Disease regression was observed in 82% of women with endometrial hyperplasia with atypia and 43% of women with endometrial cancer after treatment for 6 months with a hormonal intrauterine device in a phase II study reported during the virtual edition of the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer.1 With 165 patients enrolled, the study appears to be the largest yet to evaluate this experimental noninvasive approach to managing early endometrial cancer and precancer.
The feMMe trial (ANZGOG 1301) also found that two adjunctive therapies—a weight loss intervention and metformin—essentially added no additional benefit to the levonorgestrel intrauterine device alone. Altogether, pathologic complete response was achieved by 61% of patients randomly assigned to receive the levonorgestrel intrauterine device only, by 67% of those receiving the device plus a weight loss intervention program, and by 57% of those given the device plus metformin, reported senior investigator Andreas Obermair, MD, Professor at the University of Queensland in Brisbane, Australia.
Andreas Obermair, MD
Hormonal Therapy Used ‘Ad Hoc’
“Standard treatment of endometrial cancer is total hysterectomy and bilateral salpingo-oophorectomy, with or without surgical staging. However, for two groups of patients, this is problematic: young women who wish to preserve fertility, and elderly and frail women with multiple medical comorbidities who are at risk of a prolonged hospital stay, procedure-related adverse events, and the high cost of care. Therefore, professional societies, clinicians, and patient advocacy groups have called for nonsurgical options for these patients,” Dr. Obermair said.
Oral progestins have been used, but they carry a risk of significant adverse effects, including thromboembolic events, worsening of diabetes, and weight gain. Thus, in the past, the levonorgestrel intrauterine device has been offered “ad hoc” to patients who are not suitable for surgery, although “robust evidence” of efficacy has been lacking, he said.
In 2012, Dr. Obermair and colleagues performed a meta-analysis on studies of oral progestins and intrauterine devices, finding pathologic complete response rates of 73% and 68%, respectively.2 All available studies were observational and retrospective. Independently, it has also been reported that metformin, a common diabetes drug, has antiproliferative effects on the endometrium and that weight loss is associated with a reduced risk of endometrial cancer and improved overall survival after such a diagnosis. What has not been clear, noted Dr. Obermair, was if those effects can be confirmed in prospective studies and whether these approaches are more effective when used together.
Details of feMMe Trial
The open-label phase II study enrolled 96 patients with endometrial cancer (58%) and 69 patients with endometrial hyperplasia with atypia (42%). The objective was to determine whether the effectiveness of the levonorgestrel intrauterine device could be increased by adding metformin or a weight loss intervention. Patients were required to have a body mass index (BMI) of at least 30 kg/m2 and a CA-125 level less than 30 U/mL. The mean patient age was 53 years, the average BMI was 47.7 kg/m2, and 43% were premenopausal.
Patients with grade 2 or 3 disease or high-risk cell types were not eligible for this trial. Also ineligible were patients who received progestins as recently as 12 weeks prior to study entry or had received pelvic radiotherapy.
The women were randomly assigned in a 3:3:5 ratio to receive the levonorgestrel intrauterine device (52 mg of levonorgestrel) plus observation, the device plus a weight loss intervention, or the device plus metformin (250 mg twice daily). If patients were already taking metformin, they were randomly assigned to receive the levonorgestrel intrauterine device alone or the weight loss intervention.
The weight loss intervention consisted of a 6-month subscription to Weight Watchers, with patients encouraged to lose 7% of their total body weight within 6 months. After 3 months, patients underwent an endometrial assessment to exclude disease progression; at 6 months, they were assessed for pathologic complete response.
Achievement of Pathologic
Complete Response
The rates of pathologic complete response by randomization, as assessed at 6 months, were as follows:
82% for women with endometrial hyperplasia with atypia and 43% for women with endometrial cancer overall
61% with the levonorgestrel intrauterine device alone, 67% with the device plus weight loss, and 57% with the device plus metformin
61% with the levonorgestrel intrauterine device, 67% with the device plus weight loss, and 62% with the device plus metformin, in the sensitivity analysis
48% in patients receiving the levonorgestrel intrauterine device plus both the weight loss intervention and metformin.
“The difference in response rate [between endometrial cancer and endometrial hyperplasia with atypia] is what previous studies with much smaller case numbers reported, and it is not surprising. As cells move from healthy to cancer, they lose the capability to respond to levonorgestrel,” explained Dr. Obermair.
As the results indicate, the addition of metformin did not improve the efficacy of the levonorgestrel intrauterine device by itself. “When we started feMME in 2012, metformin was the flavor of the year. Everyone celebrated metformin in advance. We thought it was the anticancer agent, but it’s not. We are certainly less enthusiastic about its performance in feMMe now,” he commented.
The only predictor of treatment response was diagnosis. Compliance in all arms was good (only three women expelled the intrauterine device), and side effects were minimal. The target goal of at least 7% weight loss was achieved by 19% of patients receiving the levonorgestrel intrauterine device alone, by 25% of patients who also participated in a weight loss intervention, and by 16% who also took metformin, Dr. Obermair said. “Weight loss may accelerate response to progestin treatment.”
Clinical Applications
Dr. Obermair was asked how he would apply the study’s findings in the clinic, to which he responded: “The response rates to the levonorgestrel intrauterine device in endometrial hyperplasia with atypia were extraordinarily strong and similar to those recently reported by Westin et al: 91% pathologic complete response in endometrial hyperplasia with atypia and 66% in endometrial cancer.3 Because of this extremely high response rate, I think when we have obese, frail, and medically compromised women, with a high risk of conversion from a minimally invasive procedure to open surgery, and in young women who wish to preserve their uterus, we should consider a levonorgestrel intrauterine device as an alternative treatment option.”
Dr. Obermair considers the study’s strengths to be its prospective and randomized design and its enrollment of a large number of endometrial cancers (n = 96). However, he cautioned, it is a phase II study and thus does not provide definitive evidence of the effectiveness of the intervention(s). More research is needed on long-term outcomes, including recurrence, fertility, and hysterectomy rates, and the benefit of longer treatment. These outcomes will be assessed during a 3-year follow-up, he noted.
DISCLOSURE: Dr. Obermair reported relationships with SurgicalPerformance, Medtronic, Baxter Healthcare Australia & New Zealand, and AstraZeneca Australia.
REFERENCES
1. Janda M, Robledo K, Gebski V, et al: Complete pathological response following levonorgestrel intrauterine in clinical stage 1 endometrial adenocarcinoma: Results of a clinical trial (feMMe trial, ANZGOG1301). SGO 2021 Annual Meeting on Women’s Cancer. Abstract 72. Presented March 21, 2021.
2. Baker J, Obermair A, Gebski V, et al: Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: A meta-analysis and systematic review of the literature. Gynecol Oncol 125:263-270, 2012.
3. Westin SN, Fellman B, Sun CC, et al: Prospective phase II trial of levonorgestrel intrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am J Obstet Gynecol 224:191.e1-191.e15, 2021.
