Key messages
• We found many different treatment options for fertility-sparing treatment of endometrial cancer (cancer of the womb lining) and atypical endometrial hyperplasia (precancer). We don't know which treatment is most effective or what is the best way to deliver it.
• Adding metformin to progesterone treatment could be of benefit when treating endometrial cancer and precancer. Levonorgestrel-intrauterine system (hormone-releasing coil) may be of benefit because it obtains a similar response with fewer unwanted effects compared to oral progesterone.
• We need more well-designed studies to evaluate and compare the different treatment options.
What are endometrial cancer and atypical endometrial hyperplasia?
Endometrial cancer is cancer of the womb lining. It is the sixth most common cancer worldwide and the fourth most common in high-income countries, where rates are increasing. Atypical endometrial hyperplasia (precancer) is the growth of abnormal cells in the lining of the womb. If it's not treated, it may develop into endometrial cancer. Delays in childbearing and increasing obesity rates are both risk factors for cancer and precancer. The most effective treatment for endometrial cancer and precancer is to remove the womb (hysterectomy). Endometrial cancer and precancer are more common after the menopause, but up to 25% of cases occur in younger women. This means that more women are now diagnosed with cancer whilst still wishing to conceive. This leads to an increasing number of women who may want to consider fertility-sparing (preserving) treatment.
Treatment with progestins (a female hormone) is usually recommended. In addition, other treatments, such as metformin (a treatment used for diabetes) or bariatric surgery (surgery for obesity) or hysteroscopic resection (a procedure with a thin camera and special tools inserted through the vagina to remove abnormal tissue) are currently being investigated. However, the best treatment options remain uncertain.
What did we want to find out?
We wanted to find out which treatments are effective for endometrial cancer and precancer, and whether they are also effective for preserving women's fertility.
What did we do?
We searched for studies that investigated treatments for endometrial cancer and precancer that also aimed to preserve fertility. We were interested in various treatments, such as different medicines, surgery, and weight-loss programmes. We wanted to know the effects of the different treatments on women's overall survival, how many women had a baby (live birth rate), how long women survived with no cancer recurrence, how many women completely recovered (complete pathological response rate), any severe unwanted effects of the treatments, whether there were any psychological symptoms or impact on quality of life, how many women became pregnant, and how many needed a hysterectomy following unsuccessful treatment. We summarised and compared the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 12 studies that involved 904 women. These included six studies where women were randomly assigned to treatments and six studies where treatment was not randomly assigned.
Main results
Metformin plus progestin compared to progestin alone may slightly increase the complete response rate (absence of any detectable cancer after treatment) and may have little to no effect on live births or the need for surgery for persistent/progressive disease. The studies reported no serious unwanted effects. No information is available about the effect on how long women survive overall, or survive before their disease re-grows, or quality of life.
Levonorgestrel intrauterine system is a hormone-releasing coil inserted inside the womb. Compared to progestins taken by mouth, it may have no effect on complete response (absence of detectable cancer), and fewer unwanted effects such as weight gain. Women may be more likely to continue treatment with this device. There is no available information about other outcomes.
Adding a hormone-releasing coil to progestin taken by mouth may make no difference to survival, live births, cure rate, quality of life or need for future surgery. It also appears not to increase unwanted effects.
What are the limitations of the evidence?
Our confidence in the evidence is low, for several reasons. Firstly, in some studies, women were not randomly placed into different treatment groups. This means that differences between the groups could be due to differences between women rather than between the treatments. Secondly, some evidence focused on a specific group of women, such as obese women, whereas the question we hoped to address was broader. Finally, some studies were very small. Therefore, further research is likely to change or confirm these results.
How up-to-date is the evidence?
The evidence is current to 3 February 2025.
Vollständige Zusammenfassung lesen
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.
Zielsetzungen
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.
Suchstrategie
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.
Auswahlkriterien
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).
Datensammlung und ‐analyse
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.
Hauptergebnisse
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).
Schlussfolgerungen der Autoren
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.
