Validation of the 2023 FIGO staging schema for advanced endometrial cancer

In 2023, the International Federation of Gynecology and Obstetrics (FIGO) revised the endometrial cancer staging schema [[1]Berek J.S. Matias-Guiu X. Creutzberg C. Fotopoulou C. Gaffney D. Kehoe S. et al.Endometrial Cancer Staging Subcommittee, FIGO Women's Cancer CommitteeFIGO staging of endometrial cancer: 2023.Int J Gynaecol Obstet. 2023; https://doi.org/10.1002/ijgo.14923Crossref Scopus (44) Google Scholar]. This is the first revision in the past 15 years from prior revision occurred in 2009 [[2]Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium.Int J Gynaecol Obstet. 2009; 105: 103-104Crossref PubMed Scopus (2270) Google Scholar]. One of the key changes is greater sub-division in advanced stages from 6 to 11 subgroups based on anatomical site of disease and histologic subtype (Table S1) [[1]Berek J.S. Matias-Guiu X. Creutzberg C. Fotopoulou C. Gaffney D. Kehoe S. et al.Endometrial Cancer Staging Subcommittee, FIGO Women's Cancer CommitteeFIGO staging of endometrial cancer: 2023.Int J Gynaecol Obstet. 2023; https://doi.org/10.1002/ijgo.14923Crossref Scopus (44) Google Scholar]. These include low-grade endometrioid tumours with adnexal-only metastasis that are downstaged from stage IIIA to IA3 disease. Nodal metastasis is further classified according to metastasis size (micrometastasis or macrometastasis). Stage IVB is subdivided based on the location of metastasis (abdominal carcinomatosis or distant metastases). The performance characteristics of the revised 2023 FIGO staging schema for endometrial cancer have not been evaluated well. The objective of this study was to validate the prognostic ability of the 2023 FIGO staging schema for advanced endometrial cancer. The detail of study design and analytic approach is described in Method S1. Briefly, the National Cancer Institute’s Surveillance, Epidemiology, and End Results Programme was retrospectively queried [3Surveillance, epidemiology, and end results program. National Cancer Institute. 〈https://seer.cancer.gov/〉. [Accessed 13th June 2023].Google Scholar, 4Collaborative Stage Data Collection System v02.05. American College of Surgeons. 〈https://www.facs.org/quality-programs/cancer-programs/american-joint-committee-on-cancer/collaborative-staging-schema-v02–05/〉. [Accessed 13th June 2023].Google Scholar, 5CorpusCarcinoma. Collaborative Stage Data Set. 〈https://web2.facs.org/cstage0205/corpuscarcinoma/CorpusCarcinomaschema.html〉. [Accessed 13th June 2023].Google Scholar, 6International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). World Health Organization. 〈https://www.who.int/standards/classifications/other-classifications/international-classification-of-diseases-for-oncology〉.[Accessed 13/th June 2023].Google Scholar]. The study cohort was selected based on the 2009 schema: stage IIIA-IIIB (n = 1295), IIIC (n = 1365), and IV (n = 2813) diseases, respectively. The main outcome measure was endometrial cancer-specific mortality according to the 2009 and 2023 schemas, assessed with competing risk analyses by fitting the Gray test [[7]Gray R.J. A Class of k-sample tests for comparing the cumulative incidence of a competing risk.Ann Stat. 1988; 16 (accessed 6/13/2023): 1141-1154〈https://www.jstor.org/stable/2241622〉Crossref Google Scholar]. The University of Southern California Institutional Review Board deemed this study exempt because it included only publicly available, deidentified data (Patient informed consent: not required). For stage IIIA-IIIB cohort, the median follow-up of censored cases was 77 months (interquartile range (IQR) 58–95). During the follow-up, endometrial cancer deaths occurred in 372 (28.7%) patients. Based on the 2009 schema, the 5-year endometrial cancer-specific mortality rates were 24.9% and 41.5% for historical IIIA and IIIB disease, respectively (Fig. 1A and Table S2). According to the 2023 schema, the 5-year endometrial cancer-specific mortality rate in the downstaged IA3 group was 11.0% which was significantly lower compared to the new IIIA1–2 groups (31.6–31.8%, P < 0.001; Fig. 1B and Table S2). The 5-year endometrial cancer-specific mortality rates were similar for the stage IIIA1 and IIIA2 groups (31.8% versus 31.6%; Fig. 1B and Table S2). In the 2023 schema, IIIB1–2 groups had higher mortality than the IIIA1–2 groups (5-year endometrial cancer-specific mortality rates, 41.4–42.0% versus 31.6–31.8%, P < 0.001; Fig. 1B); the 5-year endometrial cancer-specific mortality rates were, however, similar between the IIIB1 and IIIB2 groups (41.4% versus 42.0%) (Table S2). For stage IIIC cohort, the median follow-up of censored cases was 10 months (IQR 5–17). During the follow-up, endometrial cancer deaths occurred in 75 (5.5%) patients. According to the 2009 schema, the 1.5-year endometrial cancer-specific mortality rates were 8.8% for IIIC1 disease and 13.9% for IIIC2 disease, respectively (P = 0.074; Fig. 1C and Table S2). According to the 2023 schema, macrometastasis in para-aortic lymph node (IIIC2-ii) had the worst endometrial cancer-specific mortality followed by macrometastasis in pelvic lymph node (IIIC1-ii), but micrometastasis in para-aortic (IIIC2-i) and pelvic lymph (IIIC1-i) nodes had similar mortality (1.5-year rates, 14.9%, 10.5%, 5.9%, and 5.1%, respectively; P = 0.041; Fig. 1D). In the different angle, macrometastasis had higher endometrial cancer-specific mortality compared to micrometastasis in the regional lymph nodes (10.5–14.9% versus 5.1–5.9%; Fig. 1D). For stage IV cohort, the median follow-up of censored cases was 72 months (IQR 55–94). During the follow-up, endometrial cancer deaths occurred in 1879 (66.8%) patients. According to the 2009 schema, the 5-year endometrial cancer-specific mortality rate was 56.3% for historical IVA disease and 67.4% for historical IVB disease (P < 0.001; Fig. 1E and Table S2). When applying the 2023 schema (Fig. 1F), the 5-year endometrial cancer-specific mortality rates were 56.3%, 62.7%, and 71.4% for stage IVA, IVB, and IVC disease, respectively (Table S2). The mortality rate in the IVC group diseases was significantly higher compared to the new IVB group (71.4% versus 62.7%, P < 0.001). Abdominal carcinomatosis and pelvic peritoneal metastasis had distinct oncologic outcomes (5-year endometrial cancer-specific mortality rates for new IVB versus IIIB2, 62.7% versus 42.0%, P < 0.001; Fig. S1). In exploratory analysis, the extent of distant metastasis either to liver, lung, bone, brain, or inguinal lymph node was assessed in stage IVC disease (n = 1361). The majority of IVC diseases were single distant metastases (69.4%), followed by multiple distant metastases (2 distant metastases 22.6%, and ≥3 distant metastases 8.0%). Patients with multiple distant metastases had higher endometrial cancer-specific mortality compared to those with single distant metastasis (5-year rates, 78.9%, 75.2%, and 69.3% for triple or more, double, and single; P < 0.001; Fig. S2 and Table S3). There are several important limitations in this study. Recurrence data is a key outcome measure but is not available in the data. Molecular classification data is also not available in the database, but this is a major driver of endometrial cancer classification and outcome [8Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. et al.Cancer Genome Atlas Research NIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3438) Google Scholar, 9Crosbie E.J. Kitson S.J. McAlpine J.N. Mukhopadhyay A. Powell M.E. Singh N. Endometrial cancer.Lancet. 2022; 399: 1412-1428Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. Evaluation of stage I-II diseases was not possible as the database does not have information on lympho-vascular space invasion which is the key staging factor in early disease. Small sample size and limited follow-up were other limitations that may possibly risk type II error. Stage IA3 disease may be overcaptured due to the lack of informatoin for myometrial invasion, laterality, and lympho-vascular space invasion. Further, our data represent selected regions of the U.S. and may not be generalisable to other areas. Based on these data together with the increasing number of historical stage IVB endometrial cancers in the United States (Fig. S3), the revised staging schema for stage IVB-IVC diseases appears to provide important discriminatory data on survival and may be useful for informing both treatment and prognostication. Together with the fact that this group has dismal prognosis almost similar to advanced epithelial ovarian cancer [[10]Matsuo K. Machida H. Matsuzaki S. Grubbs B.H. Klar M. Roman L.D. et al.Evolving population-based statistics for rare epithelial ovarian cancers.Gynecol Oncol. 2020; 157: 3-11Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar], this calls for special attention and more investigations to improve the oncologic outcome. Similarly, the removal of patients with low-grade endometrioid tumours with isolated adnexal disease from stage III appears to be warranted based on the favourable outcome of this group. However, the re-classification of patients with stage III tumours may be of more limited value as the new criteria have resulted in sub-groups with very similar endometrial cancer mortality and, in the case of patients with nodal metastasis either to pelvic or para-aortic region, the size of metastasis was prognostic but not the anatomical site. In conclusion, the 2023 FIGO endometrial cancer staging schema is a major revision from the 2009 FIGO schema. Almost doubled enriched sub-stages based on detailed anatomical metastatic sites and incorporation of histological information enable more robust prognostication in advanced disease. Ensign Endowment for Gynecologic Cancer Research (K.M.). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.