Treatment of low-risk endometrial cancer

INTRODUCTION — Cancer of the endometrium is the most common gynecologic malignancy in resource-abundant countries and the second most common in resource-limited countries (where cervical cancer is more common). The stage at diagnosis, histologic subtype, and grade of endometrial carcinoma are used to assign risk for recurrent or persistent disease into low-, intermediate-, and high-risk. For patients with low-risk endometrial cancer, surgery is the standard treatment, and the prognosis is usually excellent; adjuvant therapy is typically not recommended for such patients.

This topic will focus on the management of patients with low-risk endometrial cancer and will explain why adjuvant therapy is not recommended for patients with low-risk disease. An overview of endometrial cancer, as well as details on the treatment of intermediate- and high-risk endometrial cancers, are discussed separately.

●(See "Overview of resectable endometrial carcinoma".)

●(See "Adjuvant treatment of intermediate-risk endometrial cancer".)

●(See "Adjuvant treatment of high-risk endometrial cancers".)

CLASSIFICATION

Definition of low risk — Low-risk endometrial cancer is defined as having all of the following characteristics (algorithm 1) (see "Overview of resectable endometrial carcinoma", section on 'Low-risk disease'):

●Cancer that is endometrioid or nongastrointestinal mucinous type, and

●Histologic grade 1 or 2, and

●Limited to the endometrium, or invading less than one-half of the myometrium, with no lymphovascular space invasion (LVSI)

With the publication of the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system (table 1 and table 2) [1], our assessment of low-risk tumors may evolve to include extensiveness of LVSI (focal conferring less risk than extensive) and molecular classification (eg, mutations involving polymerase epsilon [POLE_mut] conferring a more favorable prognosis than those involving P53 [p53_abn]). However, we do not yet use these factors in treatment decisions of low-risk cancers. This topic will utilize the 2023 FIGO staging system except when describing studies that used older staging systems.

Patients with low-risk endometrial cancer who did not undergo nodal evaluation are considered unstaged but given that their risk of nodal involvement is low (<5 percent), we do not perform surgical staging in this population (if not done as part of the primary surgery). Nodal evaluation of endometrial cancer is discussed separately. (See "Endometrial carcinoma: Staging and surgical treatment", section on 'Staging system'.)

Patients with lower uterine segment involvement — In this topic, patients with lower uterine segment involvement (but the absence of other risk features), are included in the low-risk disease population; lower uterine segment involvement alone does not qualify as intermediate-risk disease. This differs slightly from the guidelines of the National Comprehensive Cancer Network, in which involvement of the lower uterine segment is considered as part of the group with intermediate-risk endometrial cancer [2].

While lower uterine segment involvement appears to be associated with worse survival outcomes, this may be due to the strong association of lower uterine segment involvement with lymph node involvement [3-5].

INITIAL MANAGEMENT

Surgery as preferred option — Surgical staging with total hysterectomy, bilateral salpingo-oophorectomy (BSO), lymph node evaluation, and evaluation for extrauterine disease is the standard initial approach to most patients with newly diagnosed endometrial cancer. However, patients who desire fertility preservation may be candidates for medical therapy, and patients who are not candidates for surgery (eg, due to frailty or multiple comorbidities) may undergo primary radiation. (See "Endometrial carcinoma: Staging and surgical treatment" and 'Fertility preservation as alternative in selected patients' below and "Endometrial carcinoma: Staging and surgical treatment", section on 'Inoperable patients'.)

Clinical rather than surgical staging may underestimate the extent of disease, particularly for higher-grade tumors. The best available data regarding the rate of unsuspected advanced disease in patients presumed to be stage I based on clinical evaluation are from a database study including 621 patients with endometrial cancer, among whom 22 percent were found to have disease outside the uterus [6]. The rate of nodal metastases increased with increasing tumor grade (grade 1: 3 percent; grade 2: 9 percent; grade 3: 18 percent). This seminal study, with its recognition of the potential for metastatic spread, prompted the shift from clinical staging to surgical staging of endometrial cancer. Subsequent studies have found a low risk of difference in the findings of frozen section versus permanent section of the uterus in endometrial cancer and in the identification of factors associated with a low risk for nodal metastases (well-differentiated endometrioid tumor with lack of myometrial invasion and small size) [7,8]. While these studies are reassuring regarding basing management on clinical staging and frozen sections, more precise assessment of risk may include other uterine histopathologic factors, which will not be determined definitively if the uterus is preserved.

Limited role of adjuvant therapy — We recommend that all patients with pathologically confirmed low-risk endometrial cancer undergo surveillance following surgery rather than adjuvant therapy. While the primary risk in patients with low-risk endometrial cancer is local recurrence (eg, at the vaginal vault), this risk is low (≤5 percent) [9-13]. (See "Overview of approach to endometrial cancer survivors", section on 'Follow-up post-treatment'.)

The rationale against adjuvant treatment is as follows:

●Radiation therapy – For patients with low-risk endometrial cancer, we do not pursue adjuvant radiation. While radiation therapy (RT) can reduce the risk of local recurrence, it does not improve overall survival. Patients with low-risk endometrial cancer have a low likelihood of recurrence (≤5 percent), and thus, the absolute likelihood of benefit of adjuvant radiation is small. Furthermore, adjuvant pelvic external-beam RT (EBRT) may increase the risk of treatment-related complications. While vaginal brachytherapy (VBT) is associated with less toxicity, there are no benefits to treatment to warrant its use in these patients.

In a 2012 meta-analysis of eight trials enrolling patients with stage I endometrial cancer, among the 517 patients with low-risk disease, RT was associated with an increased risk of death related to endometrial cancer compared with observation (relative risk [RR] 2.6, 95% CI 1.1-6.7) [14]; however, there were few deaths and the confidence interval was wide. Another study reinforced the lack of benefits and the heightened risks associated with EBRT for long-term survivors [15]. In this study, 560 patients with uterine-confined endometrial cancer underwent brachytherapy and were randomly assigned to pelvic EBRT versus no further treatment. At a median follow-up of 20.5 years, EBRT did not improve survival, and among patients under 60 years, EBRT was associated with a higher mortality risk (hazard ratio [HR] 1.36, 95% CI 1.06-1.76). It was also associated with a higher rate of secondary malignancies and serious complications.

Similarly, VBT has failed to demonstrate benefits in low-risk disease. In a multi-institutional European study, 645 patients with grade 1 to 2 endometrioid endometrial cancer invading less than one-half of the myometrium were allocated to either surgical treatment alone or to surgery plus VBT [16]. Cancer-specific and overall survival were similar between groups. However, VBT was associated with an increase in genitourinary symptoms (eg, dysuria, frequency, incontinence [2.8 versus 0.6 percent]).

●Progestin therapy – We do not administer adjuvant progestin therapy for patients with low-risk endometrial cancer. However, progestin therapy is an option for patients who are willing to take the risk of less effective therapy to achieve fertility preservation. (See 'Fertility preservation as alternative in selected patients' below.)

Because most endometrial cancer is associated with excess estrogen production, it has been hypothesized that progestin therapy may be effective adjuvant therapy. However, in a meta-analysis of four trials, the risk of death at five years between adjuvant progestin therapy compared with no further treatment was similar between groups [17].

Fertility preservation as alternative in selected patients

Selection criteria — Reproductive-age patients with low-risk endometrial carcinoma should be asked about whether they wish to preserve fertility.

●Candidates – Optimal candidates for fertility-sparing treatment of endometrial cancer include patients with all the following characteristics:

•Well-differentiated (grade 1) endometrial adenocarcinoma with histology and grade confirmed on dilation and curettage.

•Tumor confined to the endometrium (confirmed by imaging with pelvic ultrasound and magnetic resonance imaging).

•Reproductive age and desirous of future childbearing.

•No contraindications to hormonal therapy.

•Understanding of the nonstandard nature of treatment, including risk of occult cancer and risk of recurrent and/or persistent cancer. A clinical challenge is that patients who are managed with a fertility-sparing approach are staged clinically, rather than with surgical exploration, and that the endometrium is not fully evaluated. This means that more advanced disease may be present than is appreciated by clinical assessment. (See 'Surgery as preferred option' above.)

The most common approach to fertility preservation for such patients is progestin therapy and deferral of surgical staging (including hysterectomy and BSO) until after completion of childbearing. Use of this approach is limited to patients with low-risk disease only, as the risk of recurrent or persistent disease is likely higher than with hysterectomy. Patients who are candidates should be counseled about the risks and benefits so they can make an informed decision. In addition, patients should be counseled that adherence to oral treatment regimens may be difficult, as suggested by at least one study of patients with gynecologic malignancies [18].

Details on how to administer fertility-preservation treatment for low-risk endometrial cancer are found elsewhere. (See "Fertility preservation in patients with endometrial carcinoma", section on 'Progestin therapy'.)

●Contraindications – Patients who are not optimal candidates for fertility preservation include:

•Patients with Lynch syndrome – In our practice, we do not offer fertility preservation to patients with endometrial cancer who have Lynch syndrome. For such patients, tumorigenesis is secondary to a defect in mismatch-repair genes, not excessive estrogen stimulation [19]. In addition, there are a lack of studies of response to progestins in patients with Lynch syndrome. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)

•Patients with grade 2 and 3 tumors or myometrial invasion– While there are reports of patients with grade 2 to 3 differentiated tumors with superficial myometrial invasion being conservatively managed, the collective experience is insufficient to recommend fertility-sparing progestin therapy for this patient population [20-22].

In one study of 621 patients with clinical stage I endometrial cancer, no patients with grade 1 cancer limited to the endometrium had extrauterine spread at the time of surgical staging [6]. However, the overall incidence of extrauterine spread in the study was higher, with 22 percent of patients having disease outside of the uterus (lymph node metastasis, adnexal disease, intraperitoneal spread, and or/malignant cells in peritoneal washings). In a United States database study evaluating fertility preservation in over 23,000 patients <50 years old diagnosed with stage I endometrial cancer between 2004 and 2014, use of progestin therapy was associated with decreased five-year survival in patients with cancer involving >50 percent of the myometrium; this is discussed in more detail below (see 'Efficacy relative to surgery' below). These data underscore the importance of patient selection for fertility-sparing treatment based on grade and depth of invasion, even among patients without clinical evidence for extrauterine spread.

Efficacy relative to surgery — Observational data have suggested that fertility preservation yields comparable outcomes to hysterectomy for endometrial cancer that is limited to the endometrium, but not higher stages.

In the United States cancer database study discussed above (see 'Selection criteria' above), patients treated with progestins (872 patients) compared with hysterectomy had a lower five-year survival rate (96.4 versus 97.2 percent) and higher mortality risk (HR 1.92, 95% CI 1.15-3.19) [23]. The study did not report route or dose of the progestin regimens. However, in subset analysis, patients with tumor confined to the endometrium or involving <50 percent of the myometrium had equivalent five-year survival outcomes (97.5 in both treatment groups) and mortality risk, while survival was lower with progestins in those with cancer involving >50 percent of the myometrium (75 versus 97.5 percent; HR for mortality 3.52, 95% CI 1.57-7.9) and stage I-not otherwise specified tumors (HR for mortality 3.91, 95% CI 1.41-10.82).

Reproductive outcomes — Systemic reviews of relevant studies have reported live birth rates between approximately 35 and 45 percent. These outcomes are discussed in detail elsewhere. (See "Fertility preservation in patients with endometrial carcinoma", section on 'Reproductive outcomes'.)

POST-TREATMENT SURVEILLANCE — Post-treatment surveillance for patients with endometrial cancer is the same regardless of risk and is discussed in detail separately. (See "Overview of resectable endometrial carcinoma", section on 'Post-treatment considerations'.)

PROGNOSIS — Patients with low-risk endometrial cancer have an excellent prognosis with a low recurrence risk and expected survival of ≥90 percent [16,24]. (See "Overview of resectable endometrial carcinoma", section on 'Stage and histology'.)

Because of the excellent prognosis with low-risk endometrial cancer, non-cancer-directed interventions may be a particularly effective means of improving outcome in this group of patients. Most patients with low-risk endometrial cancers will die of another cause [25,26]. The risk of both cancer and non-cancer-related death following endometrial cancer is elevated in patients with diabetes [25], and the leading cause of death among endometrial cancer patients is cardiovascular disease [26]. An association of the metabolic syndrome with endometrial cancer has also been reported [27,28]. Although there are no data demonstrating that outcomes can be improved by more effective management of associated medical conditions, the provision of a survivorship care plan is indicated in patients with low-risk endometrial cancer.

These and other issues regarding survivorship for patients who have completed treatment for endometrial cancer are discussed separately. (See "Overview of cancer survivorship care for primary care and oncology providers".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis, staging, and surgical treatment (Beyond the Basics)" and "Patient education: Endometrial cancer treatment after surgery (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – After surgical and pathologic staging, patients with endometrial cancer are defined as having low-risk disease if their tumor has all the following characteristics (algorithm 1) (see 'Definition of low risk' above):

•Cancer that is endometrioid or nongastrointestinal mucinous type, and

•Histologic grade 1 or 2, and

•Limited to the endometrium, or invading less than one-half of the myometrium, with no lymphovascular space invasion

●Initial management

•For most patients with low-risk endometrial cancer, we recommend surgery rather than medical therapy (Grade 1B). The risk of disease progression is higher without surgery, and surgical staging (which includes total hysterectomy, bilateral salpingo-oophorectomy, lymph node evaluation, and evaluation for extrauterine disease) is more accurate compared with endometrial sampling and imaging alone. (See 'Surgery as preferred option' above.)

•However, fertility preservation may be an appropriate alternative for patients with grade 1 endometrial adenocarcinoma confined to the endometrium, as determined by endometrial sampling and imaging. Such patients who wish to preserve fertility should be counseled about treatment with progestins with surgery deferred until after childbearing, including the risks of recurrent and persistent disease. (See 'Fertility preservation as alternative in selected patients' above and "Fertility preservation in patients with endometrial carcinoma".)

•For patients with low-risk endometrial cancer who are unfit for surgery, primary radiation therapy may be acceptable treatment. (See "Endometrial carcinoma: Staging and surgical treatment", section on 'Inoperable patients'.)

●Limited role of adjuvant therapy – For patients with surgically and pathologically defined low-risk endometrial cancer, we recommend surveillance rather than adjuvant therapy (Grade 1B). While such patients can experience local recurrence (eg, at the vaginal vault), the risk of recurrence following surgery is low (≤5 percent). Furthermore, adjuvant therapies such as radiation may increase the risk of treatment-related complications. (See 'Limited role of adjuvant therapy' above.)

●Prognosis – Patients with low-risk endometrial cancer have an excellent prognosis with a low recurrence risk and expected survival of ≥90 percent. (See 'Prognosis' above.)