Levonorgestrel-releasing intrauterine system treatment for endometrial hyperplasia and early endometrial cancer: a systematic review

Background: Levonorgestrel-releasing intrauterine systems (LNG-IUS) are considered off-label and investigational in the United States for treating non-atypical endometrial hyperplasia (NAEH), atypical endometrial hyperplasia (AEH), and early-stage endometrial cancer (EC), though evidence suggests potential benefit. Objectives: To summarize the available evidence regarding the use of LNG-IUS, with or without other therapies, for the treatment of NAEH, AEH, and early-stage (FIGO I/IA) EC. Design: Systematic literature review and meta-analyses. Data sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews (CDSR) were searched from database inception through May 2022. Methods: Data from studies reporting complete outcome definitions and study populations that were aligned with the 2014 World Health Organization (WHO) endometrial hyperplasia classification criteria or were defined as FIGO grade 1 stage I/IA EC were extracted and assessed in random-effects meta-analyses. A risk of bias assessment was completed using recommended study-design-specific tools. Results: 1085 unique records were reviewed; 80 publications were included, with data from 30 assessed in meta-analyses: NAEH, n = 14; AEH, n = 21; EC, n = 5. Complete response (CR) rates at 12 months were high: 86.3% (95% confidence interval (CI): 78.50%–91.55%; n = 342) of patients with NAEH, 83.9% (95% CI: 71.95%–91.34%; n = 196) of patients with AEH, and 51.1% (95% CI: 16.30%–84.90%; n = 20) of patients with EC. LNG-IUS was associated with significantly greater odds of CR at 12 months compared to oral progestins in NAEH and AEH populations, with odds ratios ranging from 2.16 (95% CI: 1.38–3.36) to 4.56 (95% CI: 2.57–8.09). No comparative data were available for EC. Safety information was consistent with that of approved LNG-IUS indications. Risk of bias varied across study designs. Conclusion: The findings suggest that NAEH, AEH, and early-stage (FIGO I/IA) EC can be effectively treated with LNG-IUS, with the evidence being strongest for NAEH and weakest for EC. Greater availability of LNG-IUS treatment could provide meaningful benefit to these patients. Trial registration: Not applicable.