Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study

doi:10.1016/j.jogc.2017.06.037

Journal of Obstetrics and Gynaecology Canada

Volume 40, Issue 3, March 2018, Pages 328-333

https://doi.org/10.1016/j.jogc.2017.06.037 Get rights and content

Abstract

Objective

For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry.

Methods

This was a retrospective population-based cohort study of women under age 45 in British Columbia from 2003 to 2015 with CAH or grade I endometrioid EC who used progestins as initial management. Demographics, treatment type, response to treatment, determinants of definitive surgery (hysterectomy), pathologic findings, and obstetrical outcomes were reviewed.

Results

There were 50 women under age 45 with CAH (n = 29) and EC (n = 21). Median age at diagnosis was 36 years (range 25–41), and most were nulliparous (88%) with a median BMI of 32.9 (range 21–70). After 6 months of therapy, 58% of women had persistent disease, and only 35% had full resolution at last follow-up (median 23 months). There were 32 women who had a hysterectomy, including 27 because of persistent/recurrent disease, and 5 who chose surgery despite complete response to progestins. The majority of hysterectomy specimens (85%) had minimal or no residual pathology, even among those with disease on preoperative biopsy. Only 10% of women had successful pregnancies.

Conclusion

There is a moderate to high risk of persistence of CAH or EC on progestin therapy. However, for those undergoing hysterectomy, the vast majority has low-risk disease confined to the endometrium, implying the possibility of further conservative management of persistent disease.

Résumé

Objective

Les jeunes femmes aux prises avec une hyperplasie complexe avec atypies (HCA) de l'endomètre ou un cancer de l'endomètre (CE) désireuses de préserver leur fertilité se font actuellement prescrire un traitement reposant essentiellement sur des progestatifs. L'objectif de cette étude consistait à évaluer, à partir d'un registre des cas de cancer dans la population, les issues de ce traitement pour ces femmes en matière d'oncologie et de reproduction.

Methods

Une étude de cohorte rétrospective en population générale a été menée sur des femmes de la Colombie-Britannique âgées de moins de 45 ans aux prises avec une HCA ou un cancer endométrioïde de grade 1 et ayant amorcé un traitement de progestatifs entre 2003 et 2015. Ont été examinés le profil démographique, le type de traitement, la réaction au traitement, les facteurs ayant entraîné une chirurgie permanente (hystérectomie), les résultats pathologiques et les issues obstétricales.

Results

En tout, 50 femmes de moins de 45 ans atteintes d'une HCA (n = 29) ou d'un CE (n = 21) ont été recensées. L'âge médian au moment du diagnostic était de 36 ans (écart : 25–41 ans). La plupart étaient nullipares (88 %), et leur IMC médian se chiffrait à 32,9 (écart : 21–70). Après six mois de traitement, 58 % des femmes avaient une maladie persistante, et seulement 35 % étaient pleinement rétablies au moment de leur suivi (médiane : 23 mois). En tout, 32 femmes ont subi une hystérectomie, dont 27 en raison d'une maladie persistante ou récurrente; 5 femmes ont opté pour la chirurgie malgré une réaction complète au traitement. La majorité des échantillons provenant des hystérectomies (85 %) n'affichaient pas ou peu de traces résiduelles de pathologie, même parmi les cas où une maladie avait été détectée durant la biopsie préopératoire. Seulement 10 % des femmes ont mené une grossesse à terme.

Conclusion

Le risque de persistance de l'HCA et du CE dans le contexte d'un traitement aux progestatifs varie de modéré à élevé. Toutefois, la vaste majorité des femmes ayant subi une hystérectomie avaient initialement une maladie de faible risque, limitée à l'endomètre, laissant présumer qu'une prise en charge plus conservatrice des maladies persistantes serait envisageable.

Introduction

As obesity rates continue to rise in developed countries, the incidence of endometrial cancer also continues to increase, including among premenopausal women.¹ Up to 20% of cases are diagnosed among women under age 50.² Although standard treatment remains definitive surgery (hysterectomy with bilateral salpingo-oophorectomy, with or without lymph node dissection), this is often unacceptable to younger women who still desire fertility. This poses a unique challenge for clinicians, especially because the risk factors for development of endometrial cancer are also factors associated with infertility. In fact, more than 50% of premenopausal patients with endometrial cancer appear to be nulliparous.³ For those diagnosed with endometrial cancer before childbearing, progestin therapy is a non-surgical alternative that provides the opportunity to conceive.

Hormone therapy with progestin is thought to reverse the endometrial hyperplasia and carcinoma by stromal decidualization and subsequent thinning of endometrial lining.⁴ It is generally accepted that conservative therapy should be restricted to those with low-grade, early-stage cancer with no myometrial invasion. While there are guidelines on the management of young women with progestin therapy,⁵ there is still uncertainty regarding the optimal type and dose of progestin and follow-up schedule.

The objective of this study was to review clinical outcomes of women with complex atypical hyperplasia or grade I endometrioid endometrial cancer who had fertility-sparing progestin therapy from a population-based study. Patient characteristics, type, dose and duration of treatment, treatment failures, pathologic findings from hysterectomy, and reproductive outcomes were reviewed.

Section snippets

Materials and Methods

This study was approved by the Research Ethics Board of the University of British Columbia and BC Cancer Agency (REB #H11-02698). Women under the age of 45 with a diagnosis of CAH or grade I endometrioid EC were first identified through the BC Cancer Agency Information System database from 2003 to 2015, and those who did not have definitive surgery as primary treatment were then reviewed in detail. Diagnosis of CAH or EC was based on office endometrial biopsy or dilatation and curettage, and

Results

Of the 245 women under age 45, there were 50 patients who met the inclusion criteria. Median age at diagnosis was 36 (range 25–41). There were 29 women with a diagnosis of CAH and 21 with grade I endometrioid EC. The majority (88%, n = 44) were nulliparous, with high BMI (median 32.9, range 21–70). Only 6% had a history of type 2 diabetes. All 50 cases underwent germline Lynch testing and none had Lynch syndrome. Two had a previous malignancy (one with thyroid cancer and one with endometrioid

Discussion

In this population-based study, complete response rates to progestin therapy among young women with complex atypical hyperplasia and endometrial cancer were around 35%. This seems lower than other reports in the literature of around 50%.⁶ This could be attributed to the observational nature of this population-based study. Unlike a single institution study, these patients received treatment from various health care providers across the province. The variability in treatment reflects the

Conclusion

There was a low complete response rate to progestin therapy among women with complex endometrial hyperplasia or endometrial cancer in this population-based study. However, among those undergoing hysterectomy, the majority had disease confined to the endometrium, which raises the possibility of additional conservative treatment. It appears that progestin therapy with some additional intervention, whether surgical or medical modality, should be pursued further in order to improve the outcomes of

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Cited by (19)

Fertility outcomes with assisted reproductive technology after fertility-sparing treatment for endometrial neoplasia: a systematic review
2023, F and S Reviews
To review the literature on the fertility outcomes for individuals using assisted reproductive technologies (ARTs) after fertility-sparing treatment (FST) for endometrial neoplasia. Answering this question has the potential to influence clinical practice, improve patient counseling, and guide further research.
Inclusion criteria were as follows: prospective and retrospective studies evaluating patients with complex atypical hyperplasia, endometrial intraepithelial neoplasia (EIN), or endometrial adenocarcinoma (EAC) who underwent FST, have a group or subgroup of patients who used ART, and discuss pregnancy-related outcomes for the ART cycles or proportion of patients using ART methods. Articles not in English were excluded. Four independent reviewers reviewed articles for inclusion. Twenty-five articles met the inclusion criteria, including 19 retrospective studies, 5 prospective studies, and 1 randomized control trial.
Assisted reproductive technology utilization among this population is high; although live birth rate per transfer is lower than expected, cumulative pregnancy rates approach what may be expected in other groups. Factors associated with success with in vitro fertilization (IVF) may include endometrial thickness >8 mm and shorter time to treatment after complete remission. Additionally, IVF does not increase mortality from EIN/EAC.
Overall, this review demonstrated that ART can be an effective treatment option for individuals desiring fertility after FST for EIN/EAC; however, additional research is needed into pregnancy outcomes with ART methods after FST and the timing of treatment initiation. Providers should be diligent in referring individuals who desire pregnancy after FST to reproductive endocrinology and infertility services to increase the chances of pregnancy before disease recurrence.
Imaging of Endometrial Cancer
2023, Radiologic Clinics of North America
The role of prolonged progestin treatment and factors predicting successful fertility-sparing treatment for early endometrial endometrioid adenocarcinoma
2021, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
However, a Korean study recently reported 122 patients treated with oral progestin and found a 12-month CR rate of 59% but reached 83.6% at 24-month [17]. Furthermore, in a study investigating pathologic findings of hysterectomy specimens in non-responders after 6 months of treatment, 85% had minimal or no residual pathology [18]. All these results suggest a role for prolonged medical management in some of these initial non-responders, although recent clinical guidelines still suggest discontinuation of fertility-sparing treatment in cases of persistent disease after 6–12 months of attempt [19,20].
Fertility-sparing progestin therapy is highly effective in selected young women with endometrial cancer. In present study, we attempted to evaluate the role of prolonged medication and identify factors predicting successful treatment, and also assess fertility outcomes among young women with early stage endometrial endometrioid carcinoma (EC).
We retrospectively reviewed clinical data from patients aged <45 years with well-differentiated EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility. They were managed with oral progestin at Kaohsiung Chang Gung Memorial Hospital between June 2005 and June 2019.
Forty-five patients were included with a median follow-up of 53.5 months (range 12–170 months). Forty-one patients (91.1%) had complete remission, the cumulative complete response (CR) rates at 3, 6, 9, 12, and >12 months were 17.7%, 48.9%, 60.0%, 68.9% and 91.1%, respectively. Among the 41 responders, 23 attempted to conceive and nine (39.1%) achieved pregnancy with 12 live newborn infants. Eleven (27.5%) responders experienced recurrence at a median of 22 months from CR (range 3–54 months). Multivariate Cox regression analysis revealed that non-diabetes (HR: 4.59; 95% CI: 1.62–12.98) and endometrial thickness <2 cm (HR: 0.39; 95% CI: 1.41–17.67) were significantly factors associated with treatment response.
We concluded that prolonged oral progestin treatment was possible with a certain proportion of responders (24.4%) being responded after one year. Diabetes controlled on metformin and endometrial thickness <2 cm could be used as surrogate markers to predict better treatment response.
Prominent decidualization following progestin treatment for endometrial hyperplasia and carcinoma as a mimic of large residual tumor: A cautionary tale
2021, Gynecologic Oncology Reports
Progestin-based therapy is common for patients with endometrial neoplasia who desire fertility preservation, but some patients ultimately require surgery. Intraoperative assessment, which can use gross lesion size, may impact the extent of surgery performed. We sought to characterize the extent to which grossly identified lesions in the setting of progestin therapy correspond to microscopic findings.
Thirteen hysterectomy specimens with progestin-treated atypical hyperplasia or endometrioid carcinoma were identified. Clinicopathologic factors were collected by chart review. Slides were assessed for the extent to which decidualized stroma (DS) comprised grossly identified lesions and comparisons were drawn with tumor size, age, and menopausal status.
Mass lesions were described in 11 cases with a median of 4.5 cm (range 1–8.2) and the 2 cases without discrete masses had diffuse thickening. Two patients had only focal residual hyperplasia despite having mass lesions (7 & 2.2 cm). DS was more prominent in premenopausal patients (median 65%, range 10–90%) than in postmenopausal patients (median 18%, range 10–40%; p = 0.06). The distribution of DS throughout mass lesions was variable.
Large mass lesions following progestin therapy may histologically consist of DS with little to no residual neoplastic disease, such that perceived tumor size does not necessarily reflect extensive residual disease, especially in pre-menopausal patients. Intraoperative gross assessment alone may lead to unnecessary lymphadenectomy and/or oophorectomy, but this can potentially be prevented by using frozen section.
ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma
2021, Radiotherapy and Oncology
Citation Excerpt :
So far, there are no available randomized controlled trials comparing different methods of conservative treatment in women with AH/EIN or presumed stage IA grade 1 endometrioid carcinoma. Existing data suggest that patients who received hysteroscopic resection followed by progestin therapy achieve the highest complete remission rate as compared with other existing fertility-preserving treatments [262–268,277–294]. Intrauterine progestin therapy such as levonorgestrel-releasing intrauterine system combined with gonadotropin-release hormone receptor agonist/progestin have a satisfactory pregnancy rate and low recurrence rate.
A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.
ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives.
The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
Radiation and hormonal therapy for primary treatment of stage I endometrial cancer and long-term survival
2020, Gynecologic Oncology
Citation Excerpt :
Patients ≤45 years old were excluded to reduce the possibility of patients seeking fertility sparing treatment in the study population. This conservative age limitation was based upon previous studies evaluating progestin therapy for stage I EEC in fertility sparing populations have been limited to patients ≤45 years old [15–18]. The study population was categorized into two cohorts by the exposure of interest: (1) patients who underwent surgical management with a hysterectomy within 90 days of diagnosis and (2) those who primarily underwent NSM with either hormonal therapy, radiation therapy, or both within 90 days of diagnosis.
Estimate the association between non-surgical management (NSM) (e.g. hormonal or radiation therapy) and overall survival among women with stage I endometrioid endometrial cancer (EEC) and identify patient and facility characteristics associated with receipt of NSM.
Women >45 years of age with clinical stage I EEC were identified in the National Cancer Database from 2004 to 2016. Women treated with NSM were compared with women treated initially with hysterectomy. Patient and facility characteristics associated with NSM were evaluated using logistic regression models. Association with overall survival was examined using log-rank tests, Kaplan-Meier curves, and Cox proportional hazards regression models with and without propensity score matching (PSM).
A total of 112,469 women underwent treatment for stage I EEC between 2004 and 2016. 2776 (3%) received NSM, of whom 1987 (71%) received radiation therapy, 688 (25%) received hormonal therapy, and 101 (4%) received both. Older age, black race, higher Charlson-Deyo scores, Medicaid insurance, and low annual facility hysterectomy volume were associated with receiving NSM. The 5-year survival rate was 40% (95%CI: 37%–42%) for women with NSM compared to 89% (95%CI: 88%–89%) for hysterectomy. Women treated with NSM died at a faster rate than those who underwent primary hysterectomy (HR 7.6, 95%CI: 7.2–8.0; p < 0.001). This statistically significant difference in survival persisted in adjusted Cox proportional hazards models and after PSM.
Women treated with NSM had a significantly higher risk of death compared to those undergoing hysterectomy for stage I EEC. Caution should be used when selecting patients for NSM given its worse outcomes.

View all citing articles on Scopus

: Competing interests: None declared.

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FertilityFertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study

Abstract

Objective

Methods

Results

Conclusion

Résumé

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Materials and Methods

Results

Discussion

Conclusion

Eur J Cancer

Gynecol Oncol

Contemp Clin Trials

Am J Obstet Gynecol

Canadian cancer statistics 2014

SEER Cancer statistics review, 1975–2013

Progestational agents in the treatment of carcinoma of the endometrium

N Engl J Med

Fertility
Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study