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Hormonal therapy with an intrauterine device (IUD) led to complete tumor regression in two-thirds of women with early-stage endometrial cancer or precancerous lesions, a randomized pragmatic phase II study showed.

At 6 months, the pathologic complete response (pCR) rate was 61% for patients randomized to a levonorgestrel-containing IUD alone, 67% for those also encouraged to participate in a weight-loss intervention, and 57% for those who received metformin in addition to the IUD, reported Andreas Obermair, MD, of the University of Queensland in Brisbane, Australia.

The only factor that significantly predicted response was diagnosis, with the pCR rate reaching 82% across study arms for women with endometrial hyperplasia with atypia, a precancerous lesions, compared to 43% for those with stage I endometrioid adenocarcinoma (P<0.001), according to findings presented at the Society of Gynecologic Oncology (SGO) virtual meeting.

Obermair concluded that the treatment was safe and effective with high compliance, but that long-term follow-up is necessary.

"Standard treatment of endometrial cancer is total hysterectomy, bilateral salpingo-oophorectomy with or without surgical staging," explained Obermair. "However, for two groups of patients this is challenging -- for young women who wish to preserve fertility and also for elderly and frail women with multiple medical comorbidities who are at risk of prolonged hospital stay, higher risk for procedure-related adverse events, and high cost."

Medical societies, clinicians, and patient groups have called for non-surgical options for these patients, he said, and while levonorgestrel IUDs have been used in the past in this setting, "robust evidence" was lacking.

The open-label three-arm phase II trial randomized patients in a 3:3:5 ratio to the IUD (52 mg levonorgestrel) plus observation, the IUD plus a weight-loss intervention, or the IUD plus metformin (250 mg twice daily). The weight-loss intervention consisted of a 6-month subscription to Weight Watchers, with patients encouraged to lose 7% of total body weight within 6 months. At month 3, patients underwent endometrial assessment to check for disease progression.

Obermair explained that metformin, a common diabetes drug, has been shown to have anti-proliferative effects in endometrial cancer, while weight loss can reduce the risk of the disease and is associated with improved overall survival in patients diagnosed with endometrial cancer.

"One of the things that most interested me in this study is the remarkable weight loss that you saw across these various arms," said SGO discussant Angeles Alvarez Secord, MD, of Duke Cancer Center in Durham, North Carolina. "In my clinical experience and the research that we have conducted, it is very difficult for endometrial cancer patients to lose weight even when you do perform counseling, and most often these women continue to gain weight."

In the weight-loss arm, 25% of patients shed the target goal of at least 7% of their initial body weight by the 6-month timepoint, as compared to 19% in the observation arm and 16% in the metformin group.

"While the [pCR] results in the women with atypical endometrial hyperplasia were very reassuring, the findings in endometrial cancer were lower than what I expected," added Alvarez Secord.

She asked Obermair if he would treat a patient with atypical endometrial hyperplasia using such an approach in the clinic come Monday.

"When we have very obese, frail, and medically compromised women with a very high risk of a conversion from a minimally invasive to open [surgery], we should really consider levonorgestrel IUD as an alternative because the response rate is extremely high," he said.

Study Details

Patients were eligible if they had stage I endometrioid adenocarcinoma (International Federation of Gynecologists and Obstetricians grade 1, MRI showing depth of invasion below 50%) or endometrial hyperplasia with atypia, BMI greater than 30, and CA-125 levels lower than 30 U/mL. Those with grade 2/3 disease or high-risk cell types were excluded, as were patients who received progestins as recently as 12 weeks prior to study entry or had received pelvic radiotherapy.

Overall, 58% of the study patients had endometrioid cancer and 42% had endometrioid hyperplasia. The median age was 53, average BMI was 47.7, and 43% were premenopausal. A little more than a fourth of patients had a Charlson Comorbidity Index score of 0 and a little more than a fourth were already on metformin at study entry -- these patients were randomized between the weight loss and observation arms. The pCR rate among women on metformin randomized to the weight loss arm was 48%.

Stratification factors included diagnosis (endometrioid adenocarcinoma or endometrial hyperplasia with atypia), BMI, menopausal status, and tumor location. For pragmatic reasons, women with a contraindication to metformin were randomized into either the weight loss or observation arms and women ineligible for the weight-loss arm were randomized to either the observation or metformin arms.

In terms of compliance, three of 165 patients expelled the IUD; eight of 58 assigned to Weight Watchers never registered; and by the 6-month timepoint, 23 of 39 patients who attended the program at all were still participating. Nearly all patients (91.4%) started metformin in that arm, with 78.9% completing metformin at the 6-month assessment.

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