Fertility-sparing treatments for patients with endometrial cancer: A comprehensive review
Article information
Abstract
Endometrial cancer (EC) in young women is relatively likely to be early-stage, low-grade, and without risk factors. Fertility-sparing treatment with progestin is a potential primary approach for certain patients. However, several factors should be considered according to available guidelines. The potential indication for fertility-sparing treatment in patients with EC, as recommended by various societies of gynecologic oncology, includes young women with grade 1 endometrioid adenocarcinoma confined to the endometrium. Magnetic resonance imaging should be performed to rule out myometrial invasion and extrauterine disease before initiating fertility-sparing treatment. Other imaging modalities may also be used to exclude extrauterine disease. Various fertility-sparing therapies exist, the most common of which is high-dose oral progestin. After initiating fertility-sparing treatment, pathological re-evaluation of the endometrium at 3 to 6 months is recommended. The optimal duration of fertility-sparing treatment is up to 15 months, but guidelines recommend continuing progestin therapy until attempting conception. Ovarian stimulation drugs used for pregnancy are considered safe after a complete response is achieved. Hysterectomy is recommended after childbearing, while oophorectomy is not mandatory for young women. Close surveillance should continue for women who do not wish to undergo surgery after childbirth. Based on existing evidence, fertility-preserving treatments have demonstrated effectiveness and do not appear to negatively impact prognosis. If a qualified patient expresses a strong desire for fertility preservation despite the potential for recurrence, the physician should consider fertility-sparing treatment while maintaining vigilant monitoring.
Introduction
Endometrial cancer (EC) is the sixth most common malignancy among women worldwide [1,2]. Approximately 80% of EC cases are estrogen-related. Unopposed estrogen exposure is associated with factors such as nulliparity, hormone therapy during menopause, early menarche, late menopause, and obesity, which represent key risk factors for EC [3]. Obesity is an especially critical factor in the development of EC due to its increasing prevalence globally, with a considerable proportion of EC cases attributed to obesity [4]. As obesity rates have climbed, EC has also become more common [5]. The incidence of EC in women aged ≥50 years has reportedly been increasing by approximately 1% per year since the mid-2000s. Moreover, the incidence rate in younger women has risen by around 2% per year since the mid-1990s [6,7]. Younger patients with EC often have a favorable prognosis due to early-stage disease, low-grade tumors, and the absence of additional risk factors. Many of these patients, particularly those who are nulliparous, prefer fertility-sparing treatments [8,9]. The initial management of EC typically involves surgical staging, which includes the removal of the uterus, bilateral salpingo-oophorectomy, and lymph node assessment from the external iliac, internal iliac, obturator, and common iliac nodes, with or without para-aortic nodal dissection [10]. However, this approach results in the loss of fertility, which is a particular concern for young patients who desire to have children in the future.
Fertility-sparing treatment is an option for women with EC who have the potential to reproduce, provided they meet certain clinical criteria. The foundational approach to fertility-sparing treatment involves continuous progestin therapy [11], with numerous studies exploring a range of medical treatment methods [2,12-17]. Nevertheless, practitioners should be mindful of several considerations regarding fertility-sparing treatment as outlined in the guidelines [11]. This article aims to review and summarize the current literature and data on issues related to fertility-sparing treatment.
Criteria for fertility-sparing treatment based on prognosis in patients with EC
Target patient selection is a crucial first step in fertility-sparing treatment. Before such treatment is initiated, patients should be evaluated regarding disease status and potential for pregnancy. Regarding disease status, various gynecological oncology societies have established guidelines for selecting suitable candidates for fertility-sparing treatment. The American Society of Clinical Oncology, National Comprehensive Cancer Network, Japan Society of Gynecologic Oncology, European Society of Gynaecological Oncology (ESGO), British Gynecological Cancer Society, and Society of Gynecologic Oncology concur that fertility-sparing treatment should be reserved for patients with grade 1 endometrioid adenocarcinoma that is confined to the endometrium [18-22]. The Korean Society of Gynecologic Oncology (KSGO) shares this view, noting that fertility-sparing treatment may be considered in cases of well-differentiated endometrioid adenocarcinoma without myometrial invasion, particularly when strongly desired by the patient [23].
The ESGO, along with the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy, have recommended fertility-sparing treatment as an option for selected women, contingent upon a thorough evaluation of their reproductive potential. To date, no specific research is available regarding the reproductive potential of women with EC. Nevertheless, standard fertility markers, such as anti-Müllerian hormone, antral follicle count, day 2–5 follicle-stimulating hormone levels, age, and body mass index, can be used to assess ovarian function and the capacity for oocyte production [11]. A meta-analysis examining pregnancy outcomes in women with early-stage EC who underwent conservative therapy found that the live birth rate was associated with the woman’s age [24]. Another study demonstrated that weight loss in women with obesity could positively impact both pregnancy and live birth rates [25]. Polycystic ovarian syndrome frequently affects patients with EC, especially women with obesity under 35 years old. These patients exhibit a higher failure rate for medroxyprogesterone acetate (MPA) treatment [26] and are often impacted by metabolic syndrome, highlighting the importance of incorporating lifestyle changes in conjunction with medical treatment. Lynch syndrome is another condition associated with EC. Evidence regarding the safety of fertility preservation in this population remains scarce [27].
Recently, the International Federation of Gynecology and Obstetrics (FIGO) released the updated 2023 staging for EC, which now incorporates diverse histological types, tumor patterns, and molecular classifications to more accurately represent the underlying biological behavior of EC. However, the indications for fertility-sparing treatment in relation to the updated stages have not been addressed, suggesting a need for further research [28]. Until criteria for fertility-sparing treatment indications are established in accordance with the updated staging system, clinicians should continue to follow the criteria outlined in the existing guidelines.
Considering the guidelines provided by these societies, suitable candidates for conservative treatment include reproductive-aged patients with well-differentiated grade 1 endometrioid adenocarcinoma confined to the endometrium. These individuals should express a strong desire for fertility preservation and undergo an assessment of their reproductive potential by a fertility specialist [11].
Initial assessment of disease extent before treatment
Before starting fertility-sparing treatment, patients must meet all the criteria to be considered for fertility-sparing options in the management of EC. These criteria include the presence of grade 1 endometrioid adenocarcinoma, confirmed by expert pathology review following dilatation and curettage (D&C). Additionally, the disease should be confined to the endometrium, as indicated by magnetic resonance imaging (MRI, preferred) or transvaginal ultrasound (US). No suspicious or metastatic disease should be evident on imaging, the patient should have no contraindications to medical therapy or pregnancy, and counseling should emphasize that fertility-sparing options are not considered standard care [29]. The absence of myometrial invasion and extrauterine disease must be confirmed before the commencement of fertility-sparing treatment [11]. Transvaginal US and pelvic MRI can be used to evaluate the involvement of the myometrium and cervical stroma in early-stage disease. According to a meta-analysis and systematic review, transvaginal US exhibits a sensitivity of 75% and a specificity of 82% in evaluating deep myometrial invasion. The sensitivity and specificity of pelvic MRI in detecting myometrial invasion are 83% and 82%, respectively, without significant differences [30]. One advantage of MRI over transvaginal US is its capacity to assess extrauterine disease. Furthermore, standardized high-quality MRI protocols can achieve the highest possible accuracy [11,31]. In early-stage, low-grade EC, the likelihood of extrauterine disease is very low. However, radiologic staging should be performed before making decisions regarding fertility-sparing treatment, as surgical staging is not an option. Abdominal computed tomography (CT) can be employed to assess for abdominal organ metastasis, and chest CT can be used to exclude pulmonary metastasis. Lymph node metastasis can be evaluated using CT, MRI, and positron emission tomography-CT [32-35].
The frequency of synchronous or metachronous endometrioid ovarian cancer in patients with early-stage EC has been reported to range from 5% to 29%. A cross-sectional study examining disease profiles by age found that patients with EC who are 45 years old or younger are about five times more likely to have synchronous ovarian tumors than women older than 45 years [36]. A large multicenter retrospective study conducted by KSGO revealed that the incidence of synchronous ovarian cancer in patients aged 40 years or younger was 4.5%, and no synchronous cancers were detected in individuals with low-risk EC [37]. Consequently, KSGO has stated that diagnostic laparoscopy to evaluate ovarian cancer is not necessary in patients with low-risk early-stage EC prior to fertility-sparing treatment [37].
The new FIGO 2023 staging system has incorporated the presence of the POLE and P53 mutations into its molecular classification [28]. However, no established research has yet examined the association between these molecular statuses and the feasibility of fertility preservation. Consequently, separate molecular analyses are not required solely to confirm the potential for fertility preservation. Nevertheless, given the substantial impact of this information on patient prognosis, conducting testing is essential, and the results should be thoroughly discussed with the patient.
Oncologic and fertility outcomes following fertility-sparing treatment
The standard fertility-preserving treatment for patients with EC is continuous progestin-based therapy (Table 1). While various medical treatments exist for early-stage EC, no randomized controlled trials have directly compared them. A meta-analysis evaluated the safety and efficacy of these medical treatments [38]. MPA and megestrol acetate (MA) are the most frequently used progestins, while another method of progestin delivery is through the levonorgestrel-releasing intrauterine system (LNG-IUS). The dosage of progestin reported in the literature varies.
A systematic review of 38 studies was conducted to compare various fertility-preserving therapies [39]. The overall complete response (CR) rate was 79.4% following treatments such as hysteroscopic surgery, progesterone therapy, and the use of LNG-IUS [39]. However, no clear consensus has been drawn regarding the type, dosage, or duration of treatment necessary to achieve an effective response. Another systematic review recommends a high-dose progestin protocol [38]. The suggested dose of MA is between 160 and 320 mg/day. For MPA, the recommended dosage ranges from 400 to 600 mg per day [18]. The efficacy of the intrauterine release of progestin, specifically LNG at a dose of 52 mg, has also been assessed. A retrospective study investigated the outcomes of progestin therapy in young women diagnosed with stage IA, grade I endometrioid adenocarcinoma. The study found that 77.7% of patients achieved CR with MPA, and MPA was associated with a lower risk of recurrence compared to MA [13]. Additionally, a multicenter phase II study involving 600 mg of MPA and low-dose aspirin reported a 55% CR rate in women with EC undergoing fertility-sparing treatment [40].
LNG-IUS is another option that may increase local effectiveness while minimizing systemic adverse effects. It can be used as monotherapy or in conjunction with oral medication. In a prospective trial involving the daily administration of 500 mg of oral MPA alongside LNG-IUS, the results included a CR rate of 87.5% and an average time to CR of 9.8±8.9 months [2]. The Korean Gynecologic Oncology Group conducted a multicenter prospective study to evaluate the effectiveness of combined oral MPA and LNG-IUS therapy. At 6 months, the CR rate was only 37.1%. As the average follow-up period was 11.8 months, further long-term data are required [2].
Another fertility-sparing treatment option includes combined treatment with hysteroscopic resection followed by either oral or intrauterine-released progestins, or gonadotropin-releasing hormone analogs. This approach may be an effective fertility-sparing treatment for reproductive-aged patients. Combined treatment can limit disease progression and allow for optimal cytoreduction [41,42].
Various medical treatments are available, such as hydroxyprogesterone caproate, natural progesterone, aromatase inhibitors (letrozole, anastrozole), norethisterone acetate, and combined oral contraceptives. Although some research is available, no comparative study has yet been conducted [43,44].
Fertility outcomes following fertility-sparing treatment have varied considerably across studies. The first published series on conservative surgery, followed by 6 months of 160 mg/day MA, reported a pregnancy rate of 65% [45]. Research on hysteroscopic conservative surgery accompanied by either MA or LNG-IUS indicated a 45% pregnancy rate without the use of assisted reproductive technology (ART) [46]. Alonso et al. [47] observed an overall pregnancy rate of 22%, which rose to 66% with the aid of ART following hysteroscopic resection and hormone therapy. A recent systematic review noted a pregnancy rate of 69% following hysteroscopic resection combined with progestin therapy [48].
Response evaluation and surveillance after fertility-sparing treatment
The current general principle for evaluating response or conducting follow-up after treatment involves performing endometrial biopsies at 3-month intervals, although the literature includes some variation [49,50]. Recent guidelines from ESGO, the European Society for Radiotherapy & Oncology, and the European Society of Pathology recommend assessing the success of fertility-sparing treatment by obtaining at least two consecutive endometrial biopsies that demonstrate CR, with a minimum interval of 3 months between them [18].
Methods for reassessing the endometrium at 3 months after treatment include endometrial aspiration biopsy (EAB), D&C, and hysteroscopic biopsy. However, some research suggests that because the endometrium atrophies after progesterone treatment, EAB may not be sufficient to collect endometrial tissue. Therefore, D&C or hysteroscopic biopsy can be recommended over EAB [49]. The recent literature advises that, following fertility-preserving treatment, histological evaluation via hysteroscopy is necessary when managing fertility with the intent of achieving pregnancy [49]. Additionally, maintenance treatment should continue at least until pregnancy is planned, with CR being essential during follow-up. Pelvic and US examinations are recommended every 3 months. If necessary, MRI may also be considered on a case-by-case basis [49].
Maintenance treatment after regression
The duration of treatment is not precisely defined and varies within the literature [11]. Most studies report that regression is typically achieved within approximately 4 to 6 months [11,50]. A longer treatment period is known to be necessary in the presence of risk factors such as obesity or insulin resistance; thus, it is recommended that the treatment duration for achieving CR be between 6 and 12 months [51]. If no response occurs even after 6–12 months of treatment, surgery may be considered [52]. One study suggested that patients who do not achieve CR after 6 months of fertility-sparing treatment and who do not show signs of progressive disease may continue receiving additional fertility-sparing treatment. However, the study suggests that the optimal cut-off for fertility-sparing treatment is 15 months, provided there is no disease progression [53].
The response rates to fertility-sparing treatment in early-stage, low-grade endometrial carcinoma are relatively high, ranging from 75% to 79.4% [39,43,54]. The highest CR rates are achieved with a combination of progestin therapy, either oral or via an intrauterine device, following hysteroscopic resection, with documented success rates varying between 90% and 95.3% [11,39,55]. Although reported outcomes vary in the literature, the rates of no response appear to range from 17.2% to 20.9%, while partial response rates have been reported between 4.7% and 7% [38,56]. Due to the lack of consensus on the optimal duration of maintenance treatment, patients who achieve CR should plan and attempt pregnancy as soon as possible [11,49].
ART should be considered to increase the likelihood of pregnancy and shorten the time to conception without raising the risk of recurrence [11]. However, for women with good fertility, attempting natural conception may be advisable within a 6- to 9-month period [11,14]. After the first pregnancy and childbirth, the approach to maintenance treatment can differ based on the desire for future pregnancies. For women who do not wish to undergo surgery immediately postpartum and are not planning an immediate second pregnancy, maintenance therapy with LNG-IUS is recommended, accompanied by close monitoring for recurrence [11,57]. Pregnancy rates following fertility-sparing treatment vary according to the method used and whether ART is employed. A meta-analysis and systematic review revealed pregnancy rates of 34% with oral progestin therapy, 18% with LNG-IUS, and 40% when both treatments were used concurrently [58]. An analysis of 217 patients with atypical hyperplasia or grade 1 EC who received fertility-sparing treatment in Japan showed a pregnancy rate of 47% (102/217) and a live birth rate of 40.1% (87/217). However, these figures include cases of atypical hyperplasia as well as EC [59].
Safety of ART following fertility-sparing treatment
Women who have undergone fertility-sparing treatment for endometrial hyperplasia or EC should be encouraged to begin trying to conceive as soon as they achieve complete remission [11]. Although natural conception is a viable option for these women, it may take additional time. Moreover, extended periods of attempting to conceive naturally can increase the risk of recurrence. Consequently, it is essential to consider ART, such as in vitro fertilization (IVF), to improve the chances of successful pregnancy [11].
The safety of ovarian stimulation for achieving pregnancy following fertility-sparing treatment in women with EC remains unclear [49]. Few studies have directly compared ART methods with expectant management for patients with EC who have no history of infertility [11]. In younger patients without known infertility issues, attempting natural conception with close monitoring over a set period may be a viable option [57,60]. Conversely, several systematic reviews indicate that the use of ART is crucial in facilitating pregnancy. This approach may shorten the time to definitive surgical treatment and decrease the risk of recurrence in women with endometrial hyperplasia or early-stage EC who have received fertility-sparing treatment [51,61-63].
Concerns have been raised about the use of ovarian stimulation medications, as they may increase the risk of EC recurrence by elevating estradiol levels during the follicular phase [49]. Park et al. [64] studied 141 women with stage IA EC who underwent fertility-sparing treatment with progestins. Within this group, 44 patients received ovarian stimulation with either clomiphene citrate or gonadotropins. The 5-year disease-free survival rate showed no significant difference between those who underwent ovarian stimulation and those who did not (p=0.335) [64]. A more recent retrospective study evaluated 22 women who pursued IVF after progestin treatment for stage IA EC. The study reported an overall pregnancy rate of 26.5% and a live birth rate of 14.3% [65]. Notably, during a median follow-up period of 41 months (range, 9 to 150), six patients (27.3%) required definitive hysterectomy due to the recurrence of EC [65].
To ensure optimal treatment outcomes, the protocol for ovarian hyperstimulation and ART strategies must be carefully tailored to each patient’s unique circumstances, in close collaboration with a multidisciplinary team [11,49]. It is imperative to rigorously monitor for EC recurrence during fertility treatment when employing ovarian stimulation agents [65].
Strategies for post-childbearing management
Definitive surgical treatment for EC involves surgical staging, which typically includes total hysterectomy, bilateral salpingo-oophorectomy, and lymph node assessment, except when patients opt for fertility-sparing alternatives. The primary goal of this surgical approach is to remove the uterus, which is the most common site of recurrence. For patients of reproductive age, the decision to remove the ovaries is tailored to the individual, as a meta-analysis has demonstrated no statistically significant difference in overall survival rates for patients with early-stage EC, regardless of whether oophorectomy was performed [66].
The decision to proceed with oophorectomy should incorporate factors such as patient age, evidence of ovarian invasion, the risk of primary ovarian cancer, the presence of other adnexal pathologies (affecting the ovaries and fallopian tubes), and the potential impact of surgical menopause on the patient’s overall health and quality of life [18]. Definitive surgical treatment is advised for patients who have completed childbearing, do not respond to conservative therapy, cannot conceive naturally for any reason, or experience recurrence or disease progression [11]. In patients undergoing oophorectomy before reaching natural menopause, estrogen replacement therapy should be considered to alleviate the adverse effects of surgical menopause. For those at high surgical risk or who choose not to undergo surgery, medical management or a combination of oral progestins and LNG-IUS may be appropriate alternatives [67].
Conclusion
Although high-quality evidence regarding fertility-sparing treatments is limited, prevailing recommendations are outlined in the guidelines established by gynecologic oncology societies. These guidelines, along with existing research, indicate that fertility-sparing treatments can be effective for selected patients. When a patient with an indication for fertility preservation expresses a strong desire to maintain reproductive capacity, the clinician should carefully assess the disease status and consider fertility-sparing treatment options, accompanied by rigorous monitoring.
Notes
Conflict of interest
Sanghoon Lee is the editorial board member of Clinical and Experimental Reproductive Medicine; however, he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflict of interest relevant to this article was reported.
Author contributions
Conceptualization: SL. Methodology: AS, HGJ, SL. Formal analysis: AS. Data curation: SL. Project administration: AS. Visualization: AS, HGJ. Writing-original draft: AS, HGJ. Writing-review & editing: AS, HGJ, SK, SL. Approval of final manuscript: AS, HGJ, SK, SL.