Which patients with stage IB endometrioid endometrial cancer are at high risk of distant recurrences

Objectives: Women with stage IB endometrioid endometrial cancer (EEC) are at risk of developing non-vaginal recurrences. However, it is unclear which patients have high enough risk to justify testing systemic therapies. Our aim is to identify significant risk factors for non-vaginal recurrence. Methods: This is a retrospective multicenter study, including patients who underwent complete surgical staging for EEC at Mayo Clinic, Rochester (MN, USA) between January 1999-December 2017, and at Fondazione Policlinico Gemelli (Rome, Italy) between March 2002-March 2017, with a final FIGO stage IB. Patients without lymph node assessment were excluded. Recurrences were categorized into isolated vaginal and non-vaginal (hematogenous, peritoneal, lymphatic, or multi-site). The follow-up was restricted to the first 5 years following surgery. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method. Cox proportional hazards models, stratified by center, were fit to evaluate the association of clinical and pathologic characteristics with the risk of recurrence. Results: Three hundred eighty-six patients were identified. The mean myometrial invasion (MI) of the cohort was 70.4% (SD 13.2). The majority of the patients received either vaginal brachytherapy (VB) or no adjuvant therapy (N=256, 66.3%), 57 patients (14.8%) received EBRT ± chemotherapy ± VB, 38 (9.8%) received chemotherapy ± VB, and 35 (9.1%) unknown. Greater MI was associated with increased histologic grade and lymph vascular space invasion (LVSI). We identified 51 recurrences (14 isolated vaginal, and 37 non-vaginal); the median follow-up of the remaining patients was 4.5 (IQR, 2.3-6.9) years. The 5-year RFS for non-vaginal recurrences was 88.1% (95% CI 84.4-91.9%). There was a strong linear relationship between the percent of MI and the risk of recurrence. Patients with the deepest MI (≥90%) had a rate of recurrence as high as 40%. At univariate analysis, the risk of non-vaginal recurrence increased as the percent of MI increases (vs. MI 50-69.9%), with a hazard ratio (HR) of 3.33 (95% CI, 1.46-7.58) in patients with MI 70 to 89%, and HR of 8.47 (95% CI, 3.26-22.01) with MI≥ 90%. Patients with grade 3 disease had a higher risk of non-vaginal recurrence compared to grade 1-2 (HR 3.58, 95% CI, 1.86-6.88). At multivariate analysis, both histologic grade and depth of MI were independent predictors of recurrence. In particular, the subset of patients with MI≥ 70% and grade 3 tumors have the poorest RFS; however, we noticed also that patients with myometrial invasion ≥ 90% have a very high risk of recurrence independently from histologic grade (Table). Download : Download high-res image (68KB) Download : Download full-size image Conclusions: Considering women with stage IB endometrioid endometrial cancer, the rate of non-vaginal recurrences at 5 years is very high (> 30%): (1) in patients with any grade with MI≥ 90%; and (2) in grade 3 patients with MI≥ 70%. In the future, these pathologic findings could help us identify subgroups of patients in which systemic therapies may be tested.