Abstract

The hormonal treatment with progestins, in low-grade G1 endometrioid endometrial cancers, has been approved as an alternative fertility-sparing treatment in young patients, under 40 years old, with fertility wishes and the possibility of close follow-up.  However, it’s use in postmenopausal patients continues being debated.

Objective: To analyze the short and medium-term results of conservative hormonal treatment applied to postmenopausal patients with low grade G1 endometroid endometrial cancer.

Keywords: Endometrial Cancer; Conservative Treatment; Hormonal Treatment; LNG-IUS

Introduction

Endometrial cancer represents the most commonly diagnosed gynecological malignancies in developed countries, accounting for approximately 63,000 newly diagnosed cases in 2018 in the United States. The incidence in 2018 was about 382,000 new cases worldwide. The mortality rate was above 89,000 in 2018 [1].

Staging of endometrial cancer was changed from clinical to surgical in 1988, by the FIGO Gynecologic Oncology Committee [2]. Surgery is the primary treatment for endometrial cancer and it is possible to obtain operability ranging from 92 to 96% of patients in addition to primarily treating the disease with curative intention and the histopathological information necessary to determine the risk factors in order to select patients for adjuvant treatment [3]. Hysterectomy with or without bilateral salpingo-oophorectomy enables tumor removal and classification on the basis of histology, grade and myometrial invasion depth. The role of retroperitoneal staging is still controversial; however, intraperitoneal and retroperitoneal evaluation should be considered equally important aspects in surgical staging. If the tumor grade, histological type and imaging techniques (magnetic resonance or PET-scan) are available preoperatively or intraoperatively, lymphadenectomy may be avoided to a greater or lesser extent, in cases of low risk of recurrence [4].

The conservative hormonal treatment with progestins, in low-grade G1 endometrioid endometrial cancers, has been approved as an alternative fertility-sparing treatment in young patients under 40 years old, with fertility wishes and the possibility of close follow-up [5-7]. The aim of the present article is to analyze the short and medium-term results of conservative hormonal treatment applied to postmenopausal patients with low grade G1 endometroid endometrial cancer [7].

Material and Method

Inclusion Criteria

• Patients with Endometrioid Adenocarcinoma of Endometrium G1 – Low Risk Ones
• Clinical Contraindications for Surgery
• Refusing the Radiotherapy Treatment by the patient

Exclusion Criteria

• Medium and High Risk Endometrioid Adenocarcinoma of Endometrium
• Other Endometrial Histotype of Endometrial Cancer
• Second Neoplasms

It was evaluated:

• End point 1: evaluation of the Disease Free Interval (DFS)
• End point 2: evaluation of the Overall Survival (OS)

This is a prospective trial which began in January, 2015. There were included 7 postmenopausal patients: 4 with endometroid GH1 adenocarcinoma (Fig. 1) and 3 with complex atypical hyperplasia (Fig. 2).

The patients characteristics were Body Mass Index> 40, DBT type II, hyperlipidemia, smokers and high cardiovascular risk. All the patients were initially biopsied by hysteroscopy and endocervical disease was ruled out. Furthermore, the abdominal-pelvic MRI was performed for the diagnosis of myometrial invasion and lymph nodes involvement to decide the conservative treatment.

All patients had contraindication for surgery. So, Hormonal treatment was indicated as an alternative to Radiotherapy (RT). The four patients declined to RT. The Hormonal treatment was placing Levonorgestrel -Releasing Intrauterine Device (LNG-IUS) (Fig. 3). The Follow-up was performed as follows: at least 4 months – maximum 6 months by pelvis examination, hysteroscopy with endometrial biopsy and abdominopelvic MRI. Survival rates, pathological findings and follow up were analyzed.

Results and Discussion

The median age of the patient was 68 years old. In all the cases, the biopsies performed showed a progressive pathological regression of the initial lesions, leading to an atrophic endometrium in the last controls (Fig. 4).  There were no adverse effects related to treatment. Up to now – 10 years of follow-up, all the patients are alive and free of disease (disease free interval and overall survival rates of 100%).

Figure 1: Endometrioid G1 adenocarcinoma.

Figure 2: Complex atypical hyperplasia.

Figure 3: Levonorgestrel intrauterine device.

Figure 4: Atrophic endometrium.

Discussion

Since Creasman, et al., described the correlation between the extrauterine spread and the uterine pathological risk factors in endometrial cancer, the surgical exploration of the lymph nodes status has been mandatory [8,9]. Surgical staging, including lymphadenectomy, is part of the standard treatment for this disease [4,7,10].

The majority of endometrial cancers are diagnosed early stage (80% in stage I) and usually described in postmenopausal women, however, it is diagnosed in a 4-5% of patients under fourty years old. and with fertility wishes [5-7]. So, there were described conservative treatments for those cases, but it is controversial in postmenopausal women [7].  Most patients with endometrial cancer have an excess of estrogen and typically show a characteristic clinical profile: high Body Mass Index (BMI) that is considered as overweight (BMI 25-30) or obese (BMI 30), often with other components of metabolic syndrome (hypertension, diabetes) [7,10,11]. This is the most commonly identified risk factor because obesity is associated with peripheral estrogen conversion via aromatization in adipose tissue [7,10,12,13].

Conservative management of Endometrial Cancer is based principally on medical treatment with oral progestins. Hormonal therapy, alone or in a combination with hysteroscopic ablation. Progestins used are medroxyprogesterone acetate or megestrol acetate [5,14,15]. Anastrozole 1 mg is also described as an hormonal option alone or after medroxyprogesterone with or without placing a levonorgestrel-releasing IUD in premenopausal women [16,17].

Anchezar et al., published the Buenos Aires experience in conservative treatment for 25-40 years old patients (pts) with low risk endometrioid endometrial cancer G1, using high dose 200-500 mg. of medroxyprogesterone, three month minimum. This paper described 6/7 pts had a complete pathological response; 3/7 became pregnant (in one patient twice), obtaining four new healthy newborns. All these women were free of disease after 7-12 years follow-up without completing surgical staging treatment at the time or after the delivery.

Another method of treatment is Levonorgestrel-releasing IUD for 12 months minimum [9,18,19]. It produces a local pathological regression of the tumor in the medium and long term using, with or without GnRH analogues or in combination with oral progesterone [20]. The IUD is removed when patients are ready to attempt pregnancy [9,18,19].

In postmenopausal women, conservative hormonal treatment it is not the first choice of treatment, yet. Radiotherapy is the election therapy when surgery is contraindicated related to adverse clinical conditions [7,10]. But which should be the therapy of choice for patients when standard surgery is contraindicated and refused radiotherapy?

In our initial experience, we believe we are opening a new therapeutic door for those cases. In the four patients treated, a complete pathological regression to atrophic endometrium was observed. There were no adverse effects related to treatment. Up to now, all the patients are alive and free of disease (disease free interval and overall survival rates of 100%). In this pandemic context, the International Gynecologic Cancer Society recommendations, supports our protocol of treatment [21].

In conclusion, these excellent results obtained with the use of hormonal therapy with LNG-IUD in those postmenopausal patients with high surgical risk and who in turn refuse to receive radiotherapy,showed to be safe and feasible. This treatment could be taken into account as a conservative alternative therapeutic option for the for low-grade endometroid adenocarcinoma in postmenopausal women, as well as, for those patients who are affected by this COVID-19 pandemic, that in all the cases, a complete regression of the initial lession was observed [21].

The advances in molecular staging of endometrial cancer, will help us to select the correct patient for this conservative therapeutic approach. The question is, if it must be add antiaestrogens as anastrazolas part of the treatment for confirmed molecular and imaging low risk endometrial cancer with the presence of hormonal receptors. On the other hand, the study of BCRA1 and 2 and PDL-1 receptors, could be necessary in order to a possible mainteinance therapeutic plan with PARP inhibitors and immunotherapy [22]. Despite these results obtained, it would be necessary to increase the number of cases and studies in this regard to routinely validate it. We are asking ourselves if all those modified strategies of treatment have arrived for a permanently staying? We believe a new door was opened to this respect. The research and time will give us the answer.

Conclusion

Excellent results were obtained with the use of hormonal therapy in those postmenopausal patients with high surgical risk and who in turn refuse to receive radiotherapy. This treatment could be taken into account as a conservative alternative treatment option for the for low-grade endometroid adenocarcinoma in postmenopausal patients, as well as, for those patients who are affected by this COVID-19 pandemic, that in all the cases, a complete regression of the initial lession was observed. Despite these results obtained, it would be necessary to increase the number of cases and studies in this regard to routinely validate it.

Conflict of Interest

No conflict of interest from any source.

Ethical Approval and Consent to Participate

Ethical approval was obtained by the Health Ethical Committee of the University of Calabar Teaching Hospital and consent to participate was issued and participants counseled on the importance of the research.

Consent for Publication

Consent was given for publication.

Funding

There are no sources of funding to declare.

Author’s Contribution

Conceptualization, methodology and validation, Soderini,Alejandro – Aragona, Alejandro.

Formal analysis, investigation, resources and data curation,Crespe, Martin.

Writing-original draft preparation, Moschen, Horacio.

Writing-review and editing,Crespe, Martin – Mendez, Martin.

Visualization and supervision,Serini, Juan Manuel.

Project administration, Soderini, Alejandro.

All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Data supporting these findings are available within the article or upon request.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to the delay and impact of the COVID-19 pandemic.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.

Sample Availability

The authors declare that no physical samples were used in this study.

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