Staging of a tumor is a consistent and concise nomenclature of the anatomical scope of tumor invasion. Staging is the cornerstone of diagnosis and treatment, which can predict outcome indicators, promote comparison between different diagnosis and treatment methods, and determine the applicability of clinical trial results to individual patients.
Recently, the International Association for the Study of Lung Cancer (IASLC) leveraged its global multidisciplinary influence to develop a new staging of breast malignancies (lungs, pleura, thymus, and esophagus) using a sophisticated approach. The 9th edition of TNM staging of thoracic malignancy is being further refined and is scheduled to be met in 2024. This article focuses on the specific work of IASLC in the 9th edition TNM staging of lung cancer.
To update lung cancer 9th edition TNM staging, IASLC has once again assembled a large international multicenter database for multifaceted analysis. The proposed new staging needs to maintain a high degree of consistent differentiation among patients with different clinical backgrounds and modes of diagnosis and treatment.
The general process is developed in new phases
The subcommittee of the Committee on Staged and Prognostic Factors (SPFC) regularly holds teleconferences and networks with participants at the annual World Lung Cancer Conference organized by IASLC. Proposals for revised phases are first formulated within the subcommittees and then presented and discussed at joint meetings.
After revision and proper validation, the proposal will be submitted to the SPFC as a whole for further revision and formal approval. It is then submitted to the International Union Against Cancer (UICC) and the American Union oncology (AJCC), both of which were able to finalize the TNM staging of thoracic malignancies in the 9th edition.
Sources of data for new stagings
The size of the 9th edition of the TNM staging database is similar to that used in the 7th edition (81,495 cases) and the 8th edition (77,156 cases) for lung cancer staging, and contains lung cancer data from at least 25 countries to ensure broad representation.
The database consists of data pre-entered into the Electronic Data Acquisition (EDC) system from approximately 50 points of participation and "batch" datasets from different countries and institutions. The data elements of the bulk dataset must be mapped to data elements that include the IASLC database on Cancer Research and Biostatistics (CRAB). Data came primarily from 25 countries in Africa, Asia, Australia, Europe, the Middle East, North america, and South America.
The IASLC database on cancer research and biostatistics (CRAB) has both advantages and disadvantages. As this is a voluntary database, the SPFC does not have the ability to control the size, regional distribution, or integrity of data elements other than to encourage participation. The SPFC strongly encourages the use of the EDC system because it brings more complete data, but it is still used by a minority. Some areas have an over-represented case rate (around 70% in Asia/Australia and around 40% in Japan alone), while other regions have a low proportion of cases (Africa).
However, in the new staging release, under-resourced countries and high-staging cases contribute more to the current database than in previous versions, reflecting the IASLC's direct efforts in these areas.
Considerations for the new staging
At the beginning of the staging, os is the only outcome factor to consider. OS metrics are a logical choice in situations where treatment outcomes, access to care, early detection, and data availability are limited. For the 9th TNM staging, SPFC still considers the OS to be the primary endpoint.
However, for early and inert tumors, recurrence is considered a more representative evaluation indicator of the tumor's range of influence. Therefore, the SPFC approach first assesses clinical relevance, assesses factors that may influence observations, and then adds statistical evaluation to supplement the interpretation of conclusions and improve credibility.
For the calculation of survival, the survival period was calculated from the date of clinical diagnosis of the tumor and the date of surgical pathological diagnosis of the tumor, respectively, and the Kaplan-Meier method was used for analysis. Cases lacking relevant data were excluded from the analysis. Compare survival estimates using the likelihood ratio test for Cox proportional risk regression. Cox regression analysis using SAS version 9.4, with baseline factors (e.g., age, sex, region, cell type) adjusted for the analysis.
Attached: Guidelines for the new phased development
Existing definitions of T, N, and M should be maintained unless there is compelling evidence to support the change. This will ensure vertical compatibility with previous staging systems wherever possible. (This is less important for stage grouping because compatibility can be achieved if consistent T, N, and M categories are available.)
T, N, and M classes and staging should group clinically significant tumors and distinguish between cohorts of different clinical significance.
This should be based on relevant data whenever possible. Key indicators are consistent distinctions between categories and groups (across different settings, tissue types, global regions, clinical settings [clinical (c) staging, pathological (p) staging, residual tumor (R) status] to ensure universality.
Practical considerations affect clinical relevance (e.g., versatility, familiarity, ease of use, prevalence of features, ease of identification of features, applicability of treatment considerations).
Lung cancer staging must meet the general rules for TNM grading of malignancies:
The TNM system consists of 3 parts: T is the primary tumor range, N is the regional lymph node involvement range, and M is the distant metastatic range.
Clinical staging (cTNM) includes all available information that reflects the anatomical extent of the tumor prior to treatment. This may involve symptoms, physical examination, imaging, endoscopy, biopsy, and surgical exploration. Therefore, clinical staging and confidence in evaluation may develop with the assessment of the patient's tumor progression, thereby assessing the extent of the tumor.
Pathological staging (pTNM) includes all information obtained by surgical resection (or attempted resection) and supplements all available information for clinical staging.
Specific TNM categories can be combined into staging groups.
The T, N, M categories and stagings of clinical and pathological staging should be defined identically.
The definition of TNM categories and stagings can be adjusted or expanded for clinical or research purposes without changing the basic definitions of TNM categories and stagings.
If you have doubts about the correct T, N, or M category that a case should be assigned to, you should select a lower (less advanced) category.
If there are multiple primary tumors in an organ, the tumor with the highest T classification should be classified, and the number or number of tumors should be indicated in parentheses, such as T2(m) or T2(5). (In lung cancer, this applies to multifocal grounded ground glass adenocarcinoma/squamous adenocarcinoma, but not to isolate primary tumors).
The specific process of the new phased development
1. Planning Phase - Identify potential factors to consider, including:
Disadvantages of version 8 (ambiguity, poor enforceability).
Potential heterogeneity within a 8th edition category or group.
External analysis (literature) of the proposed factors.
Factors that were previously recommended for further analysis (version 7 or 8).
Factors proposed in stage assessment (imaging, interventions) progress.
Factors recommended for new decision points in therapeutic interventions.
Factors proposed by the SPFC Subcommittee.
2. Implementation Phase - Developing Strategies:
Define the details of the potential analysis (see related text).
Assess the problem-solving capabilities of the IASLC-CRAB database 2011-2019 (sample size, number of incidents, prevalence, robustness of internal assessments).
Identify additional data sources that are useful for analyzing specific factors.
Determine the source of external validation.
Select factors that are feasible for the analysis.
3. Exploratory Analysis:
Collating and evaluating the IASLC-CRAB database (eliminating errors, assessing adjustments that need to be made when merging data of different types/sources, assessing patterns of missing data).
Generate relevant outcome charts by underlying factors (all cases and across subpopulations: such as clinical and pathological settings, relevant T, N, M categories, and associated treatment patterns).
Assess the acceptability of potential factors by appropriate clinical relevance and consistent ranking.
Internal universal assessment of lung cancer tissue type and continents.
Identify and analyze additional subsets to address potential confusion and exploration inconsistencies.
Consider supplemental charts and interpretations of additional outcomes (e.g., recurrence, progression).
4. Validation Analysis and Selection:
Assess differences in potential factors identified in exploratory analysis—i.e., assess the statistical significance of differences between adjacent categories, groups (given clinical relevance and sample size issues—for example, when sample size limits the ability to detect, a predominantly consistent and insignificant ordering may be acceptable).
Assess homogeneity within groups (e.g., confidence intervals for survival parameters, statistical significance analysis), note that the argument for reasonable homogeneity does not preclude the discovery of outliers or additional parameters that can be used to segment groups.
Selection factors after a detailed review of the steps so far and discussion within the Subcommittee and prior to spFC as a whole.
5. Internal and external validation (which may coincide with refinement, review, and release):
Versatility of internal validation, including history, geography, methodology, disease spectrum, follow-up intervals, etc.
External validation in the appropriate database.
6. Amendment, Review and Publication of Proposals:
Proposals for the subcommittees are presented and discussed among all members of the Association
The draft is circulated to all SPFC members for modification and approval
External journal review process
Published in JTO, with open dissemination and open commenting capabilities
7. The International Cancer Alliance (UICC) and the American Oncology Federation (AJCC) accept the final new stage.
The new staging uses the advantages and disadvantages of different endpoint metrics
Image source: Courtesy of the author
Curator: GoEun, Mei Zhe
Title image source: Station Cool Helo PLUS
bibliography
Detterbeck FC, Nishimura KK, Cilento VJ, Giuliani M, Marino M, Osarogiagbon RU, Rami-Porta R, Rusch VW, Asamura H; IASLC Staging and Prognostic Factors Committee and Advisory Boards. The IASLC Lung Cancer Staging Project: Methods and Guiding Principles for the Development of the 9th Edition TNM Classification. J Thorac Oncol. 2022 Mar 9: S1556-0864(22)00107-1. doi: 10.1016/j.jtho.2022.02.008. Epub ahead of print. PMID: 35278692.
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