Editor’s Note: For more on the Staging and Prognostic Factors Committee’s work on recommended revisions for the 9th edition of the TNM Classification system, read ILCN’s interview with SPFC Chair Hisao Asamura, MD.
The achievements of IASLC’s Staging and Prognostic Factors Committee in revising the TNM staging of lung cancer represent a landmark in the management of lung cancer—an ongoing project notable for its scientific rigor and harmonious international and multidisciplinary collaboration. As the committee finalizes its recommendations for the upcoming 9th edition, we were pleased to see challenges and opportunities of revising the nodal classification discussed in a recent article in the Journal of Thoracic Oncology.1 The committee’s continuing work on the significance of the various N-descriptors is an important piece of the staging and prognostic factors puzzle.
The pre-eminence of pathologic staging in the current system may be a major reason why surgical cases comprise the predominant proportion of cases contributed to the IASLC staging database. As clinicians with longstanding interests in lung cancer staging, but who are not surgeons, we seek to add to that discussion with some additional insights on the nodal classification project from a non-surgical perspective.
Considering Alternative Approaches
As in previous revisions to TNM, prognosis discriminatory ability has been selected as the criterion for separating groups (rather than suitability for a particular treatment, for example). A survey of the N-descriptors subcommittee members led to the selection of a difference of 5% in five-year survival as a rough benchmark as the minimum between groupings. This might be appropriate for a population undergoing curative-intent surgical resection or stereotactic ablative body radiotherapy (SABR). However, it may not be applicable to those patients with more advanced NSCLC—i.e. T4N0 as well as T1-3N3—who receive treatment that may have little effect on five-year survival but can nevertheless result in meaningful prolonging of survival in the shorter term.
For example, in a prospective study of the effect of primary tumor and nodal volume on survival in patients treated with curative radiotherapy or chemoradiotherapy for NSCLC, there was an adverse effect of larger volume on survival in the first 18 months, but not thereafter.2 We observed a similar weakening of the hazard ratio over time between tumor size groups in a previous analysis restricted to radiotherapy patients in an earlier IASLC staging database.3 Although N status was not the focus of these analyses, they do illustrate that TNM may perform differently depending on whether the primary treatment has been surgical excision or high dose radiotherapy, thus questioning its generalizability beyond the surgical domain.4
Complicating matters further are the recently reported improvements in five-year survival associated with the use of immune checkpoint inhibitors in patients with metastatic disease.
For example, in the recently reported KEYNOTE-1895 and CheckMate 2276 long-term trial results, immunotherapy was associated with a greater than 5% difference in five-year overall survival compared with chemotherapy alone in patients with metastatic disease. Many patients treated initially with curative-intent surgery or SABR will subsequently relapse with metastatic disease. We would expect these patients to be treated with immunotherapy, targeted agents, or in the case of oligometastasis, SABR or further surgery.
How then do we disentangle the effects of treatment versus nodal status on five-year overall (opposed to relapse-free) survival?
Most of the cases in the database being used to make recommendations for the 9th edition are likely to be surgical, and while nodal status at surgery may predict risk of subsequent relapse, it is unlikely to have any implications for prognosis following what are now effective second- or even third-line treatments.
Radiologic vs. Histologic Confirmed Clinical Nodal Stage
Pathologic (histologic) staging is prioritized over clinical staging, and there can be no doubt that clinical staging inadequately quantifies the burden of nodal disease. This can be demonstrated by the differences in outcomes between clinically staged and pathologically staged R0 tumors.7 As an illustration, 60-month survival between T3 patients staged cN0 and pN0 differs by as much as 18%.
Few patients undergoing curative-intent chemoradiation for locally advanced disease undergo comprehensive nodal staging. Therefore, while the clinical N-stage descriptors from the 8th edition TNM demonstrate prognostic value for all patients, pathologic descriptors cannot be known in those patients undergoing non-surgical care.
Alternate approaches to improve the staging of patients receiving non-surgical care, such as minimally invasive nodal staging via endobronchial ultrasound (EBUS),8 are not always routine practice. While not perfect, the detection rate of nodal disease by surgical staging following negative EBUS remains low.8 Systematic lymph node sampling could be encouraged, and the information collected to allow the IASLC database to be more accurate than current image-based clinical staging, especially for patients with N2/locally advanced disease, and better inform the attempts to sub-group N1 and N2 stages according to the number of lymph node stations involved.7
Applying IASLC residual tumor descriptors recommendations to patients receiving chemoradiation would see the vast majority of our patients with locally advanced disease staged R-uncertain due to a failure to systematically evaluate mediastinal lymph nodes.9 Such a paradigm may afford patients with locally advanced disease the opportunity to benefit from comprehensive staging and may also further assist refinement of the nodal staging system.
Improving Station Labeling to Improve Nodal Staging
The IASLC lymph node map was first published in 2009.10 Subsequently, Pitson et al have drawn attention to a number of ambiguities in the anatomical definition of the nodal stations, particularly as they might affect radiation oncology practice.11 However, some discrepancies have not been resolved.
For example, the lower border of station 1 is defined as the clavicles, but the upper border of station 2 is the apex of the lung, which may be higher than the clavicle as illustrated in their article. The resulting overlap means that the line of demarcation between potentially resectable N2 (station 2) and unresectable N3 (station 1) is unclear. We feel that a review of the wording of the station definitions in the map would be worthwhile to improve its precision.
We are pleased that the IASLC TNM Committee has widened its brief in name and activity beyond the anatomical extent of disease exemplified by TNM. The challenge will be to keep up with the rapid pace of progress in lung cancer biology and treatment when the revision cycle is in the range of seven to 10 years.
References
- 1. Osarogiagbon RU, Van Schil P, Giroux DJ, Lim E, Putora PM, Lievens Y, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Overview of Challenges and Opportunities in Revising the Nodal Classification of Lung Cancer. J Thorac Oncol. 2022.
- 2. Ball DL, Fisher RJ, Burmeister BH, Poulsen MG, Graham PH, Penniment MG, et al. The complex relationship between lung tumor volume and survival in patients with non-small cell lung cancer treated by definitive radiotherapy: a prospective, observational prognostic factor study of the Trans-Tasman Radiation Oncology Group (TROG 99.05). Radiother Oncol. 2013;106(3):305-11.
- 3. Ball D, Mitchell A, Giroux D, Rami-Porta R, Committee IS, Participating I. Effect of tumor size on prognosis in patients treated with radical radiotherapy or chemoradiotherapy for non-small cell lung cancer. An analysis of the staging project database of the International Association for the Study of Lung Cancer. J Thorac Oncol. 2013;8(3):315-21.
- 4. Ball D. TNM in non-small cell lung cancer: a staging system for all oncologists or just for surgeons? Ann Transl Med. 2019;7(Suppl 3):S103.
- 5. Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Domine M, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023:JCO2201989.
- 6. Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023;41(6):1200-12.
- 7. Asamura H, Chansky K, CrowleyJ, Goldstraw P, Rusch VW, Vansteenkiste JF, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2015;10(12):1675-84.
- 8. Annema JT, Rabe KF. Endosonography for lung cancer staging: one scope fits all? Chest. 2010;138(4):765-7.
- 9. Edwards JG, Chansky K, Van Schil P, Nicholson AG, Boubia S, Brambilla E, et al. The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non-Small Cell Lung Cancer. J Thorac Oncol. 2020;15(3):344-59.
- 10. Rusch VW, Asamura H, Watanabe H, Giroux DJ, Rami-Porta R, Goldstraw P, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4(5):568-77.
- 11. Pitson G, Lynch R, Claude L, Sarrut D. A critique of the international association for the study of lung cancer lymph node map: a radiation oncology perspective. J Thorac Oncol. 2012;7(3):478-80.
