Fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer

Endometrial cancer is the sixth most common cancer in women worldwide, and the fourth most common in high-income countries, where its incidence is increasing. Atypical endometrial hyperplasia (AEH) is an overgrowth of the womb lining and can be a precursor of endometrial cancer. Between 14% and 25% of cases of endometrial cancer are diagnosed in premenopausal women. Due to delays in childbearing age and increasing obesity rates, a growing number of women wish to explore fertility-sparing management of endometrial cancer or AEH.

To compare the effectiveness and safety of fertility-sparing treatments, including pharmacological interventions (e.g. oral progestin, levonorgestrel intrauterine system (IUS), metformin) and bariatric or hysteroscopic surgery, for AEH and presumed stage IA grade 1 endometrioid endometrial cancer.

We searched the following electronic databases to 3 February 2025: CENTRAL; Ovid MEDLINE; and Ovid Embase. We also searched five trials registers and conference proceedings and abstracts.

We included randomised controlled trials (RCTs) that compared fertility-sparing therapy for presumed stage IA grade 1 endometrioid endometrial cancer or AEH with oral progestin compared to levonorgestrel IUS or metformin or other pharmacological interventions, or bariatric or hysteroscopic surgery (any comparison); or any of these interventions with the usual treatment (surgery). Other comparative non-randomised studies were also eligible for inclusion (quasi-randomised trials, non-randomised studies (NRS), and prospective and retrospective cohort studies).

Two review authors independently extracted data and assessed the methodological quality of the studies. We used standard Cochrane methodological procedures. Where possible, we pooled data from RCTs in a meta-analysis. Otherwise, we provided a narrative description of the results. Primary outcomes are overall survival and live birth rate. Secondary outcomes are progression-free survival, complete pathological response rate (CR), severe adverse events, psychological symptoms, quality of life, pregnancy rate, and surgery for persistent/progressive disease. We assessed the certainty of the evidence using GRADE. We assessed the risk of bias only in RCTs, using the Cochrane risk of bias tool, RoB 1.

We included 12 studies with 904 participants; six RCTs and six NRSs. Four studies included women with AEH, two, women with endometrial cancer, and six, both AEH and endometrial cancer. We judged the studies at high risk of overall bias. We pooled two RCTs into one meta-analysis and described the remaining comparisons narratively. None of the included studies provided evidence for overall survival, progression-free survival or quality of life for any comparison. Metformin plus progestin compared with progestin Metformin plus progestin may have little to no effect on live birth rate (risk ratio (RR) 1.80, 95% confidence interval (CI) 0.88 to 3.68); 2 RCTs, 72 women; low-certainty evidence) but may slightly increase CR (RR 1.85, 95% CI 1.07 to 3.19; P = 0.03; 2 RCTs; 141 women; low-certainty evidence). No fatal adverse events were observed. Weight gain was the most frequent adverse event in one RCT, with 5/74 (6.8%) cases of grade 3-4 weight gain in the progestin group versus 2/76 (2.6%) in the metformin plus progestin group (RR 0.39, 95% CI 0.08 to 1.95; 1 RCT; 150 women; low-certainty evidence). Metformin plus progestin may make little to no difference in the need for surgery for persistent/progressive disease (RR 0.96, 95% CI 0.24 to 3.78; 2 RCTs; 166 women; low-certainty evidence). Levonorgestrel IUS compared to oral progestin Only one RCT evaluated live birth rate, showing little to no difference between levonorgestrel IUS and oral progestin (RR 1.80, 95% CI 0.74 to 4.39; 1 RCT, 34 women; low-certainty evidence). Data from two RCTs showed no evidence of a difference in CR in women with AEH (data not pooled): RR 1.78 (95% CI 0.98 to 3.25; 89 women), and RR 1.24 (95% CI 0.86 to 1.78; 19 women), both low-certainty evidence. One RCT found that levonorgestrel IUS may decrease severe adverse events (weight gain) slightly (RR 0.19; 95% CI 0.04 to 0.84; 1 RCT, 118 women; low-certainty evidence). Evidence on surgery for persistent/progressive disease information was incomplete. Oral progestin plus levonorgestrel IUS compared to oral progestin One RCT in endometrial cancer evaluated live birth rate, finding no difference between oral progestin plus levonorgestrel IUS and oral progestin alone (RR 1.40, 95% 0.46 to 4.24; 1 RCT, 33 women; low-certainty evidence). Similarly, no differences were found in women with AEH (RR 1.38, 95% CI 0.50 to 3.82;1 RCT, 47 women; low-certainty evidence). Data from two RTCs showed no difference in CR in women with endometrial cancer (RR 1.30, 95% CI 0.47 to 3.59; 1 RCT, 54 women) or with AEH (RR 1.45, 95% CI 0.77 to 2.76; 1 RCT, 86 women low-certainty). The only grade 3 adverse event was weight gain, with no difference between the groups for endometrial cancer (RR 1.11, 95% CI 0.17 to 7.34; 1 RCT, 59 women; low-certainty evidence) and AEH (RR 0.97, 95% CI 0.43 to 2.20; 1 RCT, 112 women; low-certainty evidence). Surgery for persistent/progressive disease was also similar in the two treatment arms, both for women with endometrial cancer (RR 2.07, 95% CI 0.20 to 21.60; 1 RCT, 59 women; low-certainty evidence) and with AEH (RR 1.00, 95% CI 0.06 to 15.48; 1 RCT, 86 women; low-certainty evidence).

In light of the low certainty of the evidence, it is unclear which intervention and which route of administration or dose of progestins could be of benefit compared to others for fertility-sparing management of endometrial cancer or AEH. The addition of metformin to progestins may increase complete response slightly. Levonorgestrel IUS may result in no difference in efficacy in complete response, compared to oral progestins, whilst it may reduce adverse events slightly. Therefore, levonorgestrel IUS may improve quality of life and compliance with treatment.