Background: As the number of young women with early-stage endometrial cancer is increasing, there is growing interest in use of progesterone-based therapy to allow fertility preservation. To date, there is a paucity of data on the safety and long-term outcomes of progesterone therapy. The objective of our study was to determine the safety and long-term outcomes of hormonal therapy for clinical stage I endometrial cancer in premenopausal women. Methods: The National Cancer Database was used to identify patients 18-49 years of age with clinical stage I, grade 1-2, endometrioid endometrial cancer diagnosed from 2004-2020. Primary treatment was defined as hysterectomy or hormonal therapy. Trends in the use of hormonal therapy were examined. A multivariable regression model was developed to examine the association between hormonal therapy and demographic factors. After propensity score matching, survival was compared between patients treated primarily with hormonal therapy and with primary hysterectomy. Results: A total of 15,849 patients, including 14,662 (92.5%) treated with primary hysterectomy and 1,187 (7.5%) who received primary hormonal therapy were identified. The use of hormonal treatment increased from 5.2% in 2004 to 13.8% in 2020 (P<0.0001). In a multivariable model, younger age, more recent year of diagnosis, non-White race, lower tumor grade, and earlier stage were associated with use of hormonal therapy (P<0.05 for all). After propensity score balancing, 5-year survival was 98.5% (95% CI, 97.3-99.2%) for hysterectomy and 96.8% (95% CI, 95.3-97.8%) for hormonal therapy (HR=1.84; 95% CI 1.06-3.21). Among patients <40 years of age, there was no difference in survival between hysterectomy and hormonal therapy (HR=1.00; 95% CI, 0.50-2.00). However, for patients age 40-49, hormonal therapy was associated with a significantly increased risk of death (HR=4.94; 95% CI, 1.89-12.91). There was no statistically significant difference in outcomes for hormonal therapy compared to hysterectomy in sub-set analyses stratified by grade (1 or 2) or stage (1A or 1B). Conclusions: The use of fertility-preserving hormonal therapy among reproductive age patients with early-stage endometrial cancer has increased over time. Among women age 40-49, hormonal therapy is associated with decreased survival.

HR, hazard ratio; CI, confidence interval.