Adjuvant treatment of high-risk endometrial cancers

INTRODUCTION — Adenocarcinomas of the endometrium are the most common gynecologic malignancy in developed countries and the second most common in developing countries. 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 staging system is presented in the table (table 1 and table 2). In addition to stage, other pathologic factors are used to assign risk of recurrence into low-, intermediate-, and high-risk categories.

Women 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:

●Serous adenocarcinoma (any stage)

●Clear cell adenocarcinoma (any stage)

●Grade 3 deeply invasive endometrioid carcinoma

•The Cancer Genome Atlas analysis suggests that a subset of grade 3 endometrioid cancers are biologically similar to serous carcinomas, although not all grade 3 lesions are high risk. For example, POLE-mutated cancers may be grade 3, but they appear to have a low risk for recurrence even in the absence of adjuvant therapy. Unfortunately, the POLE-mutated subgroup has not been well-defined using conventional clinicopathologic factors [1]. Some newer protocols include the use of genomic testing in early-stage disease. We include grade 3 deeply invasive endometrioid carcinoma as a high-risk lesion per its classification as such in clinical trials.

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

The evidence to support our definition of high risk is reviewed below.

Uterine serous or clear cell carcinoma — Compared with endometrioid adenocarcinomas, uterine serous and clear cell carcinomas are biologically very different and are more aggressive histologic types [2]. This was demonstrated in a Surveillance, Epidemiology, and End Results study of cases diagnosed from 1998 to 2001 [2]. 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 [3].

Deeply invasive grade 3 endometrioid carcinoma — Outcomes among patients with endometrioid cancers appear to differ based on grade. Specifically, patients with deeply invasive (T1b or greater) grade 3 cancers have a poor prognosis. 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) were assigned to whole-pelvic radiation therapy, which yielded a five-year overall survival of 58 percent [4].

Stage III/IV disease — Compared with women with stage I or II 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 [2] and is seen regardless of histology:

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

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

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

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

Special consideration for high-intermediate-risk disease — Individual experts and cooperative groups may also include women with intermediate-risk endometrial cancer in clinical trials of high-risk, early-stage endometrial cancer. A discussion on the approach to women with high-intermediate-risk endometrial cancer is covered separately. (See "Adjuvant treatment of intermediate-risk endometrial cancer", section on 'High-intermediate-risk disease'.)

TREATMENT APPROACH — For resectable disease, surgery is the mainstay of endometrial cancer therapy. Given the clinical heterogeneity of the disease and the lack of high-quality data to help guide recommendations, there is no uniform approach to the adjuvant treatment of women with high-risk endometrial cancer. For women with surgically and pathologically defined high-risk endometrial cancer, we take into account whether disease is confined to the uterus (stage I/II) or whether disease extends outside of the uterus (stage III or IV) (table 1) as well as other high-risk features (algorithm 1). Too few patients with clear cell endometrial cancer are included in most trials for definitive conclusions about the treatment of this histologic subtype.

Overview

For women with high-risk, early-stage (stage I or II) disease, our approach is as follows:

●Women with clear cell or serous-histology cancers that are stage IA without myometrial invasion may be observed. However, alternatively, adjuvant vaginal brachytherapy (VBT) may be offered, depending on patient and provider preferences. (See 'Noninvasive stage IA disease' below.)

●Women with clear cell or serous-histology cancers that are stage IA with myometrial invasion, stage IB, or stage II; or with grade 3 endometrioid cancers that are stage IB or II and may be treated with pelvic radiation therapy (RT) alone or with chemotherapy, with or without VBT. (See 'Invasive stage IA, IB, or II disease' below.)

For women with locally advanced or advanced disease (stage III or IV), our approach is as follows:

●Women with stage III or IV disease who have undergone resection are treated with adjuvant chemotherapy, often with the addition of VBT for high-risk features for local recurrence. (See 'Stage III disease' below.)

●Women with unresectable stage III or IV disease are treated with chemotherapy. The role of pelvic RT in these women must be individualized based on burden of disease (see "Management of locoregional recurrence of endometrial cancer"). In recent years there has been an increased use of surgery after chemotherapy for disease that is initially unresectable (neoadjuvant chemotherapy). No randomized trials have tested this approach but it appears to be associated with lower toxicity than primary surgery for stage IVb disease [5,6].

Early-stage disease — Patients with early-stage disease may be considered high risk on the basis of serous or clear cell histology or high-grade, deeply invasive endometrioid histology.

Noninvasive stage IA disease — Our approach to patients with high-risk stage IA disease without myometrial invasion is to offer observation or VBT given that in noninvasive serous tumors there can be up to a 10 percent risk of vaginal cuff recurrences.

A review of cases of stage IA 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 overall survival (OS) or PFS [7]. Patients in this study received adjuvant chemotherapy with or without RT (intravaginal or pelvic), RT (intravaginal or pelvic) alone, or no adjuvant treatment.

Invasive stage IA, IB, or II disease — Women with stage IA disease with myometrial invasion, stage IB or II grade 3 endometrioid, or serous carcinoma may be treated with pelvic RT alone or with chemotherapy, with or without VBT. Given similar efficacy but improved tolerability with pelvic RT, some UpToDate contributors prefer pelvic RT. However, others prefer chemotherapy plus VBT, noting that much of the toxicity associated with the latter is asymptomatic hematologic toxicity. If chemotherapy is administered in this setting, we typically administer six, rather than fewer, cycles; other clinicians may administer up to eight cycles.

The Gynecologic Oncology Group (GOG)-249 trial reported that VBT with three cycles of carboplatin/paclitaxel chemotherapy had efficacy similar to pelvic RT, but greater acute toxicity. In this trial, 601 women with high-intermediate-risk or high-risk, early-stage (I and II) endometrial cancer were randomly assigned to VBT followed by three cycles of paclitaxel/carboplatin chemotherapy or to pelvic RT alone (using either three-dimensional conformal RT or intensity-modulated RT) [8,9]. Eligibility criteria are described in the table (table 3). Patients receiving pelvic RT versus those receiving VBT followed by chemotherapy had comparable 36-month recurrence-free survival (RFS, both 82 percent) and 36-month OS (88 versus 91 percent). At a median follow-up of 53 months, the five-year RFS and OS were also 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) [10]. Compared with those treated with pelvic RT, women treated with VBT plus chemotherapy had more nodal recurrences (to the pelvic and/or para-aortic nodes, 9 versus 4 percent at 5 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) [8,9]. Patients receiving pelvic RT, but not VBT and chemotherapy, reported that fatigue recovered to pretreatment levels at 11 weeks [10]. Based on these results, pelvic RT appears to be less toxic and equally effective as three cycles of chemotherapy plus VBT. Whether results of treatment would differ if six cycles were used instead is unanswered. Furthermore, this trial was not powered to analyze outcomes among those with clear cell or serous cell carcinoma separately.

In the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC-3) trial, discussed in further detail below, chemoradiation and pelvic RT were compared among patients with high-risk, stage I disease (grade 3 with deep myometrial invasion and/or lymphovascular invasion); stage II or III disease; as well as tumors with serous or clear cell histology [11]. 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 versus 82 percent; 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 'Stage III disease' below.)

We await the results of the ongoing ENGOT-EN2-DGCG trial, which randomly assigns women with stage I clear cell, serous, or grade 3 tumors with surgically negative nodes to chemotherapy with six cycles of carboplatin/paclitaxel or no prescribed adjuvant therapy. Use of VBT is optional in either arm; no pelvic RT is used.

Stage III disease — For most women with stage III (or resectable stage IV) endometrial cancer, we suggest adjuvant chemotherapy, with or without VBT, rather than whole-pelvic RT. When administering chemotherapy, we typically administer six, rather than fewer, cycles; other clinicians may administer up to eight cycles. For women who undergo adjuvant chemotherapy, we sometimes also offer VBT to help control local recurrence (eg, for those with deep invasion or bulky lymphadenopathy). 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 RT [12] with or without chemotherapy for this histology.

In the PORTEC-3 trial, women 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 women with high-risk, stage I disease (grade 3 with deep myometrial invasion and/or lymphovascular invasion); stage II or III disease; or tumors with serous or clear cell histology [11]. 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. 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) [13]. Survival benefits began to emerge only after about 2.5 to 3 years.

•Benefit was seen particularly 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, stage I/II tumors, differences were slight and not statistically significant. (See 'Invasive stage IA, IB, or II disease' 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) [14]. At five years, reported grade 3 adverse events occurred in 8 percent in the chemoradiation group and 5 percent in the RT group, a difference that was not statistically significant.

However, the use of chemoradiation for treatment of endometrial cancer did not improve survival when compared with chemotherapy in the GOG-258 trial.

●In GOG-258, over 700 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 were randomly assigned to chemoradiation (cisplatin and volume-directed RT followed by carboplatin and paclitaxel for four cycles) versus chemotherapy alone (carboplatin and paclitaxel for six cycles) [15]. 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) or OS between the two groups.

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.

Given the results of these two trials, for most women 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.

Stage IV disease — Women with disease limited to the pelvis or abdominal carcinomatosis may be candidates for surgical cytoreduction and adjuvant chemotherapy based on retrospective series showing superior outcomes with optimal surgical debulking versus suboptimal or no debulking, regardless of histologic subtype [16-19]. The approach for women with resectable stage IV disease is analogous to that for women with stage III disease and is discussed above. (See 'Stage III disease' above.)

However, upfront surgery may be challenging, and chemotherapy (potentially followed by surgery) may instead be appropriate. (See 'Overview' above.)

The management of patients with newly diagnosed, stage IV disease is discussed in further detail elsewhere. (See "Initial treatment of metastatic endometrial cancer", section on 'Overview of treatment'.)

Timing of pelvic radiation with chemotherapy — For those in whom RT is indicated, acceptable approaches include giving RT after completion of six cycles of chemotherapy, "sandwiched" in between three cycles of chemotherapy before and after RT, or concurrently, as in GOG-258 and PORTEC-3. Of these, we typically prefer to administer RT after the completion of all adjuvant chemotherapy, though only limited observational data exist [20]. (See "Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies".)

CHOICE OF CHEMOTHERAPY REGIMEN — For most women with high-risk endometrial cancer receiving chemotherapy, we suggest carboplatin and paclitaxel. This is based on the results of Gynecologic Oncology Group (GOG)-209 [21], which compared carboplatin plus paclitaxel versus doxorubicin and cisplatin followed by paclitaxel in 1300 women with chemotherapy-naïve advanced endometrial cancer, including women 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 'Rationale for multiagent chemotherapy'.)

Women with stage III/IV endometrial cancer, particularly those with serous or grade 3 histologies should have their tumors tested for human epidermal growth factor 2 (HER2), and those with HER2-positive disease should be considered for the addition of adjuvant trastuzumab to chemotherapy. Updated overall survival results from a small randomized phase II trial of the addition of trastuzumab to carboplatin/paclitaxel showed in the patients with stage III/IV disease that median survival was not reached in the trastuzumab arm versus 25.4 months in the control arm (hazard ratio [HR] 0.49, 90% CI 0.25-0.97) [22]. (See "Initial treatment of metastatic endometrial cancer", section on 'HER2-overexpressing serous tumors'.)

SPECIAL CONSIDERATIONS

Older women — Older age has been associated with higher rates of clinical failure, but to what degree age represents an independent prognostic factor is controversial. Women 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 women become older, the risks of chemotherapy are potentially magnified. As such, it becomes less clear if women will live long enough to experience potential survival benefits of treatment to justify the expected risks of chemotherapy. Therefore, we advise older women 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".)

Obese women — Endometrial cancer is associated with obesity, and morbid 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 women 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 [23]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

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 women with high-risk endometrial adenocarcinoma, we do not use endocrine therapy as adjuvant treatment as there have been multiple older negative trials.

PROGNOSIS — Women 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 III/IV 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 stage IB grade 3 endometrioid carcinoma, serous or clear cell adenocarcinoma (any stage), or pathologic stage III/IV disease (table 1). (See 'Definition of high risk' above.)

●Adjuvant treatment – The adjuvant treatment approach depends on stage as well as the presence or absence of other features (algorithm 1). (See 'Overview' above.)

•For women with clear cell or serous-histology cancers that are stage IA without myometrial invasion, we suggest either adjuvant vaginal brachytherapy (VBT) or observation rather than more aggressive approaches such as pelvic radiation therapy (RT) or chemotherapy (Grade 2C). A choice between VBT and observation depends on patient and provider preferences. (See 'Early-stage disease' above.)

•Women with clear cell or serous-histology cancers that are stage IA with myometrial invasion, stage IB, or stage II; or with grade 3 endometrioid cancers that are stage IB or II and may be treated with pelvic RT alone or with chemotherapy, with or without VBT. (See 'Invasive stage IA, IB, or II disease' above.)

•For most women with stage III or resectable stage IV endometrial cancer, we suggest adjuvant chemotherapy, with or without VBT, 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 'Stage III disease' above.)

•Management of unresectable disease is discussed elsewhere. (See "Initial treatment of metastatic endometrial cancer".)

•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 chemotherapy regimen' above.)

•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'.)

●Older patients – Because organ function declines and the number of comorbidities increases as women become older, we advise older women 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".)

●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.)