INTRODUCTION — Endometrial cancer is cancer of the uterine lining. Surgery is the standard treatment for women with low-risk endometrial cancer, and the prognosis is usually excellent. Adjuvant therapy is most often not recommended with low-risk disease.
This review will focus on the options for adjuvant treatment in endometrial cancer and will explain why it is not recommended for women with low-risk disease. An overview of endometrial cancer, as well as further details on the treatment of intermediate- and high-risk endometrial cancers, is discussed separately.
●(See "Overview of 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 (see "Endometrial cancer: Pathology and classification"):
●Histologic grade 1 or 2
●Cancer limited to the endometrium; or invading less than one-half of the myometrium, with no lymphovascular space invasion (table 1)
●Cancer that is not a high-risk histologic type (eg, clear cell, serous, or carcinosarcoma)
Patients with low-risk endometrial cancer who did not undergo nodal evaluation are considered unstaged, but given that their risk of nodal involvement is less than 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'.)
Special consideration for lower uterine segment involvement — In this topic, lower uterine segment involvement alone does not qualify as intermediate risk disease; in the absence of other risk features, women with lower uterine segment involvement are included in the low-risk disease population. 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 [1].
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 [2-4].
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 women with newly diagnosed endometrial cancer. (See "Endometrial carcinoma: Staging and surgical treatment".)
However, women who desire fertility preservation may be candidates for medical therapy. (See 'Fertility preservation as alternative in select women' below.)
The rationale for surgical staging is that clinical staging may underestimate the extent of disease, particularly for higher-grade tumors.
The best available data regarding the rate of unsuspected advanced disease in women presumed to be stage I based on clinical evaluation are from a database study including 621 women with endometrial cancer, among whom 22 percent were found to have disease outside the uterus [5]. 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) [6,7]. 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.
Is there a role for postoperative treatment? — Following surgery, the primary risk in patients with low-risk endometrial cancer is local recurrence (eg, at the vaginal vault). However, the risk is ≤5 percent [8-12]. Therefore, we recommend that all patients undergo surveillance following surgery for pathologically confirmed low-risk endometrial cancer. (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. Women 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 women 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) [13].
●Another study reinforced the lack of benefits and the heightened risks associated with EBRT for long-term survivors [14]. In this study, 560 women 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 women under 60 years 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 women with grade 1 to 2 endometrioid endometrial cancer invading less than one-half of the myometrium (surgical stage IA) were allocated to either surgical treatment alone or to surgery plus VBT [15]. There were no differences in cancer-specific or overall survival. However, VBT was associated with an increase in genitourinary symptoms (eg, dysuria, frequency, incontinence [2.8 versus 0.6 percent]).
These data show there are more risks than benefits associated with RT for patients with low-risk endometrial cancer.
●Progestin therapy – We do not suggest adjuvant progestin therapy for women with low-risk endometrial cancer. However, progestin therapy is an option for women who are willing to take the risk of less effective therapy to achieve fertility preservation. (See 'Fertility preservation as alternative in select women' below.)
Because 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, there was no difference in the risk of death at five years between adjuvant progestin therapy compared with no further treatment (RR 1.00, 95% CI 0.85-1.18) [16].
Fertility preservation as alternative in select women
Selection criteria — Reproductive-age women with low-risk endometrial carcinoma should be asked about whether they wish to preserve fertility. For women who are candidates for fertility preservation, the most common approach is progestin therapy and deferral of surgical staging (including hysterectomy and BSO) until after completion of childbearing. 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'.)
Use of this approach is limited to women with low-risk disease only, as the risk of recurrent or persistent disease is likely higher than with hysterectomy. Women who are candidates should be counseled about the risks and benefits so they can make an informed decision.
Optimal candidates for fertility-sparing treatment of endometrial cancer include women with the following characteristics:
●Well-differentiated (grade 1) endometrial adenocarcinoma with histology and grade confirmed on dilation and curettage.
●Tumor confined to the endometrium, stage IA (table 1).
●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 women 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.)
However, adherence to oral treatment regimens may be difficult for some patients, as suggested by one study of patients with gynecologic malignancies [17].
For women with Lynch syndrome, tumorigenesis is secondary to a defect in mismatch-repair genes, not excessive estrogen stimulation [18]. Based on the difference in pathogenesis from the general population and the lack of studies of response to progestins in women with Lynch syndrome, in our practice, we do not offer fertility to preservation to women with endometrial cancer who have Lynch syndrome. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)
While there are reports of women 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 [19-21]. In one study of 621 patients with clinical stage I endometrial cancer, those with grade 1 cancer limited to the endometrium had a 0 percent incidence of extrauterine spread at the time of surgical staging [5]. 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). A large database study found comparable efficacy for progestin therapy and surgery in women with stage IA disease but lesser progestin efficacy in stage IB [22]. 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 stage IA disease, but not higher stages.
A United States cancer database study evaluating fertility preservation included over 23,000 women <50 years old with stage I endometrioid endometrial cancer diagnosed from 2004 to 2014 [22]. Progestin therapy was given in 872 women; the study did not report route or dose of the progestin regimens. Patients treated with progestins 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).
However, in subset analysis, women with stage IA disease had equivalent five-year survival outcomes (97.5 in both treatment groups), while survival was lower with progestins in stage IB (75.0 versus 97.5 percent). Similarly, progestin therapy was associated with similar mortality as surgery for stage IA disease (HR 1.20, 95% CI 0.53-2.68), but higher mortality rates for women with stage IB (HR 3.52, 95% CI 1.57-7.90) and I-not otherwise specified tumors.
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 women with endometrial cancer is the same regardless of risk. (See "Overview of endometrial carcinoma", section on 'Post-treatment surveillance'.)
PROGNOSIS — Women with low-risk endometrial cancer have an excellent prognosis with a low recurrence risk and expected survival of ≥90 percent [15,23]. (See "Overview of endometrial carcinoma", section on 'Prognosis'.)
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 women with low-risk endometrial cancers will die of another cause [24,25]. The risk of both cancer and non-cancer-related death following endometrial cancer is elevated in diabetics [24], and the leading cause of death among endometrial cancer patients is cardiovascular disease [25]. An association of the metabolic syndrome with endometrial cancer has been reported as well [26,27]. 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 low-risk endometrial cancer patients.
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".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 5th to 6th 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 10th to 12th 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
●After surgical and pathologic staging, women are defined as having low-risk disease if their tumor has all of the following characteristics (see 'Definition of low risk' above):
•Histologic grade 1 or 2.
•Cancer limited to the endometrium; or invading less than one-half of the myometrium, with no lymphovascular space invasion (table 1).
•Cancer that is not a high-risk histologic type (eg, clear cell, serous, or carcinosarcoma). (See 'Classification' above.)
●We recommend surgical staging for most women with low-risk endometrial cancer rather than medical therapy (Grade 1B), given the risks of disease progression without surgery, and higher accuracy with surgical staging relative to endometrial sampling and imaging alone. Surgical staging includes total hysterectomy, bilateral salpingo-oophorectomy, lymph node evaluation, and evaluation for extrauterine disease. However, fertility preservation may be an appropriate alternative for women with stage IA disease that is grade I, as determined by endometrial sampling and imaging. Such women who wish to preserve fertility should be counseled about treatment with progestins, including the risks of recurrent and persistent disease. (See 'Surgery as preferred option' above and 'Fertility preservation as alternative in select women' above and "Fertility preservation in patients with endometrial carcinoma".)
●The risk for women with low-risk endometrial cancer is primarily local recurrence (eg, at the vaginal vault) following surgery. However, the risk is ≤5 percent following surgical treatment alone. Therefore, for women with surgically and pathologically defined low-risk endometrial cancer, we recommend surveillance only rather than adjuvant therapy (Grade 1B), given the low likelihood of benefit and known risks of adjuvant therapy. (See 'Is there a role for postoperative treatment?' above.)
