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IntroductionApproximately 5% of women with endometrial cancer are under the age of 40. The majority of them have well-differentiated endometrioid estrogen-dependent tumors. Given that gynecologic malignancies often affect young women who are still in their reproductive years, the incidence of cancer in those who still want to get pregnant has somewhat increased. Fertility preservation is of paramount importance for women that have not completed their family planning and in endometrial cancer cases high dose oral progestins as well as the recently added levonorgestrel-intrauterine device (LNG-IUD) have been proposed as potential treatment alternatives. Despite that, conservative treatment with oral progestins has some disadvantages, namely increased risk of thromboembolism, hyperglycemia, weight gain and edema. A combined approach of a reduced dose of megestrol acetate (80 mg/day) together with an LNG-IUD has not been evaluated and might be equally efficacious, in terms of disease regression as it could limit the potential side-effects of the high-dose systemic treatment.The purpose of the present study is to evaluate whether the combination of a low dose megestrol acetate (80mg/day) combined with the LNG-IUD (Mirena) may serve as an alternative treatment for pre-menopausal women that wish to preserve their fertility potential.MethodsA retrospective study included all patients of reproductive age who were treated conservatively from January 2008 to August 2018 at a tertiary referral center with the combination of per os MA (80mg/day) and the LNG-IUD (Mirena) for CAH and grade I endometrioid EC. The primary study endpoint was response to treatment after 6 months following the insertion of the LNG-IUD and the first dose of megestrol acetate, a time point which was chosen based on the existing recommendations of the European Society of Gynecological Oncology Task Force for Fertility Preservation.For both CAH and EC, complete response was defined as the absence of any type of disease on the pathology report (carcinoma or hyperplasia, atypical or not). For CAH, partial response was defined as the presence of hyperplasia without atypia, whilst for EC partial response was recorded if the disease was downgraded to either atypical hyperplasia or milder forms of hyperplasia. For both endometrial cancer and CAH, stable disease was defined as absence of disease regression at 6 months. Finally, for CAH, disease progression was defined as the presence of any grade of EC. For patients with EC, progression was defined as the presence of a higher grade on the pathology report.ResultsTwenty-two patients were diagnosed with complex atypical hyperplasia (CAH) or grade I endometrioid endometrial cancer (EC). Eighteen of them were evaluated at the 6-month study point. Their mean age was 34.9 years (range 18-41) whereas their mean BMI was 26.8 (range 18-35). Three patients had already had children before the diagnosis; the remaining 15 were nulliparous. Two patients had a medical history of Diabetes Mellitus Type 2 treated with Metformin during the period of the study, and four patients were obese (BMI>30kg/m2).Five patients (27.8%) had an initial diagnosis of CAH and the other 13 (72.2%) were diagnosed with grade I endometrioid EC. Overall, the response rate was 77.7% at the 6-month evaluation exam (80% for the CAH group and 76.9% for the grade I endometrioid EC).Of the 13 patients (72%) who achieved complete response, 8(62%) patients attempted pregnancy and three (23%) of them had a live birth (two had a baseline biopsy demonstrating CAH and one was initially diagnosed with endometrioid endometrial cancer grade I). Four women (22.2%) were diagnosed with stable or progressive disease after 6 months of treatment and were subjected to hysterectomy. One woman among those who had achieved complete response to treatment at the 6-month time point, decided to proceed to hysterectomy immediately because she already had one child before treatment and was finally not interested in conceiving. During the treatment period, no remarkable adverse effects were observed in the patients.ConclusionTo date, to our knowledge no studies have investigated the efficacy of a combined approach using the LNG-IUD with a low dose of progestin therapy. The approach that we report in our study permits the reduction of the levels of systemic therapy; thus, potentially reducing the adverse effects of systemic high-dose progestin therapy, and takes into advantage the high levels of progestins that are achieved with the application of the LNG-IUD. Using this mode of treatment, we observed comparable results to those of high dose systemic therapy in terms of CAH and grade 1 EC regression. Nevertheless, the relatively small number of recruited patients and the absence of a control group renders the findings of our study rather preliminary; hence, firm results are precluded. Future randomized trials which will allow the direct comparison of high dose oral systemic therapy with the combined low-dose approach, should be conducted in order to reach firm conclusions regarding the efficacy of the latter in terms of disease regression and restriction of side-effects.
