Adjuvant treatment of high-risk endometrial cancers

INTRODUCTION — 

Adenocarcinomas of the endometrium are a common gynecologic malignancy worldwide. Among the different histologic types of adenocarcinomas, grade 1 and 2 endometrioid uterine cancers have a more favorable prognosis and typically present at an early stage. Other histologic types of uterine adenocarcinoma (eg, serous, clear cell) are associated with a poorer prognosis.

The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system is presented in the tables (table 1 and table 2). This topic will utilize the 2023 FIGO staging system except when describing studies in which older staging systems (eg, 2009 FIGO/2017 Tumor, Node, Metastasis [TNM] classification system) are used. In addition to stage, other pathologic factors are used to assign risk of recurrence into low-, intermediate-, and high-risk categories.

Females with high-risk endometrial cancer have a relatively poor prognosis following hysterectomy alone. Therefore, adjuvant treatment is often administered, although the benefit of any therapy following surgery on overall survival in most situations is unclear. This review will focus on treatment of high-risk endometrial cancer.

Evidence to support the optimal approach to adjuvant treatment for high-risk endometrial cancer is not robust. When evidence is weak, many patterns of care develop at different centers. Institutional tumor boards may be useful in guiding difficult treatment decisions. In this topic, we will review our approach, noting situations in which UpToDate contributors vary in their practice.

An overview of endometrial cancer including clinical features and an approach to diagnosis, the approach to adjuvant treatment, and treatment of low- and intermediate-risk endometrial cancer is discussed separately.

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

●(See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)

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

●(See "Treatment of low-risk endometrial cancer".)

●(See "Management of locoregional recurrence of endometrial cancer".)

DEFINITION OF HIGH RISK — 

Patients are classified as having high-risk endometrial cancer if they have any of the following:

●High-risk histology – Aggressive histologic types include serous, clear cell, undifferentiated, mixed, and mesonephric-like carcinomas, carcinosarcomas, and selected high-grade endometrioid endometrial cancers (grade 3) [1].

•According to the Federation of Gynecology and Obstetrics (FIGO), grade 3 endometrioid endometrial carcinomas are a prognostically, clinically, and molecularly heterogenous disease. As such molecular classification is necessary to allocate such cancers into the appropriate risk group (table 1 and table 2). Among grade 3 endometrioid tumors, only the p53abn (with no POLE mutation and no mismatch repair deficiency [dMMR]) have high-risk behavior. P53abn tumors that are also POLE mutant have a good prognosis conferred by the POLE mutation. If the molecular classification is unknown, high-grade endometrioid endometrial carcinomas are considered high risk, according to the 2023 FIGO classification.

•In PORTEC-3, molecular analysis in 410 endometrial carcinomas identified four subgroups: p53abn (23 percent), POLE mutant (12 percent), dMMR (33 percent), and no specific molecular profile (NSMP; 32 percent) [2]. Tumors with a POLE mutation that had abnormal p53 expression and/or MMR protein loss were classified as POLE mutant; non-POLE mutant tumors with loss of any MMR protein and a p53 mutant staining pattern were classified as dMMR. Five-year recurrence-free survival was 48 percent for patients with p53abn, 98 percent for POLE mutant, 72 percent for dMMR, and 74 percent for NSMP.

●Pathologic stages III/IV disease (table 1), of any histology.

STAGE I AND II DISEASE — 

Aggressive histologic types are composed of high-grade endometrioid endometrial carcinomas (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas.

●Impact of p53 mutation status – The presence of a p53 mutation in the absence of a POLE mutation or dMMR appears to confer worsened prognosis as discussed below (see 'p53 positive cancers' below). Serous tumors are generally associated with p53 mutations.

●Impact of histology – Compared with endometrioid adenocarcinomas, uterine serous and clear cell carcinomas are biologically very different and are more aggressive histologic types [3]. This was demonstrated in a Surveillance, Epidemiology, and End Results study of cases diagnosed from 1998 to 2001 [3]. The five-year survival rate stratified by histologic type was 45, 65, and 91 percent for serous, clear cell, and endometrioid adenocarcinomas, respectively. More contemporary studies suggest that clear cell carcinoma is a heterogeneous group of tumors with varying outcomes [4]. As with other histologic subtypes of endometrial cancer, clear cell carcinomas with p53 mutations fare worse [5].

●Impact of grade – Outcomes among patients with endometrioid cancers appear to differ based on grade. Specifically, patients with deeply invasive (50 percent or greater) grade 3 cancers were noted to have a poor prognosis in studies predating molecular classification. On the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial, patients with deeply invasive grade 3 tumors (no nodal assessment required, so some patients would have been understaged) assigned to whole-pelvic radiation therapy (no chemotherapy) had a five-year overall survival (OS) of 58 percent, with distant metastatic rate of 31 percent and 14 percent locoregional recurrence risk [6].

p53 positive cancers — In case the molecular classification reveals p53 mutated status the FIGO stage may be upgraded for those with early stage of the disease (table 2). Some authors and editors suggest chemotherapy for stage I and II p53 positive cancers while others do not. While this prognostic marker appears most relevant for tumors without a co-occurring POLE mutation or dMMR, POLE testing is not yet available at every institution. We await the results of ongoing clinical trials to provide more clarity on treatment paradigms. (See "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)

Data from patients enrolled in the PORTEC-3 trial and in international cohorts outside of clinical trials suggest that patients with p53abn endometrial cancers treated with chemotherapy in addition to radiation have superior outcomes as compared with those who received radiation alone. (See 'Rationale for systemic therapy over other modalities' below.)

Aggressive histologic types — Aggressive histologic types including serous, clear cell, undifferentiated, mixed, and mesonephric-like carcinomas, carcinosarcomas, and high-grade endometrioid endometrial cancers without molecular testing are considered high risk, irrespective of stage. (See 'Definition of high risk' above.)

Confined to endometrium — Females with high risk-histology cancers that are confined to the endometrium or a polyp without myometrial invasion may be observed. However, alternatively, adjuvant vaginal brachytherapy (VBT) may be offered, depending on patient and provider preferences.

A review of cases of polyp- or endometrium-limited endometrial cancers of clear cell, serous, or mixed histology who received a variety of adjuvant therapies showed a three-year progression-free survival (PFS) rate of 94.9 percent and no impact of adjuvant treatment on OS or PFS [7]. Patients in this study received adjuvant chemotherapy with or without radiation therapy (RT; intravaginal or pelvic), RT (intravaginal or pelvic) alone, or no adjuvant treatment.

Myometrium invasive — For females with high-risk histologies with myometrial invasion but no nodal involvement (stage IIC in 2023 FIGO), we suggest pelvic RT alone or with chemotherapy. The use of VBT in addition to either pelvic RT or chemotherapy can be considered based on local risk factors for recurrence. (See 'Inclusion of VBT in select cases' below.)

Given similar efficacy but improved tolerability with pelvic RT, some UpToDate contributors prefer pelvic RT. Intensity modulated RT (IMRT) has been shown in randomized prospective trials to decrease both acute and late genitourinary and gastrointestinal side effects compared with three-dimensional conformal RT or a four-field box, to decrease toxicity, as available. It is considered the preferred option, if available, when pelvic or pelvic and para-aortic radiation is used [8]. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

However, others prefer chemotherapy plus VBT, noting that much of the associated acute toxicity is asymptomatic hematologic toxicity which can often be ameliorated by appropriate use of hematopoietic growth factors. If chemotherapy is administered in this setting, we typically administer six, rather than fewer cycles in order to optimize systemic tumor control (although fewer cycles were used in the Gynecologic Oncology Group [GOG]-249, discussed below).

●Pelvic RT alone versus chemotherapy plus VBT – The GOG-249 trial reported that pelvic RT had similar efficacy as VBT with three cycles of carboplatin/paclitaxel chemotherapy, but lesser acute toxicity.

In this trial, 601 females with early-stage endometrioid endometrial cancer were randomly assigned to pelvic RT (using either three-dimensional conformal RT or IMRT alone) or to VBT followed by three cycles of paclitaxel/carboplatin chemotherapy [9,10]. Eligibility for patients with endometrioid histology was as follows: age 70 years or older with one uterine risk factor, age 50 years or older with two risk factors, or age 18 years or older with three risk factors. Uterine risk factors included grade 2 or 3 tumor, outer half depth of invasion, and lymphovascular invasion.

At a median follow-up of 53 months, the five-year recurrence-free survival (RFS) and OS were comparable between the two arms (RFS hazard ratio [HR] 0.92, 90% CI 0.69-1.23; OS HR 1.04, 90% CI 0.71-1.52) [11]. Compared with those treated with pelvic RT, females treated with VBT plus chemotherapy had more nodal recurrences (to the pelvic and/or para-aortic nodes, 9 versus 4 percent at five years) and experienced more serious adverse events (64 versus 11 percent), including a higher rate of neurotoxicity. However, late toxicity was comparable across groups (12 and 13 percent) [9,10].

Based on these results, pelvic RT appears to be as effective as three cycles of chemotherapy plus VBT and may have less acute toxicity. Whether results of treatment would differ if the standard six cycles of chemotherapy were used instead is unanswered.

●Chemoradiation versus pelvic RT – In the PORTEC-3 trial, discussed in further detail below, chemoradiation and pelvic RT were compared among patients with endometrial cancer that was stage I endometrioid and grade 3 with deep invasion or with lymphovascular space invasion, or stage II or III endometrioid, or nonendometrioid (serous or clear cell) histology. For the subset of patients with stage I/II disease (all histologies combined), differences in outcomes were slight and not statistically significant (five-year OS 84 percent for chemoradiotherapy versus 82 percent for radiotherapy alone; 95% CI 0.5-1.4). However, chemoradiation improved outcomes in the overall trial population compared with pelvic RT, and these results are discussed in detail below, along with subset analysis of those with stage III disease. (See 'Rationale for systemic therapy over other modalities' below.)

Molecular features may refine our approach to adjuvant therapy in the future. Further details of molecular features in endometrial cancer, including discussions of relevant trials including Rainbo and PORTEC-1 and -2, are found elsewhere. (See "Overview of resectable endometrial carcinoma", section on 'Molecular factors' and "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)

STAGE III DISEASE — 

Females with stage III or IV disease who have undergone resection are treated with adjuvant systemic therapy, with or without immunotherapy. (See 'Rationale for systemic therapy over other modalities' below and 'Incorporation of immune checkpoint inhibitors with chemotherapy for selected cancers' below.)

We often add vaginal brachytherapy (VBT) for high-risk features for local recurrence. (See 'Inclusion of VBT in select cases' below.)

Compared with females with earlier stage endometrial cancers, patients with stage III and IV endometrial cancer have a worse prognosis. This poorer prognosis is seen when stratified by stage at presentation [3], and is seen regardless of histology. Using a previous staging system (table 3):

●Among females diagnosed with stage I serous, clear cell, or endometrioid cancers, the five-year survival rate was 74, 88, and 95 percent, respectively.

●Among females with stage II cancers, it was 56, 67, and 86 percent, respectively.

●Among females with stage III cancers, it was 33, 48, and 67 percent, respectively.

●Among females with stage IV cancers, it was 18, 18, and 37 percent, respectively.

Incorporation of immune checkpoint inhibitors with chemotherapy for selected cancers — For patients with measurable stage III or stage IV mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, we recommend the addition of immunotherapy to chemotherapy, followed by immunotherapy maintenance.

For resected stage III cancers that either do not have measurable disease or are mismatch repair proficient (pMMR), the approach to adjuvant systemic therapy is divided among UpToDate contributors. Some contributors do not add immune checkpoint inhibitors to chemotherapy in such patients, noting that patients with nonmeasurable disease were largely excluded from randomized trials and the lack of overall survival (OS) benefit in patients with pMMR tumors. Other contributors add immunotherapy to multiagent chemotherapy even in these subsets, extrapolating from the trials below.

Randomized trials demonstrated benefits with the addition of either dostarlimab or pembrolizumab to carboplatin plus paclitaxel, with greater benefits observed among those with dMMR rather than pMMR tumors [12-14].

●Dostarlimab – In the RUBY trial, 494 patients with measurable stage III or IV or recurrent endometrial cancer were randomly assigned to dostarlimab versus placebo, versus dostarlimab combined with carboplatin and paclitaxel every three weeks for six cycles [12]. Subsequently, dostarlimab or placebo was continued every six weeks for up to three years. Of note, the RUBY trial included patients with carcinosarcoma. Results were as follows:

•Overall – Progression-free survival (PFS) rate in the total population at 24 months was 36 percent in the dostarlimab group versus 18 percent in the placebo group; OS rates were 71 and 56 percent, respectively (hazard ratio [HR] for death 0.64, 95% CI 0.46-0.87).

•Primary stage III disease – Among the 92 patients with primary stage III disease, PFS was similar between the dostarlimab and placebo groups (HR 1.03).

•dMMR/MSI-H – In this subset with 118 patients, the PFS rate at 24 months was better with dostarlimab than placebo (PFS 61 versus 16 percent, respectively; HR 0.28, 95% CI 0.16-0.50). OS at 24 months was also improved at 83 percent with the dostarlimab group versus 59 percent with placebo (HR 0.30, 95% CI 0.13-0.70).

Only 24 patients with primary stage III disease had dMMR/MSI-H tumors. Of these, 4 of 10 patients in the dostarlimab group and 6 of 14 patients in the placebo group experienced progression (HR 0.92, 95% CI 0.26-3.3).

•pMMR/microsatellite stable – In this subset of 376 patients, 24-month PFS was 28 percent in the dostarlimab group and 19 percent in the placebo group (HR 0.76, 95% CI 0.59-0.98) [12]. There was a trend towards improvement in OS that did not reach statistical significance (24-month OS rate of 68 versus 55 percent, respectively; HR 0.73, 95% CI 0.52-1.02).

●Pembrolizumab – In the NRG-GY 18 trial, 816 patients with measurable disease (stage III or IVA) or stage IVB were randomly assigned to pembrolizumab or placebo, along with paclitaxel plus carboplatin. Pembrolizumab or placebo every three weeks for six cycles followed by up to 14 maintenance cycles every six weeks [13]. Results were as follows:

•dMMR/MSI-H – At 12 months the PFS in the dMMR cohort (including 225 patients) was 74 percent with pembrolizumab versus 38 percent with placebo. The median PFS was 13.1 months with pembrolizumab versus 8.7 months with placebo.

•pMMR/microsatellite stable – In the pMMR subset (including 591 patients), median PFS was 13.1 months with pembrolizumab and 8.7 months with placebo (HR 0.54, 95% CI 0.41-0.71; p <0.001).

•Benefits were observed in both the dMMR and pMMR subsets, irrespective of programmed cell death ligand 1 status [14].

A separate trial (GOG-3053/KEYNOTE B-21) also showed a disease-free survival (DFS) benefit with the addition of adjuvant pembrolizumab to chemotherapy in patients with newly diagnosed, high-risk endometrial cancer that was dMMR (two-year DFS rates of 92 versus 80 percent, respectively; HR 0.31, 95% CI 0.14-0.69), but not among those with pMMR cancers [15,16]. Patients in this trial had high-risk (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology.

Rationale for systemic therapy over other modalities — Randomized trials have suggested similar outcomes between chemotherapy alone versus chemoradiation in stage III disease; and better outcomes with chemoradiation versus pelvic radiation therapy (RT). Given the results of these trials, for most patients with stage III (or resectable stage IV) endometrial cancer, we suggest adjuvant chemotherapy rather than whole-pelvic RT, adding VBT in select cases to improve the likelihood of local control. (See 'Inclusion of VBT in select cases' below.)

●Chemotherapy similar to chemoradiation – The use of chemoradiation for treatment of endometrial cancer did not improve survival when compared with chemotherapy in the Gynecologic Oncology Group (GOG)-258 trial.

•In GOG-258, over 800 patients with stage III to IVA (with <2 cm residual) disease or International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I/II serous or clear cell endometrial carcinoma (table 3) were randomly assigned to chemoradiation (cisplatin and volume-directed RT delivered with three-dimensional conformal or intensity modulated RT [IMRT], followed by carboplatin and paclitaxel for four cycles) versus chemotherapy alone (carboplatin and paclitaxel for six cycles) [17]. All patients in the chemoradiotherapy arm received growth-factor support, and almost 95 percent of the enrolled population had stage III disease. At a median follow-up of 47 months, there were no differences in relapse-free survival (HR 0.9, 95% CI 0.74-1.10). At median follow-up of 112 months, chemoradiation did not improve OS over chemotherapy alone [18].

In GOG-258, there were fewer lower vaginal recurrences with the addition of RT (2 versus 7 percent; HR 0.36, 95% CI 0.16-0.82), and fewer lower pelvic and para-aortic relapses (11 versus 20 percent; relative risk 0.43, 95% CI 0.28-0.66). There was a trend toward more distant recurrences in the chemoradiotherapy arm (27 versus 21 percent; HR 1.36, 95% CI 1.0-1.86). Rates of ≥grade 3 toxicities were similar between the arms, while quality of life was slightly inferior in the chemoradiotherapy arm.

●Chemoradiation better than pelvic RT – In the PORTEC-3 trial, females with high-risk endometrial cancer experienced a PFS and OS benefit when treated with chemoradiation (followed by systemic chemotherapy) rather than with pelvic RT alone.

•The PORTEC-3 trial enrolled 660 females with stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III endometrioid cancer; or stage I to III disease with serous or clear cell histology. Patients were randomly assigned to chemoradiation (two cycles of cisplatin with pelvic RT, followed by four cycles of carboplatin and paclitaxel) or to pelvic RT alone [19]. Radiation was primarily delivered by a four field box, but IMRT was allowed. At a median follow-up of 73 months, five-year OS was 81 percent with chemoradiation versus 76 percent compared with RT alone (adjusted HR 0.70, 95% CI 0.51-0.97), and five-year failure-free survival was 77 versus 69 percent (HR 0.70, 95% CI 0.52-0.94) [20].

-Benefit was seen particularly in patients with p53abn endometrial carcinoma (defined as above to exclude tumors with POLE mutation or dMMR). The five-year recurrence-free survival with chemotherapy-radiation versus radiation for p53abn endometrial carcinoma was 59 versus 36 percent [2].

•Benefit was also seen in patients with stage III disease (five-year OS 79 versus 69 percent; HR 0.63, 95% CI 0.41-0.99) and in patients with serous tumors (five-year OS 71 versus 53 percent; HR 0.48, 95% CI 0.24-0.96). For those with high-risk earlier stage cancers, differences were slight and not statistically significant. (See 'Myometrium invasive' above.)

•During treatment, grade 3 or higher adverse events were more frequent with chemoradiation versus RT alone (61 versus 13 percent), with most being hematologic (45 percent) [21].

STAGE IV DISEASE — 

The approach to adjuvant therapy for resectable stage IV disease is discussed in detail elsewhere. (See "Initial treatment of metastatic endometrial cancer".)

CHOICE OF SYSTEMIC THERAPY REGIMEN — 

For most females with high-risk endometrial cancer receiving chemotherapy, we suggest six cycles of carboplatin and paclitaxel. This is based on the results of Gynecologic Oncology Group (GOG)-209 [22], which compared carboplatin plus paclitaxel versus doxorubicin and cisplatin followed by paclitaxel in 1300 females with chemotherapy-naïve, advanced endometrial cancer, including females with stage III disease, and demonstrated that carboplatin and paclitaxel results in an equivalent overall response rate, similar progression-free survival, and is less toxic. The results of GOG-209 are further discussed separately. (See "Initial treatment of metastatic endometrial cancer", section on 'Multiagent chemotherapy'.)

For patients receiving immunotherapy, either dostarlimab or pembrolizumab may be used for most histologies, depending on institutional preference or agent availability. However, for those with uterine carcinosarcoma, we offer dostarlimab rather than pembrolizumab, which hasn't been studied in this population. The duration of treatment on trial was three years for dostarlimab or two years for pembrolizumab.

For those with stage IV serous endometrial carcinoma overexpressing human epidermal growth factor receptor 2 (HER2), the incorporation of trastuzumab is the same as in the metastatic setting and is discussed elsewhere. We do not combine immunotherapy with trastuzumab, as there are no data to support that approach. (See "Initial treatment of metastatic endometrial cancer", section on 'Addition of trastuzumab to chemotherapy'.)

TIMING OF PELVIC RADIATION WITH CHEMOTHERAPY — 

For those in whom radiation therapy (RT) is indicated, we typically prefer to administer RT after the completion of all adjuvant chemotherapy, though only limited observational data exist [23]. Other acceptable approaches include giving three cycles of chemotherapy, then radiation, then another three cycles of chemotherapy ("sandwich therapy") [24]; or concurrently, with chemoradiotherapy followed by chemotherapy as in GOG-258 and PORTEC-3. (See 'Rationale for systemic therapy over other modalities' above.)

INCLUSION OF VBT IN SELECT CASES — 

For females who undergo adjuvant chemotherapy, some experts offer vaginal brachytherapy (VBT) to help control local recurrence (eg, for those with cervical involvement or extensive lymphovascular invasion). However, there is variability in practice. We counsel patients that VBT likely improves local recurrences [25], but has not demonstrated overall survival benefits.

SPECIAL CONSIDERATIONS

Patients who are older or frail — Older age has been associated with higher rates of clinical failure, but to what degree age represents an independent prognostic factor is controversial. Females over the age of 65 more frequently have deep myometrial invasion, high tumor grade, and advanced tumor stage. Furthermore, less aggressive therapy could also account for some of the poor outcomes seen in older patients.

Because organ function declines and the number of comorbidities increases as females become older, the risks of chemotherapy are potentially magnified. As such, it becomes less clear if females will live long enough to experience potential survival benefits of treatment to justify the expected risks of chemotherapy. Therefore, we advise older females to undergo comprehensive geriatric assessment to aid in decisions regarding adjuvant chemotherapy. (See "Systemic chemotherapy for cancer in older adults" and "Comprehensive geriatric assessment for patients with cancer".)

If chemotherapy is felt to be too toxic, we administer adjuvant irradiation (whole-pelvic radiation therapy [RT] delivered with intensity modulated RT), although ability to tolerate this modality must also be considered.

Clear cell histology — Data are limited for those with clear cell carcinoma, and while most UpToDate experts do not alter their usual approach, others offer RT [26], with or without chemotherapy, irrespective of stage. The rationale is that, given the rarity of the disease, the benefit of chemotherapy is unknown; extrapolating from data in clear cell carcinoma of the ovary, which has a lower response rate to chemotherapy than high-grade serous carcinoma, clear cell carcinoma of the endometrium may be less responsive as well. Given this concern with chemotherapy, RT offers another method of treatment for this histology.

Obese females — Endometrial cancer is associated with obesity, and severe obesity is common among endometrial cancer patients. It may limit ability to perform lymph node dissection and adequately stage patients. Although clinical practice varies, overweight or obese females often receive intentionally reduced chemotherapy doses based upon ideal, rather than actual, body weight. However, there are no data to support this practice. We agree with guidelines from the American Society of Clinical Oncology and suggest full weight-based cytotoxic chemotherapy dosing in the adjuvant setting [27]. (See "Dosing of anticancer agents in adults", section on 'Dosing for patients with obesity and who are overweight'.)

Approach to lymph node dissection in such patients is discussed elsewhere. (See "Pelvic and paraaortic lymphadenectomy in gynecologic cancers", section on 'Lymphadenectomy procedure'.)

Is there a role for adjuvant endocrine therapy? — For females with high-risk endometrial adenocarcinoma, we do not use endocrine therapy as adjuvant treatment as there are no supporting data. This is being evaluated in the Rainbo3 trial (NCT05255653).

PROGNOSIS — 

Females with high-risk endometrial cancer are at an increased risk of disease progression and death from their disease. Beyond histologic subtype, prognosis is highly dependent on both stage and tumor grade as discussed above. (See 'Stage I and II disease' above and 'Stage III disease' above.)

POST-TREATMENT SURVEILLANCE — 

The majority of recurrences occur within three years of treatment. Approximately 70 percent of patients develop symptoms at the time of recurrence (eg, vaginal bleeding, abdominal pain, cough, weight loss). While post-treatment surveillance protocols may vary by institution, we perform clinical examination (including symptom review, symptom-directed physical examination, and pelvic examination) at three-month intervals for two years, then every six months or annually.

Detecting isolated vaginal occurrences early is of particular importance as they may sometimes be cured by radiation therapy (RT) or, in patients with prior RT, surgery. While cancer antigen (CA) 125 is used by some clinicians as part of routine surveillance, there is no high-quality evidence that CA 125 surveillance improves outcomes.

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".)

SUMMARY AND RECOMMENDATIONS

●Definition of high risk – Patients are classified as having high-risk endometrial cancer if they have a high risk histology (serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, carcinosarcomas, and high-grade endometrioid endometrial cancers), or pathologic stage III/IV disease of any histology (table 1). (See 'Definition of high risk' above.)

●Early-stage disease

•p53 positive cancers – In case the molecular classification reveals p53 mutated status (without a co-occurring POLE mutation), the FIGO stage is modified in the early stage of the disease (table 2). Some authors and editors suggest chemotherapy while others do not for early stage p53-positive cancers (see 'p53 positive cancers' above). While the staging system does not specifically take into account tumors with p53 abnormal status and coexisting mismatch repair deficiency, early work suggests these cancers are lower risk.

•Other cancers

-For females with high-risk histology cancers that are confined to the endometrium or a polyp without myometrial invasion we suggest observation (Grade 2C). However, alternatively, adjuvant vaginal brachytherapy (VBT) may be offered, depending on patient and provider preferences. (See 'Confined to endometrium' above.)

-For patients with early-stage, high-risk histologies with myometrial invasion, acceptable options include pelvic radiation therapy (RT) alone or with chemotherapy. Pelvic radiation therapy should be delivered with intensity modulated RT to decrease toxicity, as available. (See 'Myometrium invasive' above.)

●Stage III disease

•For patients with measurable mismatch repair deficient stage III endometrial cancer, we recommend the addition of either dostarlimab or pembrolizumab to chemotherapy (Grade 1B). UpToDate contributors are divided in regards to use of immune checkpoint inhibitors with chemotherapy in other stage III cancers. (See 'Incorporation of immune checkpoint inhibitors with chemotherapy for selected cancers' above.)

•For most females with stage III, we suggest adjuvant systemic chemotherapy rather than whole-pelvic RT (Grade 2B). For patients who are not candidates for chemotherapy for whatever reason, we utilize whole-pelvic RT. Additionally, data are limited for those with clear cell carcinoma, and while most UpToDate experts do not alter their usual approach, others offer radiation with or without chemotherapy for this histology. (See 'Choice of systemic therapy regimen' above.)

●Stage IV disease – Management of stage IV disease is discussed elsewhere. (See "Initial treatment of metastatic endometrial cancer".)

●Selection of systemic therapy regimen

•For patients receiving chemotherapy, we suggest carboplatin plus paclitaxel rather than other platinum-based combination regimens (Grade 2C). We administer six cycles of chemotherapy (irrespective of whether radiation is also administered). (See 'Choice of systemic therapy regimen' above.)

•For patients receiving immunotherapy, either dostarlimab or pembrolizumab may be used for most histologies, depending on institutional preference or agent availability. However, for those with uterine carcinosarcoma, we offer dostarlimab rather than pembrolizumab, which hasn't been studied in this population. The duration of treatment is three years for dostarlimab or two years for pembrolizumab.

•The addition of trastuzumab in patients with HER2-positive stage III/IV disease is discussed elsewhere. (See "Initial treatment of metastatic endometrial cancer", section on 'HER2-overexpressing serous tumors'.)

●Inclusion of VBT in selected cases — For females who undergo adjuvant chemotherapy, some experts offer VBT to help control local recurrence (eg, for those with cervical involvement or extensive lymphovascular invasion). However, there is variability in practice. (See 'Inclusion of VBT in select cases' above.)

●Post-treatment surveillance – We perform clinical examination (including symptom review, symptom-directed physical examination, and pelvic examination) at three-month intervals for two years, then every six months or annually. While cancer antigen (CA) 125 is used by some clinicians as part of routine surveillance, there is no high-quality evidence that CA 125 surveillance improves outcomes. (See 'Post-treatment surveillance' above.)