Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer

• Published in: American journal of obstetrics and gynecology 2021-02, Vol.224 (2), p.191.e1-191.e15
• Main Authors: Westin, Shannon N., Fellman, Bryan, Sun, Charlotte C., Broaddus, Russell R., Woodall, Misty L., Pal, Navdeep, Urbauer, Diana L., Ramondetta, Lois M., Schmeler, Kathleen M., Soliman, Pamela T., Fleming, Nicole D., Burzawa, Jennifer K., Nick, Alpa M., Milbourne, Andrea M., Yuan, Ying, Lu, Karen H., Bodurka, Diane C., Coleman, Robert L., Yates, Melinda S.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase 1 Family - genetics; Aldehyde Dehydrogenase 1 Family - metabolism; Biomarkers - metabolism; Biomarkers, Tumor - metabolism; Body Mass Index; Carcinoma, Endometrioid - drug therapy; Carcinoma, Endometrioid - metabolism; Carcinoma, Endometrioid - pathology; complex atypical hyperplasia; conservative; Contraceptive Agents, Hormonal - administration & dosage; endometrial cancer; Endometrial Hyperplasia - drug therapy; Endometrial Hyperplasia - metabolism; Endometrial Hyperplasia - pathology; endometrial hyperplasia intrauterine device; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Female; Gene Expression; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intrauterine Devices, Medicated; Ki-67 Antigen - genetics; Ki-67 Antigen - metabolism; Levonorgestrel - administration & dosage; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Neoplasm Grading; Neoplasm Staging; predictive biomarkers; progesterone; Quality of Life; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Retinal Dehydrogenase - genetics; Retinal Dehydrogenase - metabolism; Treatment Outcome; Wnt Signaling Pathway - genetics; Young Adult
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2020.08.032

The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility. This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma. A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months. A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7–90.3)—37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related prote