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Treatment of metastatic endometrial cancer

Treatment of metastatic endometrial cancer
Authors:
Susana M Campos, MD
David E Cohn, MD, MBA
Section Editors:
Barbara Goff, MD
Don S Dizon, MD, FACP
Deputy Editors:
Sadhna R Vora, MD
Alana Chakrabarti, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 19, 2022.

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. 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 women with metastatic EC. Early involvement of palliative care is also appropriate.

The initial treatment of low-risk, intermediate-risk, and high-risk ECs (which includes women who present with locally advanced disease); the approach to locoregional recurrence; and uterine carcinosarcoma are covered separately. In addition, chemotherapy protocols used in the treatment of EC are available separately.

(See "Overview of endometrial carcinoma", section on '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 "Treatment protocols for gynecologic malignancies".)

(See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)

CLINICAL PRESENTATION AND EVALUATION

Clinical presentation – The clinical presentation for metastatic EC is variable. Most women 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.

OVERVIEW OF TREATMENT

Newly diagnosed endometrial cancer that is metastatic — For women 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 women who undergo surgical cytoreduction of metastatic disease, we suggest adjuvant chemotherapy rather than observation alone. The administration of postoperative chemotherapy in this setting is extrapolated from the benefits of treatment for women with newly diagnosed high-risk EC. Based on the results of the GOG 209 trial, our preferred regimen is carboplatin and paclitaxel, continued until progression or unacceptable toxicity. The results of this study are discussed below. (See 'Carboplatin plus paclitaxel' below.)

Nonsurgical candidates – Patients who are not surgical candidates should be offered medical therapy, provided that they are candidates for treatment. Such patients have a poor prognosis; the reported five-year relative survival for women 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]. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer", section on 'Patient selection'.)

Metastatic recurrence — For women 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, rather than cytoreduction followed by systemic therapy. Treatment selection is as described below, according to prior treatment history. (See 'Chemotherapy-naive patients' below and 'Patients who have had prior chemotherapy' below.)

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).

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 women with advanced ovarian cancer. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction".)

Cytoreduction appears to confer a survival advantage to women 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 women 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].

CHEMOTHERAPY-NAIVE PATIENTS

Benefits of 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 (eg, three- versus two-agent combinations, or two agents versus one agent) [8]. Major findings include:

Compared with the administration of "less intensive" regimens, the use of "more intensive" regimens (eight trials, n = 1519) resulted in an improvement in progression-free survival (PFS; from six months with less intensive regimens, to seven months with more intensive ones; hazard ratio [HR] 0.82, 95% CI 0.74-0.90) and OS (from 9 to 10.5 months, respectively; HR 0.86, 95% CI 0.77-0.96). Trials that compared doxorubicin with or without additional drugs favored the arms incorporating additional chemotherapy.

The administration of "more intensive" chemotherapy also increased the risk of serious nausea and vomiting (odds ratio [OR] 2.64, 95% CI 1.71-4.09) and diarrhea (OR 2.25, 95% CI 1.09-4.63).

Although the data from this meta-analysis support the use of multiagent chemotherapy, they did not include the results from GOG 209, which compared a cisplatin-based triplet regimen with carboplatin plus paclitaxel. These data are discussed below. (See 'Carboplatin plus paclitaxel' below.)

Carboplatin plus paclitaxel — 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) [9,10]. Of these, we prefer carboplatin and paclitaxel (typically continued until progression or unacceptable toxicity) because it has similar activity to TAP but is associated with less toxicity [9].

For those with human epidermal growth factor receptor 2-overexpressing, serous papillary tumors, we suggest the addition of trastuzumab to initial chemotherapy. (See 'HER2-overexpressing tumors' below.)

The data to support carboplatin plus paclitaxel come from GOG 209 [9], which was not included in the 2012 meta-analysis discussed above.

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 women 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. Based on the presentation of results from GOG 209 during the 2012 Society of Gynecologic Oncology Annual Meeting, carboplatin plus paclitaxel resulted in:

Similar overall response rate (ORR) compared with TAP (51 percent in each arm).

Similar PFS (median, 13 months in each arm; HR for recurrence, 1.05).

Similar OS (median, 37 versus 40 months).

A statistically significant reduction in the incidence of grade 2 or greater toxicity, including sensory neuropathy (19 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).

Alternatives — Use of endocrine therapy as an alternative to chemotherapy is discussed in detail below. (See 'Endocrine therapy' below.)

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. (See 'Carboplatin plus paclitaxel' above.)

GOG 177 demonstrated the benefit of TAP, which enrolled 273 women 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) [11]. Of note, patients assigned to TAP received prophylactic growth-factor support using filgrastim. Compared with AP, TAP resulted in:

An improvement in ORR (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 endometrial cancer, with evidence that p53 mutation status may help choose between these options [12]. 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 progression-free and overall survival benefit with incorporation of bevacizumab over temsirolimus [13].

Monitoring on treatment — For patients receiving systemic treatment for metastatic disease, we typically perform computed tomography 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 women 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) [14].

PATIENTS WHO HAVE HAD PRIOR CHEMOTHERAPY — Given the recognition that recurrent or metastatic EC can be treated with immunotherapy, it is important to evaluate the mismatch repair (MMR) status in all patients using the primary tumor or tissue obtained at the time of metastatic disease. MMR status is important in assigning the optimal subsequent-line therapy after progression on chemotherapy in this population. Regardless, given the poor prognosis, all patients should be offered participation on a clinical trial, as well as a referral for palliative care services. (See "Benefits, services, and models of subspecialty palliative care".)

Tumors that are dMMR, MSI-H, or have high TMB

Immune checkpoint inhibitors — After progression on platinum-based chemotherapy, for women with tumor mutational burden (TMB; ≥10 mutations/megabase), we suggest the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab. For those with mismatch repair-deficient (dMMR) EC who have progressed on platinum-based chemotherapy, either pembrolizumab or dostarlimab (another anti-PD-1 antibody) are appropriate options [15,16]. Tumor dMMR may be determined by absent immunohistochemical staining for one or more MMR proteins, or polymerase chain reaction or next-generation sequencing demonstrating high levels of microsatellite instability (MSI-H). In the absence of direct comparisons, a choice between pembrolizumab and dostarlimab for such tumors should be based on factors such as availability and cost. We typically continue treatment until progression or unacceptable toxicity. In patients who have progressed on one of these agents, we do not initiate the other checkpoint inhibitor, as there are no data supporting such an approach.

For patients who are not candidates for immune checkpoint inhibitors, endocrine therapy is an alternative option (see 'Endocrine therapy' below). Side-effect profile should also be taken into account when choosing between these options. Immunotherapy is typically tolerated but is associated with toxicities including dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Supporting data according to biomarker

High TMB – In a study including 15 patients with EC with TMB ≥10 mutations/megabase, pembrolizumab was associated with a response rate of 47 percent [17]. These data are discussed elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

dMMR/MSI-H – In a phase II study of pembrolizumab including nine patients with progressive noncolorectal dMMR metastatic carcinomas, these patients experienced an immune-related objective response rate (ORR) of 71 percent and a 20-week immune-related progression-free survival (PFS) rate of 67 percent [18]. In a separate phase II trial including 79 patients with MSI-H/dMMR, treatment-refractory EC, the ORR was 48 percent, and median PFS was 13 months [19].

Separately, in a single-arm study including 71 patients with advanced dMMR EC, the ORR to dostarlimab was 42 percent, with 13 percent experiencing a complete response [20]. Anemia (3 percent), colitis (2 percent), and diarrhea (2 percent) were the most common grade 3 or higher treatment-related adverse events.

Further attempts are being made at identifying an appropriate biomarker for patient selection. In the phase IB KEYNOTE-028 study, among 24 patients with locally advanced or metastatic, pretreated EC with at least 1 percent of tumor cells staining for programmed cell death ligand 1, 13 percent achieved a partial response and 13 percent had stable disease, with a median duration of 25 weeks [21]. Grade 3 treatment-related toxicities occurred in 17 percent.

Other tumors — For patients whose tumors do not display dMMR or MSI and who have experienced progression despite prior chemotherapy, the choice of second-line therapy depends on the treatment-free interval.

Patients with a long platinum-free interval

Chemotherapy — For patients who have relapsed with a treatment-free interval following carboplatin and paclitaxel of ≥6 months, we typically suggest retreatment with carboplatin/paclitaxel. Here also, endocrine therapy represents an acceptable alternative for select patients. (See 'Endocrine therapy' below.)

Although we have chosen an interval of six months as a cutoff, extrapolating from the definition of platinum sensitivity in ovarian cancer, high-quality data regarding platinum sensitivity are lacking in EC. In reality, sensitivity is expected to be a continuum, and six months should not be considered an absolute condition for treatment decisions; other factors including patient preferences and tolerance of prior treatments should also be weighed.

Although there are no prospective data that a platinum-based combination improves outcomes compared with single-agent therapy in this context, the use of a platinum-based combination in second-line treatment in this population is extrapolated from the treatment of platinum-sensitive, recurrent ovarian cancer. Alternatively, pembrolizumab/lenvatinib, endocrine therapy, or single-agent chemotherapy are appropriate alternatives. (See 'Endocrine therapy' below.)

While responses are observed with single-agent chemotherapy, these are often short lived, and median overall survival (OS) across studies is typically less than one year. As a third option, endocrine therapy can be administered for those who prefer to avoid toxicities of pembrolizumab/lenvatinib and chemotherapy. (See 'Endocrine therapy' below.)

Patients with a short platinum-free interval — For patients who have relapsed with a treatment-free interval following carboplatin and paclitaxel of <6 months, we typically suggest pembrolizumab and lenvatinib rather than further chemotherapy. However, as discussed above, the cutoff of six months is somewhat arbitrary and should not be used as an absolute condition for treatment decisions. Alternatively, endocrine therapy or single-agent chemotherapy are appropriate alternatives in select patients. (See 'Alternatives or later-line options' below.)

Pembrolizumab plus lenvatinib — The combination of pembrolizumab plus the vascular endothelial growth factor (VEGF) receptor inhibitor lenvatinib is FDA approved for advanced EC that is not MSI-H or dMMR, is progressive on prior systemic therapy, and is not amenable to curative surgery or radiation [22].

A randomized trial evaluating pembrolizumab and lenvatinib versus treatment of physician's choice (TPC, between doxorubicin and paclitaxel) was conducted in 827 patients with advanced EC progressive on prior platinum-based chemotherapy (697 of whom had proficient MMR tumors and 130 of whom had dMMR tumors) [23].

Overall, pembrolizumab and lenvatinib resulted in statistically significant improvements in median PFS over TPC (7.2 versus 3.8 months; hazard ratio [HR] 0.56) as well as OS (18.3 versus 11.4 months; HR 0.62, respectively). ORR was also higher (32 versus 15 percent).

Among the subset of patients with proficient MMR tumors, pembrolizumab and lenvatinib resulted in similar improvements in PFS (median PFS, 6.6 versus 3.8 months; HR 0.60), OS (median OS, 17.4 versus 12.0 months; HR 0.68), and ORR (30 versus 15 percent) relative to TPC.

Grade ≥3 treatment-related adverse events occurred in 89 percent receiving pembrolizumab and lenvatinib and 73 percent receiving TPC, with the most common being hypertension (64 percent), hypothyroidism (57 percent), diarrhea (54 percent), and nausea (50 percent).

Similar results were observed in a prior single-arm open-label trial including 94 patients with metastatic, pretreated EC that was neither MSI-H, nor dMMR, in which the ORR to pembrolizumab with lenvatinib was 36 percent, with a complete response rate of 2 percent [24,25]. For those responding, the probability of having a response duration ≥6 months was 85 percent. Fatal adverse reactions occurred in four patients, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage, and intracranial hemorrhage.

ALTERNATIVES OR LATER-LINE OPTIONS

Endocrine therapy — For patients with estrogen receptor (ER)-positive cancers, endocrine therapy represents an acceptable alternative to first- or second-line therapy, particularly for those who wish to avoid the toxicities associated with other treatments, or for those with minimally symptomatic or more indolent disease. It may also be used in ER-positive cancers as a later-line option, for those who have progressed on chemotherapy- or immunotherapy-based options. It is typically continued until progression or unacceptable toxicity. Endocrine therapy is well tolerated and lacks the usual toxicities associated with cytotoxic chemotherapy. Approximately 15 to 30 percent of women respond to endocrine therapy, with responses most frequent in low-grade tumors [26]. While most remissions are partial and relatively brief in duration, some patients may remain progression free for extended periods of time (>2 years) [27].

Preference for megestrol acetate alternating with tamoxifen – If endocrine therapy is administered, we typically use megestrol acetate alternating in sequence with tamoxifen. The benefit of sequential therapy was demonstrated in a phase II study conducted by the GOG that enrolled 56 women assigned to treatment with megestrol acetate (160 mg orally daily for three weeks), alternating with tamoxifen (40 mg daily for three weeks) [28]. Treatment resulted in an ORR of 27 percent, with a median PFS of 2.7 months and median OS of 14 months [28]. Interestingly, the response rate among women with grade 3 tumors was 22 percent, presumably due to tamoxifen induction of progesterone receptors.

Alternative endocrine regimens – In light of the limited evidence to support the use of sequential megestrol acetate plus tamoxifen, other options for endocrine treatment are available. These include:

Single-agent progestins – Progesterone was first shown to be an effective anticancer agent for women with advanced disease in 1951, and contemporary trials report an ORR between 15 and 20 percent [29-35]. There is no evidence of a dose-response relationship with progestins. This was shown in a 2010 meta-analysis where medroxyprogesterone acetate at 1000 mg/day was associated with a higher risk of disease progression (HR 1.35, 95% CI 1.07-1.71) and death (HR 1.31, 95% CI 1.04-1.66) compared with a lower dose (200 mg/day).

Single-agent tamoxifen – Tamoxifen is the only selective ER modulator that has demonstrated activity in this population. When used for women with hormone receptor-positive tumors, response rates ranging from 10 to 46 percent have been reported [36-40].

The aromatase inhibitors appear to have little activity in EC. Both letrozole and anastrozole were tested in phase II clinical trials of women with advanced, recurrent, or persistent EC and had response rates of less than 10 percent [41,42], although evidence suggests that women may have a response rate as high as 32 percent when combined with the mechanistic target of rapamycin (mTOR) inhibitor everolimus [43]. In addition, limited data suggest that hormone-receptor expression does not appear to predict treatment outcomes from these agents. This was demonstrated in a trial of letrozole conducted by the National Cancer Institute of Canada [41]. Among 22 patients with available tissue, the majority were positive for progesterone receptor (86 percent) and ER (86 percent), but the ORR was only 9 percent.

Single-agent chemotherapy — There are limited data to inform the benefits of subsequent treatment for women who progress despite two prior regimens. However, women who relapse following first- and/or second-line chemotherapy have a poor prognosis. The median OS in clinical trials after first- or second-line agents is generally 12 months or less. We individualize our approach and take into account the patient's clinical status, including her ability to tolerate subsequent treatment; any prior toxicity experienced or persisting; her individual goals of treatment; and prior therapies. Given the poor prognosis of these women, palliative care should be offered regardless of whether subsequent treatment is administered. For women who desire further treatment, the choice of agents is similar to those listed above. However, for women who maintain a good performance status, we encourage participation in clinical trials.

Doxorubicin – There are no published, prospective data to inform the benefit of doxorubicin (60 mg/m2 every three weeks) as a later-line therapy. However, we extrapolate its administration in this setting given its activity when given as a first-line treatment, where it produces an ORR ranging from 19 to 37 percent [44]. In addition to treatment every three weeks, weekly doxorubicin (20 mg fixed dose) is sometimes administered based on low-quality data in the treatment of advanced breast cancer showing it resulted in an ORR of 19 percent and lacked serious side effects [45].

PaclitaxelPaclitaxel (175 mg/m2 every three weeks) is an option in the subsequent-line setting, particularly in patients who were not previously treated with this agent. In one study, paclitaxel resulted in a 25 percent ORR among 48 paclitaxel-naϊve patients [46]. However, weekly administration (80 mg/m2) is also a reasonable option, particularly in patients who were previously treated with paclitaxel. This is based on data showing activity with weekly treatment in women with platinum- and paclitaxel-resistant ovarian cancer [47].

Pegylated liposomal doxorubicinPegylated liposomal doxorubicin has limited activity in this setting, but is a well-tolerated agent in this population. In one study involving 46 patients treated at a dose of 50 mg/m2 on a four-week schedule, the ORR was 9.5 percent [48]. However, it was generally well tolerated with limited myelotoxicity. The only grade 4 toxicities reported were esophagitis, hematuria, and vomiting, which occurred in one patient each. For women with recurrent EC, a dose of 40 mg/m2 is generally administered to reduce the treatment-related toxicities, particularly in those patients previously treated with a platinum agent.

Bevacizumab — The anti-VEGF monoclonal antibody bevacizumab (15 mg/kg intravenous [IV] every three weeks) appears to be an active agent in EC, both as a single agent and when combined with chemotherapy. Although it is not our standard first- or second-line therapy, we consider it a reasonable later-line option for those without contraindications (eg, poorly controlled hypertension).

First-line treatment – The benefit of bevacizumab with chemotherapy as first-line treatment for advanced, metastatic, or recurrent EC was evaluated in the three-arm randomized phase II NRG Oncology/GOG 86P trial, which randomly assigned 349 patients (over 80 percent of whom had received prior radiation therapy) to treatment on one of three arms using: carboplatin and paclitaxel plus bevacizumab, carboplatin and paclitaxel plus temsirolimus (an mTOR inhibitor), or carboplatin and ixabepilone plus bevacizumab. The main results were compared with a historic reference using the data from GOG 209, which are discussed above. (See 'Carboplatin plus paclitaxel' above.)

There was no statistically significant difference in PFS compared with historic reference for any of the arms, but median OS was improved with the addition of bevacizumab to chemotherapy (34 versus 23 months) [12]. Further discussion of mTOR inhibition is covered below. (See 'Investigational agents' below.)

Treatment-refractory disease – Other studies suggest bevacizumab may have activity as a second-line treatment, but further data are needed. In the MITO Group END-2 trial, 108 patients who had received ≤1 prior platinum-based regimen and progressed >6 months after completion of first-line therapy were treated with carboplatin plus paclitaxel and randomly assigned to treatment with or without bevacizumab [49]. Compared with carboplatin plus paclitaxel, the addition of bevacizumab resulted in numerically higher ORR rates (74 versus 53 percent), median PFS (13.7 versus 10.5 months) and OS (40 versus 29.7 months), although these differences were not statistically significant. These results suggest bevacizumab may have activity for women with recurrent or metastatic EC. However, definitive data from phase III randomized trials are needed before adopting it as a standard treatment option.

Investigational agents

P13K/PTEN/AKT/mTOR pathway inhibitors – The phosphoinositide-3 kinase (PI3K), phosphatase and tensin homolog (PTEN), the protein kinase AKT, and mTOR (formerly mammalian target of rapamycin) are all involved in a key pathway that regulates metabolism, cellular growth, and survival [50]. Multiple agents have been evaluated and show promise for women with EC. As an example:

Temsirolimus – Temsirolimus (25 mg IV weekly) is an mTOR inhibitor that shows some promise in this population. In one trial, 27 women with previously treated, recurrent or metastatic EC were treated with this agent in a single-arm phase II trial [51]. The ORR was 7 percent, but 44 percent had stable disease. Eight patients experienced serious (grade 3/4) toxicities (pneumonitis, mucositis, fatigue, gastrointestinal, and pain). When combined with bevacizumab (10 mg/kg every other week), a response rate of 25 percent was seen in a separate trial that included 49 women with previously treated disease [52]. This combination resulted in serious gastrointestinal toxicities, including fistula formation (n = 2) and intestinal perforations (n = 2).

As discussed earlier, GOG 86P incorporated the mTOR inhibitor temsirolimus in one of the three treatment arms for women with advanced, recurrent, or metastatic EC not previously treated with chemotherapy. However, compared with historic reference, the addition of temsirolimus was not associated with an improvement in PFS or OS [53].

The combination of the mTOR inhibitor everolimus with the aromatase inhibitor letrozole has shown a clinical benefit rate (response or stable disease) of 40 percent in a phase II study of 38 patients with recurrent, incurable EC, though further study is needed prior to routine clinical use [43].

SPECIAL POPULATIONS

HER2-overexpressing tumors — For those with metastatic serous EC overexpressing human epidermal growth factor receptor 2 (HER2), we suggest the addition of trastuzumab to front-line chemotherapy, and continue 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 [54]. The primary endpoint was progression-free survival (PFS). Sixty-one patients were randomly assigned. Median PFS was 8 (control) versus 12.9 months (experimental; hazard ratio [HR] 0.46, 90% CI 0.28-0.76). Overall survival (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.

Older women — Age is used to stratify women 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 has been associated with higher rates of clinical relapse and decreased survival. The decision to use chemotherapy in older women 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".)

Obese women — 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 [55]. 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".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high 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".)

SUMMARY AND RECOMMENDATIONS

Introduction – While the majority of patients present with localized disease with an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary. 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 women with newly diagnosed, metastatic EC, we typically suggest surgical cytoreduction (Grade 2C).

By contrast, for women 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.)

Front-line systemic therapy

For chemotherapy-naϊve women with metastatic EC (irrespective of whether they had cytoreduction or not), we suggest carboplatin and paclitaxel rather than endocrine therapy, or another chemotherapy regimen (algorithm 1) (Grade 2C). (See 'Carboplatin plus paclitaxel' above.)

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

However, for some women with metastatic EC, endocrine therapy is a reasonable alternative to combination chemotherapy if they prefer to avoid the toxicities of chemotherapy. We consider it as an appropriate alternative for those with any of the following factors: grade 1 or 2 EC, tumors positive for estrogen and progesterone receptors, and women without (or with minimal) cancer-related symptoms. If endocrine therapy is administered, we offer megestrol acetate alternating with tamoxifen rather than other endocrine therapies. (See 'Endocrine therapy' above.)

Subsequent-line systemic therapy

For patients with mismatch repair-deficient (dMMR) or microsatellite instable-high (MSI-H) tumors, or with tumors that have high tumor mutational burden (TMB), who have experienced progression despite prior chemotherapy, we suggest an immune checkpoint inhibitor rather than further chemotherapy or endocrine therapy (Grade 2C), although endocrine therapy is considered a reasonable alternative for patients who are not candidates for immunotherapy (algorithm 1).

-Pembrolizumab is approved by the US Food and Drug Administration (FDA) for the treatment of dMMR or MSI-H cancers, including EC, that have progressed following prior treatment, and for which there are no satisfactory alternative treatment options.

-For patients with dMMR ECs, dostarlimab is another FDA-approved option. In the absence of direct comparisons, a choice between pembrolizumab and dostarlimab for such tumors should be based on factors such as availability and cost. (See 'Tumors that are dMMR, MSI-H, or have high TMB' above.)

For patients whose tumors do not display dMMR/MSI-H or high TMB and who have experienced progression despite prior chemotherapy, the choice of second-line therapy depends on the treatment-free interval. (See 'Other tumors' above.)

-For patients who have relapsed with a treatment-free interval following carboplatin and paclitaxel of <6 months, we typically suggest pembrolizumab and lenvatinib rather than further chemotherapy (Grade 2B). For select patients, particularly those with estrogen receptor (ER)-positive cancers, endocrine therapy represents an acceptable alternative, particularly for those who wish to avoid the toxicities associated with these agents, or for those with minimally symptomatic or more indolent disease.

-For patients who have relapsed with a treatment-free interval following carboplatin and paclitaxel of ≥6 months, we typically suggest retreatment with carboplatin/paclitaxel (Grade 2C). Here also, endocrine therapy represents an acceptable alternative for select patients, particularly those with ER-positive cancers.

-Although we have chosen an interval of six months as a cutoff, extrapolating from the definition of platinum sensitivity in ovarian cancer, high-quality data regarding platinum sensitivity are lacking in EC. In reality, sensitivity is expected to be a continuum, and six months should not be considered an absolute condition for treatment decisions; other factors including patient preferences and tolerance of prior treatments should also be weighed.

Special populations

The decision to use chemotherapy in older women 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. (See "Comprehensive geriatric assessment for patients with cancer".)

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Topic 126055 Version 23.0

References