IJC International Journal of Cancer

IJC International Journal of Cancer Improving the TNM classification: Findings from a 10-year continuous literature review Colleen Webber 1,2, Mary Gospodarowicz 3, Leslie H. Sobin 4, Christian Wittekind 5, Frederick L. Greene 6, Malcolm D. Mason 7, Carolyn Compton 8,9, James Brierley 3 and Patti A. Groome 1,2 1 Division of Cancer Care and Epidemiology, Queen s Cancer Research Institute, Queen s University, Kingston, ON, Canada 2 Department of Public Health Sciences, Queen s University, Kingston, ON, Canada 3 Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada 4 Cancer Human Biobank, National Cancer Institute, Frederick National Laboratory for Cancer Research, Rockville, MD 5 Institute of Pathology, University of Leipzig, Leipzig, Germany 6 University of North Carolina School of Medicine, Charlotte, NC 7 School of Medicine, Cardiff University, Cardiff, United Kingdom 8 American Joint Committee on Cancer, Chicago, IL 9 College of Health Solutions, School of the Science of Healthcare Delivery, Arizona State University, Phoenix, AZ The Union for International Cancer Control s (UICC) TNM classification is a globally accepted system to describe the anatomic extent of malignant tumors. Since its development seventy years ago, the TNM classification has undergone significant revisions to reflect the current understanding of extent of disease and its role in prognosis. To ensure that revisions are evidence-based, the UICC implemented a process for continuous improvement of the TNM classification that included a formalized system for submitting proposals for revisions directly to the UICC and an annual review of the scientific literature on staging that assessed, criticized or made suggestions for changes. The process involves review of the proposals and literature by a group of international, multidisciplinary Expert Panels. The process has been in place for 10 years and informed the development of the 7th edition of the TNM classification published in 2009. The purpose of this article is to provide a description of the annual literature review process, including the search strategy, article selection process and the roles and requirements of the Expert Panels in the review of the literature. Since 2002, 147 Expert Panel members in 11 cancer sites have reviewed over 770 articles. The results of the annual literature reviews, Expert Panel feedback and documentation and dissemination of results are described. The staging of malignant tumors is a fundamental component of the diagnosis and management of cancer. The goal of cancer staging is to describe the anatomic extent of the disease, which helps to estimate prognosis and to inform treatment selection. 1,2 The Union for International Cancer Control (UICC) TNM classification of the anatomic extent of disease (EOD) is a globally accepted cancer staging classification. 1 This system encompasses the attributes of the tumor that define its behavior and natural history, including its local tumor growth (T), spread to regional lymph nodes (N) and Key words: neoplasm staging, TNM classification, evidence-based practice, international cooperation, prognosis Grant sponsor: Union for International Cancer Control (UICC) from the Centers for Disease Control and Prevention (CDC), U.S. Dept. Health and Human Services DOI: 10.1002/ijc.28683 History: Received 9 Aug 2013; Revised 30 Nov 2013; Accepted 4 Dec 2013; Online 19 Dec 2013 Correspondence to: Dr. Patti Groome, Division of Cancer Care and Epidemiology, Queen s Cancer Research Institute, 10 Stuart Street, 2nd Level, Kingston, Ontario, Canada K7L 3N6, Fax: 1[613-533- 6794], E-mail: groomep@queensu.ca. distant metastasis (M). Stage groupings, based on the T, N and M categories, are assigned to those tumors with similar prognoses. 3 The objectives of the TNM classification, as defined by the UICC are six-fold: to aid treatment planning, to provide an indication of prognosis, to assist in the evaluation of treatment results, to facilitate the exchange of information between treatment centers, to contribute to continuing investigations of human malignancies and to support cancer control activities. 2,3 The ability of the TNM classification to predict clinical outcomes and its usefulness in treatment decision making has led to its widespread adoption. 4 The TNM classification facilitates communication between physicians and other health care providers by providing a common language that is understood by all. 4 In research, the TNM classification is used extensively to describe and stratify patients into groups that are prognostically similar to allow for the evaluation of treatment strategies. 5 Finally, with stage as an indicator of early detection of cancer, the TNM classification is also used to monitor and evaluate early detection or screening efforts. 3 In short, the TNM classification provides us with a common nomenclature on which to base cancer management, research and information exchange. Int. J. Cancer: 135, 371 378 (2014) VC 2013 UICC

372 Improving the TNM classification What s new? The Union for International Cancer Control s TNM classification undergoes periodic revisions to incorporate current knowledge of anatomic extent of disease and its relationship with patient management and prognosis. This article describes the results of an annual literature review process that was implemented in 2002 to inform revisions to the classification. Since that time, more than 770 articles have been reviewed, with the number of articles reviewed increasing over time, reflecting growing research interest in cancer staging and new developments in cancer diagnosis. The report suggests that the literature review process has enhanced recent changes to the TNM classification. The TNM classification has undergone significant revisions since the first edition was published in 1968. 2,6 Revisions are necessary to ensure that the system reflects advances in our ability to measure anatomic EOD and our increasing understanding of the role of EOD on prognosis. 1,2 The UICC TNM Prognostic Factors Core Group is responsible for updating the UICC TNM classification in collaboration with the American Joint Commission on Cancer (AJCC). Historically, revisions to the TNM classification were based on expert opinion from members of national TNM committees (including the AJCC) who were members of the UICC TNM Prognostic Factors Core Group. Although empirical evidence informed the discussions, no formal process was in place to gather the opinions of experts outside the TNM committees, and the revision process did not systematically gather relevant literature that identified opportunities for change. Leading up to the publication of the sixth edition of the TNM classification in 2002, the UICC TNM Prognostic Factors Core Group recognized the need to evolve from this consensus-based approach to one that was more inclusive and more explicitly evidence-based. 2 A formal process was also needed to vet proposals for TNM revisions submitted directly to the UICC without publication in the peerreviewed literature. Such a process needed to include documentation requirements and statistical criteria sufficient to constitute evidence for change. In response to these issues, the UICC TNM Prognostic Factors Core Group developed a process for continuous improvement of the TNM classification in 2002. 2 Briefly, the process relies on two key activities. The first is an improved process for submitting and evaluating proposals for revisions to the TNM classification to the UICC including the requirement that proposals contain adequate description of the study sample, treatment received, endpoints, statistical analyses and interpretation of the results. To date, this formal process has generated one proposal in lung cancer that came from the International Association for the Study of Lung Cancer, with involvement from the UICC TNM Prognostic Factors Core Group throughout the conduct of their study. The proposal was subsequently adopted into the 7th edition of the TNM classification. 7 9 The second activity is aimed at identifying potential opportunities for improving the TNM classification through the conduct of an annual review of the scientific literature that assessed, criticized or made suggestions for changes to the classification. This annual TNM Literature Watch relies heavily on the involvement of multidisciplinary TNM Expert Panels representing the major cancer sites who evaluate the literature identified each year. The process informed the development of the seventh edition of the TNM classification that was published in 2009. The goal of this article is to describe the annual TNM Literature Watch, its results and its importance in the refinement of the TNM classification. The process described herein could be applied to other ongoing classification and knowledge-based authoritative documents such as histological classification of tumors, tumor grading and the development and maintenance of clinical prediction tools. Material and Methods Search strategy A review of the scientific literature is conducted annually, starting in January of each year and concluding with the annual meeting of the UICC TNM Prognostic Factors Core Group meeting in early May. The starting point is a comprehensive search of the Medline database using a pre-defined search strategy (Table 1). For each annual search, the results are limited to articles published in the year prior to the search (called the current articles) and those published two years prior that were not yet indexed at the time of the previous search (called the update articles). For instance, the literature search conducted in 2011 retrieved articles published in 2010 (the current articles), as well as those published in Table 1. Medline search strategy. Medline search term 1. *Neoplasm staging 2. Neoplasm staging 3. TNM.mp. 4. UICC.mp. 5. FIGO.mp. 6. AJCC.mp. 7. 2 and 3 8. 2 and 4 9. 2 and 5 10. 2 and 6 11. 1 or 7 or 8 or 9 or 10 12. Limit 11 to (humans and yr 5 2011 )

Webber et al. 373 Table 2. Current and previous panel member distribution by country. Country Panel members USA 42 Canada 20 United Kingdom 16 Australia 15 China/Hong Kong 5 Germany 5 Italy 5 Netherlands 5 Belgium 3 Japan 3 Spain 3 Austria 2 France 2 Singapore 2 Switzerland 2 Denmark 1 New Zealand 1 Sweden 1 2009 that were not retrieved as part of the search in 2010 (the update articles). Article review process The TNM Process Task Force, which reports to the TNM Prognostic Factors Core Group, is responsible for overseeing the TNM Literature Watch. 10 The TNM Process Task Force is co-chaired by an epidemiologist (PG) and an oncologist (MM), with members representing the specialties of radiation oncology, surgical oncology and pathology. At least one member of the TNM Process Task Force and the project coordinator initially review all titles and abstracts retrieved through the literature search. References that appear to meet the inclusion criteria are selected and distributed to the remaining members of the TNM Process Task Force. The inclusion criteria are as follows: articles that compare two or more editions of the TNM classification, compare TNM against other staging systems or compare non-tnm staging systems, propose a new EOD staging classification, compare different definitions of T or N categories, assess lymph node ratios, critique the TNM classification or propose evidencebased revisions to the TNM classification. Articles are excluded if they assess the usefulness of new imaging techniques to better measure stage, examine the independent prognostic value of stage in multivariate analyses, praise or provide evidence for the value of the TNM classification, study histology rather than TNM or assess non-eod prognostic factors (e.g., biomarkers). The Process Task Force members independently review the abstracts and meet via teleconference to identify eligible articles to be reviewed by the TNM Expert Panels. TNM Expert Panel members are sent a list of selected articles corresponding to their disease site specialty which they access through their home institution in compliance with copyright restrictions. While all communication between the TNM Expert Panels and the TNM Process Task Force is currently done via email, different modes of communication were used in previous years. The process of obtaining article assessments from panel members has evolved over time toward collection of more detailed responses. The reference lists were originally accompanied by a feedback form that asked: Is there sufficient evidence in the enclosed papers to consider revising the current TNM classification? If yes, please specify the tumor site and specific modifications to be addressed. This question was revised in 2005: Is there sufficient evidence in any of the enclosed papers to consider revising the current TNM classification? If yes, please specify the tumor site and specific modifications to be addressed. In your comments, for each modification, please state whether we should make a change or if we need more evidence. While some panel members commented on individual articles, the feedback was generally related to the overall findings of the articles. Starting in 2010, article-specific feedback was requested, with the question: Does this article provide valid evidence in support of this change? Please comment. However, panel members pointed out that while articles may be relevant to the revision of the TNM classification, not all articles contained specific recommendations for change, making this question difficult to answer. In response, the question was updated in 2012 to Does the evidence provided in this paper merit consideration during the next revision of the TNM classification? Please comment. TNM Expert Panel members responses are recorded anonymously in an online bibliographic management database. 11 The TNM Process Task Force and the TNM Prognostic Factors Core Group review reports describing that year s literature searches and TNM Expert Panel feedback at their annual meeting. During the development of a new edition, TNM classification section editors are given a summary of the TNM Literature Watch results collected in the years since the publication of the last edition of the TNM staging classification The results of the TNM Literature Watch are also disseminated beyond the UICC. The products are made available to the AJCC for their staging classification revision process and to the other UICC TNM National Committees. This dissemination has been facilitated by our creation of an online bibliographic management database which houses the archived literature searches and panel members responses for each citation. It also allows users to conduct keyword and indexed field searches. Results TNM Expert Panel membership As of 2012, there are 11 TNM Expert Panels, corresponding to the following chapters of the TNM classification: head and

374 Improving the TNM classification Table 3. Expert panel membership and mean panel response rate by year. Expert Panel 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Breast 4 4 5 7 7 7 7 6 5 10 12 8 6 7 8 8 8 7 7 6 9 11 Upper gastrointestinal 6 5 7 8 8 7 6 6 6 7 10 Lower gastrointestinal Genitourinary 8 8 8 12 9 10 10 7 10 14 17 Gynaecological 6 6 6 7 7 7 7 6 6 6 6 Head and neck 4 4 8 11 11 11 8 8 8 9 13 Lung 6 6 6 7 7 7 7 6 6 8 9 Lymphoma 6 6 8 8 8 8 8 8 8 8 8 Neuroendocrine 1 6 6 8 9 10 10 10 10 10 10 10 10 10 Sarcoma and bone Skin 8 8 9 9 8 8 8 7 7 6 7 65.9 (44.4 90.0) 63.4 (33.3 100.0) 59.2 (30.0 83.3) 65.0 (50.0 100.0) 72.3 (50.0 85.7) 65.6 (36.3 85.7) 77.2 (62.5 87.7) 84.3 (66.7 100) 58.6 (42.8 75.0) 80.6 (60.0 100) 84.7 (55.6 100) Mean response rate (range) 1 Neuroendocrine panel formed in 2011. Figure 1. Number of publications retrieved through literature search and sent to TNM Expert Panels by year of publication. neck, lower and upper gastrointestinal, lung, sarcoma and bone, skin, breast, gynecologic, genitourinary, lymphoma and neuroendocrine cancers. A total of 133 experts have contributed to this process since 2002. The TNM Expert Panels are multidisciplinary, consisting of surgeons, radiation oncologists, medical oncologists, pathologists and hematologists. Panel members are recognized experts in their cancer site(s), with high quality publications and involvement in both clinical practice and academic research. Panel members also represent a wide range of geographic regions, with members from North America, Europe and Asia (Table 2). TNM Expert Panel membership is by invitation. Recommendations for new panel members are sought from the UICC TNM Prognostic Factors Core Group and the TNM Process Task Force. Panel members are recruited for a minimum three-year term, and recruitment is an ongoing process to ensure that each Panel represents a range of disciplines and geographic regions. Panel membership is renewable for members who regularly contribute. Since their development, Panel membership has increased from an average of 6.5 members per Panel in 2002 to 9.9 members per Panel in 2012. The smallest Panel had four active members at one point in time, and the largest had 17 active members. Since 2002, 22 Panel members have resigned or retired, and 17 individuals have declined or not responded to our invitation. Table 3 describes in greater detail the membership of each TNM Expert Panel over time. Articles retrieved over time Since the initiation of the TNM Literature Watch in 2002, the literature search has retrieved over 6,100 publications, and TNM Expert Panels have reviewed over 770 articles. The number of articles retrieved has increased from 592 published in 2000, to 797 published in 2010. This is mirrored by an increase in the number of articles sent to the TNM Expert Panels for review, with 39 distributed that were published in 2000 and 105 that were published in 2010 (Fig. 1). Note that the number reported for 2011 is smaller than 2010 because

Webber et al. 375 Table 4. Percent of Panel respondents reporting that no change was needed to the TNM classification system (number of articles sent to Expert Panel). Meeting Year Expert Panel 2003 2004 2005 2006 2007 2008 2009 Breast (0) 67% (4) 67% (1) 25% (6) 75% (1) 50% (5) 25% (3) Upper GI 33% (10) 33% (12) 50% (2) 25% (12) 0% (12) 0% (23) 33% (8) Lower GI 50% (2) 100% (2) 0% (5) 60% (3) 60% (6) 20% (11) 60% (4) Genitourinary 37% (4) 25% (4) 25% (4) 20% (11) 20% (17) 0% (13) 25% (2) Gynaecologic 83% (2) 100% (2) 40% (1) 40% (4) 83% (1) 50% (3) 20% (3) Head and Neck 0% (6) 0% (5) 20% (6) 37% (2) 25% (11) 20% (12) 25% (4) Lung 33% (4) 25% (3) 33% (1) 20% (9) 20% (12) 0% (13) 25% (8) Lymphoma 0% (2) 33% (2) (0) 17% (2) 40% (8) 33% (2) 20% (2) Sarcoma/bone (0) 60% (2) (0) (0) 43% (1) (0) 100% (1) Skin (0) 50% (1) 20% (2) 20% (3) 50% (2) 25% (4) 0% (3) does not yet include the 2013 update for that year. In addition to a steady background increase in the number of articles, higher numbers in 2004, 2009 and 2010 may be partially attributed to the publication of the 6th and 7th editions of the TNM classification in 2002 and 2009, respectively. Expert panel response rates over time The response rate from panel members has varied over time, ranging from a low of 58.6% in 2004, to a high of 84.7% in 2002 (Table 3). Response rates for each TNM Expert Panel have also been variable. No panel has had consistently lower or higher response rates. The lowest average response rate for a panel was 54.1% (SD 5 13.4%, range 5 33.3 76.0%), while the highest was 85.7% (SD 5 11.2%, range 5 range 66.7 100.0%). Responses to articles The TNM Literature Watch has been an evolving process so that the data and feedback that have been collected from the TNM Expert Panels have changed over time. For the meeting years 2003 2009, we are able to report on the percentage of responding panel members who said that based on the articles sent, no change was needed to the TNM classification (Table 4). The percentage of panel members indicating no change was needed was generally low, with only three instances where all panel members agreed that the articles did not warrant revisions to the staging system. For the meeting years 2010 2012, we are able to report the number of panel members who identify each article as relevant/not relevant to the revision of the TNM classification. Table 5 presents the percent of articles identified as relevant by at least 50% of responding panel members, along with the number of articles reviewed by each TNM Expert Panel. While our choice of 50% is arbitrary, these results give us some idea about the relevance of the literature we are reviewing. Overall, 24.5% of articles reviewed in 2010 2012 met this threshold. Panel members comments include a justification for their relevance assessment and they often provide their insights about the potential revisions to the TNM classification brought forward by the articles. Through a review of the content of panel members comments received since the initiation of the TNM Literature Watch, we found that they can be classified into three broad themes. First, TNM Expert Panel members have commented on the quality of the research. Panel members have particularly focused on issues with sample size and follow-up, sample source (e.g., single vs. multiple institution), the era in which patients were diagnosed and treated, whether the study was limited to only primary tumors, selection bias, inadequate definition of study variables and analysis errors. Panel members have also pointed out errors in the use and application of the TNM classification. Second, TNM Expert Panel members have identified and indicated their support for or against recommendations for changes to the staging classification made in the reviewed literature. These recommendations have included changes to stage groupings or to T, N or M categories, incorporating other factors into TNM, such as lymph node ratio or tumor deposits, or incorporating aspects of non-tnm staging systems into TNM, either because there is no TNM classification for a specific tumor site or because the alternative staging system is a better predictor of outcomes. Panel members have identified proposed staging revisions in need of further work and/or validation, and suggested clarifications needed to the current staging system. Lastly, panel members have also identified and discussed general staging issues and developments that, while they do not necessarily indicate a change the TNM classification, need to be considered as the UICC moves forward with staging revisions. These important debates have included the role of lymph node ratio in staging, the number of nodes required for accurate staging and the shift toward reduced nodal extraction and sentinel node biopsy, the importance of micrometastases and isolated tumor cells and the inclusion of non-

376 Improving the TNM classification Table 5. Percent of articles identified as relevant to TNM revisions (number of articles sent to expert panel). Meeting year Expert Panel 2010 2011 2012 Breast 0% (8) 0% (3) 33% (6) Upper GI 14% (29) 10% (30) 37% (19) Lower GI 33% (9) 0% (7) 45% (22) Genitourinary 68% (19) 31% (13) 50% (12) Gynaecologic 0% (9) 0% (7) 0% (12) Head and Neck 25% (12) 17% (12) 17% (6) Lung 0% (13) 33% (15) 12% (8) Lymphoma (0) 50% (2) 100% (1) Neuroendocrine 1 29% (7) 80% (5) Sarcoma/bone 0% (2) 0% (1) (0) Skin 0% (2) 0% (5) 40% (5) Other site 0% (1) 2 (0) (0) 1 Neuroendocrine panel formed in 2011. 2 Eye cancer article. anatomic factors in the TNM classification, such as age, tumor grade, functional status or comorbidity. Panel members have also pointed out the need to keep staging procedures simple by not requiring advanced technology or surgical skills or techniques while also recognizing that staging must keep pace with advances in evidence and diagnostic and treatment techniques. Documentation and dissemination of TNM literature watch results Summary documents from the TNM Literature Watch are presented at the annual meetings of the TNM Prognostic Factors Group and the TNM Process Task Force. The TNM Literature Watch has been an evolving process since its inception in 2002, with documentation and reporting mechanisms added over time. The records that are currently developed and reported on include a flowchart of the literature search numbers, the abstracts of all articles distributed to the TNM Expert Panels, summaries of the TNM Expert Panels responses and a summary of panel member involvement and response rates. These documents inform committee discussion about new developments and ongoing issues. The monitoring of panel member involvement informs discussions around TNM Expert Panel membership and renewal. After each annual meeting, these resources are also shared with the TNM National Committees, including the AJCC, with the goal of keeping these committees up-to-date on staging issues and to disseminate the results beyond the membership of the UICC. The products from the TNM Literature Watch had an impact on the 7th edition of the TNM classification through their use by the UICC Process and Prognostic Factors Task Forces and by the UICC TNM Classification section editors. Several new classifications as well as major modifications in the 7th edition were supported by or based on this literature review process. The establishment of defined staging criteria for esophogastric junction tumors and intrahepatic cholangiocarcinoma was supported by the literature review as were major changes to the staging classification including: revised stage groupings of vulva cancer, revised definitions of T1 and T2 categories for nasopharyngeal carcinoma, revised definitions of the T1 and N categories for esophageal carcinoma, revised definitions of the T1 category for tumors of the stomach and revised definitions of the T and M categories for lung cancer. Discussion The annual TNM Literature Watch was developed to identify current staging issues and new staging concepts. Prior to its implementation, the revision process was driven by expert opinion from several national TNM committees and individual members of the UICC TNM Committee. The revision process did not systematically capture all of the published research about cancer staging. The validity of the revision process has been enhanced through the establishment of this formal literature review which incorporates assessments by multidisciplinary TNM Expert Panels. Since its initiation, the TNM Literature Watch has retrieved over 6,100 references and panel members have reviewed 777 references. The number of articles retrieved and reviewed has increased over time, reflecting a growing research interest in cancer staging and new developments in cancer diagnosis and staging. The engagement of TNM Expert Panel members in the literature review process has been successful and we continue to strive to maintain and improve panel member involvement. Although the TNM Literature Watch has been used only once thus far, its use continues and it is playing a key role in the development of the 8th edition. The annual TNM Literature Watch has identified ongoing issues with cancer staging and played a significant role in the development of the 7th edition of the TNM classification. Its findings led the UICC TNM Prognostic Factors Core Group to conduct targeted literature reviews on isolated tumor cells, micro-metastases and lymph node status, in order to better understand their role in staging. Other issues regarding gastro-esophageal tumor staging, tumor deposits in colorectal cancer and the classification of adrenocortical carcinoma have all been brought to light by the literature review. Persistent calls in the literature for inclusion of non-eod factors into the TNM Classification supported the on-going discussion of prognostic factors and their relationship to the staging classification that constitutes part of the work of the UICC Prognostic Factors Core Group and, more specifically, the TNM Prognostic Factors Task Force. 10 The use of an electronic web-based reference management database significantly expands the potential uses of the findings of the annual TNM Literature Watch. Tailored bibliographies can be generated to include user comments with the

Webber et al. 377 citation. A folder-sharing feature facilitates access to the literature review results by members of the UICC TNM Process and Prognostic Factors Task Forces, the UICC National Committees and the AJCC. The flexibility of this database will allow expansion and modifications to meet the evolving needs of the literature review process. One could argue that we should be conducting metaanalyses on each of the proposed changes in the literature. However, such analyses would only address the prognostic role of TNM and not its role in treatment selection and as an overall measure of EOD. Such considerations require expert opinion. Also, the prognostic factor literature has been criticized on quality and the staging-related prognostic literature is no exception. These methodological failings prevent the use of metaanalyses 12 14 and it is recommended that a systematic review process, such as the one described here, be used instead. 12 The evaluations that we collect from our TNM Expert Panels are integral to the TNM Prognostic Factors Core Group s work in developing and revising the TNM classification. Incorporating expert opinion and a consensus-driven approach in the review of the literature provides another means to deal with conflicting scientific evidence. Consensus methods are recognized as valuable tools to provide guidance in the face of uncertainty, either due to inconclusive findings or a lack of relevant research. 15 17 TNM Expert Panel feedback also supplements the scientific evidence by providing insight into the clinical feasibility of EOD-related prognostic factors. For instance, the TNM Expert Panels have reviewed studies on the prognostic value of lymph node ratio and the use of tumor volume in head and neck cancer staging. As highlighted by panel members, practice variations in lymph node resection could cause significant variability in lymph node ratio calculations, and measuring tumor volume requires advanced imaging technology that may not be available in all jurisdictions. While these findings from highly controlled studies may be valid, panel member feedback has indicated that they are not practical in real-world practice. TNM Expert Panel involvement also addresses publication bias, a common issue in systematic reviews, as panel members can, through their experience, comment on unpublished prognostic factors research. Lastly, this approach requires few resources, with voluntary panel membership and use of electronic communications. The TNM Literature Watch was designed to ensure that the TNM classification reflects the most up-to-date understanding of cancer prognosis and it formalizes a process that was occurring prior to its inception. We recognize that changes to the TNM classification across successive revisions can pose challenges to the cancer surveillance community and to the conduct of long-term clinical trials. The TNM References Prognostic Factors Core Group endeavors to minimize the impact of changes by keeping major category boundaries stable whenever possible. We recognize that the time span of a clinical trial or a longitudinal cancer data analysis may extend from one TNM edition to a subsequent version. We therefore have called to the attention of the users the following statement in the current [and previous] editions: Changes made between the sixth and seventh editions are indicated by a bar at the left-hand side of the text. To avoid ambiguity, users are encouraged to cite the year of the TNM publication they have used in their list of references (page xi TNM 7th edition). 18 It must be noted that our ability to describe EOD is everchanging as imaging and other technologies improve and that cancer prognosis also improves as treatments become more effective. So the prognostic value and clinical relevance of TNM must keep pace with these changes. The TNM Literature Watch for revising the TNM classification is part of the UICC s work to enhance and promote the international recognition and use of TNM. Along with expanding the global reach of TNM through the engagement of the TNM Expert Panel members from around the world, the UICC TNM National Committees act as ambassadors for TNM in their home countries. These national committees are given access to the findings of the annual TNM Literature Watch which we hope will inform their cancer staging discussion and build awareness of current staging research. National committee members are also encouraged to facilitate knowledge exchange with other researchers and clinicians regarding TNM staging and to advocate and support the use of the TNM classification. Conclusion The TNM Literature Watch was initiated in 2002 to formalize the review of the literature on cancer staging as the UICC TNM Prognostic Factors Core Group deliberated on changes to the TNM classification. The incorporation of this process into those deliberations has enhanced the completeness and validity of the changes made to subsequent editions of the classification published in 2002 and 2009 through the use of a combined evidence and consensus-based approach to the literature and the engagement of experts from around the world. Acknowledgements Authors thank the members of the TNM Expert Panels, listed at http://www. uicc.org/resources/tnm/global-advisory-group, for their diligent work in reviewing the TNM literature. They also thank the previous TNM Literature Watch project coordinators: Melanie Walker and Suzanna Keller. Financial disclosures or conflict of interest: M. Mason sits on ad-hoc advisory boards and conducts paid lectures for Sanofi, Bayer, Bristol- Meyers, Dendreon, Ferring, Pfizer, Takeda, Astra Zeneca, and Caris. 1. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471 4. 2. Gospodarowicz MK, Miller D, Groome PA, et al. The process for continuous improvement of the TNM classification. Cancer 2004; 100:1 5. 3. Sobin LH. TNM: principles, history, and relation to other prognostic factors. Cancer 2001;91 (Suppl. 8): 1589 92.

378 Improving the TNM classification 4. Greene FL, Sobin LH. The TNM system: our language for cancer care. JSurgOncol2002;80:119 20. 5. Greene FL, Sobin LH. A worldwide approach to the TNM staging system: collaborative efforts of the AJCC and UICC. JSurgOncol2009;99:269 72. 6. Union for International Cancer Control. TNM classification of malignant tumors, 7th edn.: Changes between the 6th and 7th editions. 2009. Available at http://www.uicc.org/system/files/ private/tnm_classification_of_malignant_ Tumours_Website_15%20May2011.pdf. Accessed June 21, 2012. 7. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006;1:281 6. 8. Goldstraw P, Crowley JJ, 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 14. 9. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer staging project: Validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2007;2:694 705. 10. Union for International Cancer Control. TNM groups & panels. (2013) Available at http:// www.uicc.org/resources/tnm/how-to-use. Accessed August 5, 2013. 11. ProQuest LLC. RefWorks Web-Based Bibliographic Management Software. 2013; Version 2.0, Bethesda, MD. 12. Altman DG. Systematic reviews of evaluations of prognostic variables. BMJ 2001;323:224 8. 13. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer 2005;41:1690 6. 14. Moore HM, Kelly AB, Jewell SD, et al. Biospecimen reporting for improved study quality (BRISQ). J Proteome Res 2011;10:3429 38. 15. Fink A, Kosecoff J, Chassin M, et al. Consensus methods: characteristics and guidelines for use. Am J Public Health 1984;74:979 83. 16. Jones J, Hunter D. Consensus methods for medical and health services research. BMJ 1995;311: 376 80. 17. Armitage GM. Value of the evidence-based consensus conference. J Am Coll Dent 2005;72: 28 31. 18. Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors, 7th edn. Oxford: Wiley-Blackwell, 2009.