Initial treatment of metastatic endometrial cancer

INTRODUCTION — Adenocarcinomas of the endometrium are the most common gynecologic malignancy in developed countries and the second most common in resource-limited countries. While the majority of patients present with localized disease and have an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary tumor. For those in whom endometrial cancer (EC) recurs or progresses to distant sites, the goals of treatment are palliative rather than curative.

This topic will review the approach and treatment options for patients with metastatic EC. Early involvement of palliative care is also appropriate.

The treatment of early and locally advanced cancers, locoregional recurrence, and later-line systemic therapy for metastatic disease are discussed separately. In addition, chemotherapy protocols used in the treatment of EC are available separately.

●(See "Overview of resectable endometrial carcinoma", section on 'Role of adjuvant therapy'.)

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

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

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

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

●(See "Subsequent line systemic therapy for metastatic endometrial cancer".)

●(See "Treatment protocols for gynecologic malignancies".)

CLINICAL PRESENTATION AND EVALUATION

●Clinical presentation – The clinical presentation for metastatic EC is variable. Most patients with metastatic disease will have previously been treated for a localized primary EC, and subsequently develop a distant area of relapse or progression. A small subset will present with de novo metastatic disease.

Signs and symptoms of metastatic disease are relatively nonspecific. If locoregional disease is also present, they may include bleeding (which emanates from the vagina, bladder, or rectum), abdominal pain, pelvic pain, and lower abdominal or extremity swelling, but could also involve anorexia, weight loss, shortness of breath, cough, chest pain, or bone pain [1].

●Evaluation – For patients with suspected metastatic disease, whole-body imaging of the chest, abdomen, and pelvis is necessary for staging. Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scan, or a combined PET-CT scan are appropriate options. If cancer antigen (CA) 125 was elevated at the time of initial presentation, it is also reasonable to remeasure CA 125, though the level of CA 125 alone should not influence treatment decisions.

Additionally, pathologic confirmation of the diagnosis with a biopsy is typically performed to provide confirmation of the diagnosis. Of note, tissue obtained at this time may also be sent for genomic analysis that might lend insight into molecular features of the tumor that inform prognosis and treatment decisions.

We perform the following assessments on a biopsy specimen when metastatic disease is suspected:

•Assessment of histologic subtype – Although histologic subtype does not predict response to chemotherapy, this provides prognostic insights, as serous and clear cell histologies are associated with worsened overall survival [2].

•Receptor testing for estrogen and progesterone, which is particularly important for endometrioid histologies.

•Human epidermal growth factor receptor 2 testing by immunohistochemistry (IHC) for serous histology, with reflex testing for fluorescence in situ hybridization in IHC 2+ results.

•IHC for mismatch repair proteins or microsatellite instability testing.

•Somatic mutation testing using next-generation sequencing panels is also frequently performed in order to determine eligibility for immunotherapy, targeted therapies, and trial enrollment. It is important to evaluate the mismatch repair or microsatellite instability status in all patients using the primary tumor obtained during endometrial biopsy or on the final pathology, or biopsy of tissue obtained in evaluation of metastatic disease.

OVERVIEW OF TREATMENT

Newly diagnosed endometrial cancer that is metastatic — For patients with newly diagnosed, metastatic EC, we typically suggest surgical cytoreduction, followed by systemic treatment. We use the same criteria in EC as in ovarian cancer for deciding on upfront cytoreduction versus chemotherapy, taking into account the ability to optimally cytoreduce the disease and the performance status of the patient. Unfortunately, high-quality data are lacking for cytoreduction for EC. (See 'Surgical cytoreduction' below.)

●Surgical candidates – For patients who undergo surgical cytoreduction of metastatic disease, we suggest adjuvant chemotherapy, with or without immunotherapy, rather than observation alone. The administration of postoperative therapy in this setting is extrapolated from the benefits of treatment for patients with newly diagnosed high-risk EC. Based on the results of the GOG 209 trial, our preferred chemotherapy regimen is carboplatin and paclitaxel. The results of this study are discussed below. Incorporation of immunotherapy for select patients is also discussed below. (See 'Rationale for multiagent chemotherapy' below and 'MMR deficient or MSI-H tumors' below.)

●Nonsurgical candidates – Patients who are not surgical candidates should be offered medical therapy (chemotherapy, with or without immunotherapy), provided that they are candidates for treatment. Selection of therapy is the same as for patients who are surgical candidates. (See 'Initial therapy' below.)

Such patients have a poor prognosis; the reported five-year relative survival for patients presenting with distant disease (which encompasses stage IVB disease) is less than 20 percent [3]. However, in cases with a good response to treatment such that a complete cytoreduction becomes feasible, surgery may then be pursued [4].

Metastatic recurrence — For patients who develop metastatic EC after having been treated for localized disease, our approach is as follows:

●We typically suggest systemic therapy alone, typically with a platinum-based combination, with or without immunotherapy, rather than cytoreduction followed by systemic therapy. However, carefully selected patients with metastatic progression or recurrence may be candidates for cytoreduction (ie, those with good performance status, platinum-free interval ≥1 year, and expectation of complete cytoreduction).

●Systemic treatment selection is guided by prior treatment history.

•Initial therapy is used for patients with de novo metastatic disease and those who have recurred or progressed at least six months after completion of initial treatment (first recurrence).

•Subsequent line therapy is used for others and is discussed elsewhere. (See "Subsequent line systemic therapy for metastatic endometrial cancer".)

SURGICAL CYTOREDUCTION — As discussed above, surgical cytoreduction is appropriate in select patients with metastatic disease. (See 'Overview of treatment' above.)

The approach to primary cytoreduction of EC is identical to that for patients with advanced ovarian cancer. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction".)

Cytoreduction appears to confer a survival advantage to patients with pelvic or intra-abdominal spread of EC, but high-quality data are lacking, and management is often extrapolated from the literature on cytoreduction for ovarian cancer. However, survival in this disease is inferior to patients who undergo cytoreduction for ovarian cancer [5].

In a meta-analysis of retrospective cohort studies including over 3600 patients with advanced-stage EC undergoing primary cytoreductive surgery, maximal cytoreduction (ie, no gross residual disease) was achieved in 52 percent of patients and optimal cytoreduction to <1 cm of residual disease was achieved in 75 percent [6]. Higher-stage disease was associated with lower rates of both maximal and optimal cytoreduction. Presence of any gross residual disease was associated with worse overall survival (hazard ratio [HR] 2.57, 95% CI 2.13-3.1), as was suboptimal cytoreduction (HR 2.62, 95% CI 2.2-3.11).

An association of OS with surgical cytoreduction was also noted in a large retrospective study not included in the above meta-analysis; among 3197 patients with newly diagnosed EC, surgical cytoreduction plus chemotherapy compared with chemotherapy alone was associated with improved survival (20 versus 11 months [median]; HR 0.59, 95% CI 0.53-0.65) during the 13.4-month (median) follow-up period [7].

INITIAL THERAPY — Initial therapy is used for patients with de novo metastatic disease and those who have recurred or progressed at least six months after completion of treatment (algorithm 1).

MMR proficient tumors — For mismatch repair proficient (pMMR) tumors, we suggest multiagent chemotherapy. Although the addition of immunotherapy to chemotherapy followed by immunotherapy maintenance has improved progression-free survival (PFS) for such patients in randomized trials [8,9], an overall survival (OS) benefit has not been demonstrated in this subset. We await regulatory approval prior to use in this patient population.

Given the greater magnitude of benefit in patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, we have incorporated immunotherapy into initial treatment paradigms in this subset, as discussed below. (See 'MMR deficient or MSI-H tumors' below.)

Rationale for multiagent chemotherapy — Patients with metastatic EC are treated with systemic therapy, either following surgical cytoreduction or as primary therapy. The benefit of multiagent chemotherapy for advanced, recurrent, or metastatic EC was shown in a 2012 meta-analysis of trials that compared administration of multiagent combinations ("more intensive" regimens) with less intensive combinations [10], and found improvements in OS with more intensive regimens (on the order of one to two months), although nausea and diarrhea were more frequent.

Choice of regimen — The two most commonly used regimens to treat metastatic EC are carboplatin plus paclitaxel or the triple-drug combination of cisplatin, doxorubicin, plus paclitaxel (TAP) [11,12]. Of these, we prefer carboplatin and paclitaxel (typically continued for six cycles, unless there is progression or unacceptable toxicity) because it has similar activity to TAP but is associated with less toxicity [11]. For those with human epidermal growth factor receptor 2 (HER2)-overexpressing, serous papillary tumors, we suggest the addition of trastuzumab to initial chemotherapy, with continuation until progression. (See 'HER2-overexpressing serous tumors' below.)

The data to support carboplatin plus paclitaxel come from GOG 209 [13]. In GOG 209 (a phase III randomized trial with a statistical design aimed to demonstrate noninferiority of the experimental chemotherapy regimen over the standard regimen), 1300 patients with chemotherapy-naïve stage III, IV, or recurrent EC were randomly assigned to treatment with carboplatin plus paclitaxel or TAP. Each regimen was administered every three weeks for seven cycles. Carboplatin plus paclitaxel resulted in [13]:

●Similar PFS (median, 13 versus 14 months, hazard ratio [HR] 1.0, 90% CI 0.9-1.2).

●Similar OS (median, 37 versus 41 months, HR 1.0, 90% CI 0.9 to 1.1).

●A reduction in the incidence of grade 2 or greater toxicity, including sensory neuropathy (20 versus 26 percent), thrombocytopenia (12 versus 23 percent), emesis (4 versus 7 percent), diarrhea (2 versus 6 percent), and metabolic derangements (8 versus 14 percent).

MMR deficient or MSI-H tumors — For patients with dMMR tumors, we suggest the addition of immunotherapy to chemotherapy, followed by immunotherapy maintenance. Choice of chemotherapy is the same as for pMMR tumors. (See 'Choice of regimen' above.)

Addition of dostarlimab or pembrolizumab to chemotherapy — The incorporation of dostarlimab or pembrolizumab for patients with advanced or recurrent EC has shown benefit, particularly among those with dMMR or microsatellite instability-high (MSI-H) tumors. Dostarlimab improves both PFS and OS, and has regulatory approval in the United States in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab for advanced or recurrent endometrial cancer that is dMMR or MSI-H [14]. Pembrolizumab has only shown PFS benefits thus far; nevertheless, in the absence of head-to-head comparisons, we consider either to be an appropriate option in combination with chemotherapy, followed by maintenance immunotherapy as initial treatment of dMMR metastatic EC. Dostarlimab is continued until progression or unacceptable toxicity for up to three years, while pembrolizumab is continued for two years in total (unless there is progression or poor tolerance).

We await further data or regulatory approval prior to use in pMMR tumors. (See 'MMR proficient tumors' above.)

●Dostarlimab – A double-blind trial assigned 484 patients with primary advanced stage III or IV or first recurrent EC to dostarlimab or placebo, in combination with carboplatin and paclitaxel, followed by dostarlimab or placebo for up to three years [8]. Neoadjuvant/adjuvant systemic therapy was permitted, as long as six months had elapsed since the completion of treatment.

•In the overall group, 24-month PFS was 36 versus 18 percent with dostarlimab versus placebo (HR 0.64, 95% CI 0.51-0.80). OS was 71 percent versus 56 percent, respectively (HR 0.64, 95% CI 0.46-0.87).

•Among the 118 patients with dMMR, MSI-H tumors, 24-month PFS was 61 percent with dostarlimab versus 16 percent with placebo (HR 0.28, 95% CI, 0.16-0.50). OS at 24 months was 83 percent in the dostarlimab group and 59 percent in the placebo group (HR 0.30, 95% CI 0.13-0.70).

•Grade ≥3 adverse events were more frequent in the dostarlimab group versus the placebo group (71 versus 60 percent).

●Pembrolizumab – A double-blind trial assigned 816 patients with stage III to IVB or recurrent EC to pembrolizumab or placebo, in combination with paclitaxel and carboplatin, followed by pembrolizumab or placebo for up to 14 maintenance cycles every six weeks [9]. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months.

•Overall, median PFS was 18.8 versus 8.5 months with pembrolizumab versus placebo, respectively.

•In the dMMR cohort, median PFS was not reached with pembrolizumab versus 7.6 months with placebo, 12-month PFS was 74 versus 38 percent, respectively (HR 0.30, 95% CI 0.19-0.48).

•Grade ≥3 adverse events occurred in approximately 57 percent in the pembrolizumab group and 46 percent in the placebo group.

HER2-overexpressing serous tumors

Addition of trastuzumab to chemotherapy — For those with metastatic, serous EC overexpressing human epidermal growth factor receptor 2 (HER2), we recommend the addition of trastuzumab to front-line chemotherapy, with continuation as maintenance until progression.

In a randomized phase II trial, patients with primary stage III or IV or recurrent, HER2-positive uterine papillary serous cancer were randomly assigned to carboplatin/paclitaxel (control arm) for six cycles, without or with intravenous trastuzumab (experimental arm), until progression or unacceptable toxicity [15]. The primary endpoint was PFS. Sixty-one patients were randomly assigned. Median PFS was 8 (control) versus 12.9 months (experimental; HR 0.46, 90% CI 0.28-0.76). OS was 24.4 months in the control group and 29.6 months in the trastuzumab group (HR 0.58, 90% CI 0.34-0.99). Similarly, among 41 patients with stage III or IV disease undergoing primary treatment, median PFS was 9.3 (control) versus 17.7 months (experimental; HR 0.44, 90% CI 0.23-0.83), and OS was 24.4 months versus not reached, respectively (HR 0.49, 90% CI 0.25-0.97). Among 17 patients with recurrent disease, median PFS was 7 (control) versus 9.2 months (experimental), respectively (HR 0.12, 90% CI 0.03-0.48). Toxicity was not different between treatment arms.

Alternative chemotherapy regimens — Use of endocrine therapy as an alternative to chemotherapy is discussed in detail elsewhere. (See "Subsequent line systemic therapy for metastatic endometrial cancer".)

However, other chemotherapy options are also available. The three-drug regimen TAP has shown benefit over cisplatin and paclitaxel and is an appropriate alternative to platinum-taxane treatment, but, due to increased toxicity, is less preferred and rarely used. (See 'Choice of regimen' above.)

GOG 177 demonstrated the benefit of TAP, which enrolled 273 patients with previously untreated stage III/IV or recurrent EC and randomly assigned them to treatment with cisplatin plus doxorubicin (AP; cisplatin [50 mg/m²] plus doxorubicin [60 mg/m²] administered on day 1 every three weeks) or TAP (doxorubicin [45 mg/m² on day 1], cisplatin [50 mg/m² on day 1], plus paclitaxel [160 mg/m² over three hours on day 2] every three weeks) [16]. Of note, patients assigned to TAP received prophylactic growth-factor support using filgrastim. Compared with AP, TAP resulted in:

●An improvement in objective response rate (57 versus 34 percent).

●An improvement in PFS (median, 8 versus 5 months).

●An improvement in OS (median, 15 versus 12 months).

However, TAP also resulted in an increased incidence of serious (grade 3) neuropathy (12 versus 1 percent).

The addition of bevacizumab versus temsirolimus to chemotherapy has also been investigated for treatment-naïve metastatic EC, with evidence that p53 mutation status may help choose between these options [17]. Although both combinations performed similarly in the overall trial population, immunohistochemistry for p53 overexpression alone or when integrated with sequencing for TP53 identified a group that experienced a PFS and OS benefit with incorporation of bevacizumab over temsirolimus [18]. However, this is not yet standard practice.

MONITORING ON TREATMENT — For patients receiving systemic treatment for metastatic disease, we typically perform CT of the chest, abdomen, and pelvis every two to three cycles, or more frequently in the setting of new or concerning symptoms. As in the adjuvant setting, the data do not support the routine monitoring of serum cancer antigen (CA) 125 for patients with recurrent or metastatic EC. However, in patients whose disease was marked by an elevated CA 125, it may be reasonable to use this as a marker of disease activity alongside imaging and/or clinical examination. (See "Overview of approach to endometrial cancer survivors", section on 'Follow-up post-treatment'.)

In our practice, some criteria that we use to define disease progression include any of the following:

●Clinical deterioration during treatment (ie, increasing disease-related symptoms, declining performance status).

●Evolution of new metastases.

●Increasing size of previously documented metastatic lesions.

In clinical trials, the Response Evaluation Criteria in Solid Tumors 1.1 criteria are used to define the parameters for response and disease progression (table 1) [19].

SPECIAL POPULATIONS

Older patients — Age is used to stratify patients with either high- versus low- intermediate-risk EC. (See "Adjuvant treatment of high-risk endometrial cancers", section on 'Special consideration for high-intermediate-risk disease'.)

Older age (eg, >65 years) has been associated with higher rates of clinical relapse and decreased survival. The decision to use chemotherapy in such patients is complicated due to an increased number of comorbidities. Prior to making a decision regarding therapy, we suggest a comprehensive geriatric assessment in order to help guide discussions on primary and adjuvant treatment. This topic is addressed in more detail separately. (See "Comprehensive geriatric assessment for patients with cancer".)

Patients with obesity — Although clinical practice varies, we prefer to dose chemotherapy based on actual rather than ideal body weight. This is consistent with guidelines published by the American Society of Clinical Oncology [20]. One exception to this is the dosing of carboplatin, where we continue to use fixed dosing based on area under the curve because it reduces the risk of neurotoxicity compared with weight-based dosing. However, since patients with recurrent or metastatic disease are not able to be cured, the balance of efficacy and toxicity must always be considered. (See "Dosing of anticancer agents in adults".)

Patients with cardiac risk factors — The development of chemotherapy-related cardiotoxicity is associated with cumulative doses of doxorubicin greater than 550 mg/m². Older age, prior history of cardiac disease, and chest wall radiation therapy are also risk factors for treatment-related cardiotoxicity. For patients with cardiac risk factors who are candidates for adjuvant treatment, we recommend carboplatin plus paclitaxel rather than a doxorubicin-containing regimen. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

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

●Goals of care – For those in whom endometrial cancer (EC) recurs or progresses to distant sites, the goals of treatment are palliative rather than curative. (See 'Introduction' above.)

●Indications for surgical cytoreduction

•For patients with newly diagnosed, metastatic EC, we typically suggest surgical cytoreduction followed by systemic therapy rather than either modality on its own (Grade 2C).

•By contrast, for patients who develop metastatic EC after having been treated for localized disease, we typically suggest systemic therapy alone rather than cytoreduction followed by systemic therapy (Grade 2C). However, carefully selected patients with metastatic progression or recurrence may be candidates for cytoreduction (ie, those with good performance status, platinum-free interval ≥1 year, and expectation of complete cytoreduction). (See 'Overview of treatment' above and 'Surgical cytoreduction' above.)

●Systemic therapy

•A suggested approach to treatment is presented in the algorithm (algorithm 1).

•For chemotherapy-naϊve patients with metastatic EC (irrespective of whether they had cytoreduction or not), or for those who relapse at least six months after last treatment, we suggest carboplatin and paclitaxel rather than endocrine therapy or another chemotherapy regimen (Grade 2C). (See 'Rationale for multiagent chemotherapy' above.)

•For patients with human epidermal growth factor receptor 2-positive serous papillary tumors, we recommend the addition of trastuzumab (Grade 1B). (See 'HER2-overexpressing serous tumors' above.)

•For other cancers, if there is mismatch repair deficiency, we suggest the addition of either dostarlimab or pembrolizumab to chemotherapy (Grade 2B), and continue after chemotherapy for two years (pembrolizumab) or three years (dostarlimab). Although only dostarlimab has shown overall survival benefits, both have shown progression-free survival benefits, and we consider either agent appropriate in the absence of direct comparisons. (See 'MMR deficient or MSI-H tumors' above.)

•Endocrine therapy is a reasonable alternative to combination chemotherapy for select patients with minimal cancer-related symptoms whose cancers are grade 1 or 2 EC and positive for estrogen and progesterone receptors.