for the 7th edition of the AJCC/UICC Cancer Staging Manuals.Cancer. 2010; 116: 3763-3773Crossref PubMed Scopus (354) Google Scholar Interestingly, the split points in that analysis were precisely those used in this study for nN stages N1, N2, and N3. It had been hoped that analyses of the retrospective IASLC database, which formed the basis for the seventh edition of the lung cancer TNM classification, would lead to changes in the method of N staging. However, no differences in survival were seen according to the number of involved LN stations. Analyses by the number of involved LN “zones,” which grouped together specific LN stations (e.g., LN at levels 1–4 were grouped together as “upper zone,” those at levels 5 and 6 were considered the “aortopulmonary” or “AP” zone) suggested that N staging might be revised into three categories including N1a (single N1 zone disease), N1b plus N2a (multiple N1 or single N2 zone disease), and N2b (multiple N2 zone disease). This approach to N staging has the advantage of being easily applicable to both clinical and pathologic staging. However, even the 2538 pathologically staged N1 and N2 cases in the IASLC database, far more than the 456 such patients in this study, proved statistically inadequate to recommend a change in the N stage categories because the number of patients in each proposed N category available for analysis across each T stage was too small. Thus, the final recommendation from the IASLC Staging Committee was to maintain the previous method of N staging.6Goldstraw P Crowley J Chansky K et al.The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.J Thorac Oncol. 2007; 2: 706-714Abstract Full Text Full Text PDF PubMed Scopus (2690) Google Scholar These results emphasize that very large numbers of patients will be needed in future analyses to make evidence-based recommendations for revisions of N staging in lung cancer. It is hoped that the prospective IASLC database to which patients are now being accrued will provide a large enough sample size with sufficiently reliable international data to address current deficiencies in the lung cancer TNM staging system, including the method of N staging. Conceptually, at least three new approaches to N staging could be tested in the prospective IASLC database as well as other large datasets. These include staging according to the absolute number of involved LNs as proposed by Asamura et al.; staging according to the number of involved LN stations; and staging according to the number of involved LN zones as suggested by the previous IASLC analysis. Staging according to the number of involved LN zones takes into account both LN location and tumor, is probably the easiest approach to apply clinically as well as pathologically, and the easiest to implement across practices of varying expertise worldwide. Staging according to the absolute number of involved LNs, although theoretically applicable to clinical staging because of advances in imaging and staging techniques, will demand a much higher level of precision from radiologists and pathologists as well as clinicians. This may be difficult to achieve in countries outside Japan where all physicians involved in lung cancer management have raised staging to an enviable level of accuracy. As noted by Asamura et al., reliable reporting of the number of metastatic LNs requires that the surgeon either submit whole LN or specifically label a node removed in fragments as a single node. Similar levels of precision will be required for clinical staging by endobronchial ultrasound or mediastinoscopy. Imaging techniques such as computed or positron emission tomography may not allow such accurate clinical staging, an issue that was also controversial in gaining acceptance of the changes in the seventh edition TNM classification for esophageal cancer. In addition, as discussed by Asamura et al., evidence-based guidelines for the total number of LNs required for adequate staging in patients undergoing resection need to be developed. Such guidelines were generated for esophageal cancer through analyses of the international database.7Rizk NP Ishwaran H Rice TW et al.Optimum lymphadenectomy for esophageal cancer.Ann Surg. 2010; 251: 46-50Crossref PubMed Scopus (319) Google Scholar Current recommendations suggest that at least six LNs should be removed but this has little scientific basis. In this study, Asamura et al. found that the mean number of metastatic nodes in patients with N2 disease was 5.74, which suggests that six LNs may be a barely adequate number to achieve adequate staging. This issue needs to be examined further in future studies. Although analyses of the ongoing prospective IASLC international lung cancer database will likely provide the basis for definitive recommendations for revisions in the next edition of the TNM classification, studies such as the one presented in the study by Asamura et al. offer important hypotheses for testing in larger multicenter datasets. The authors have performed a thoughtful study that raises important questions regarding the lung cancer staging system." @default.
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• W2051200533 title "Nodal Staging in Lung Cancer: Lymph Node Location or Number?" @default.
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