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Treatment of recurrent or metastatic endometrial cancer

cindy0519
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Treatment of recurrent or metastatic endometrial cancer - UpToDate 3/14/17, 1:11 PM

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Treatment of recurrent or metastatic endometrial cancer

Authors: Susana M Campos, MD, David E Cohn, MD

Section Editors: Barbara Goff, MD, Don S Dizon, MD, FACP

Deputy Editors: Sadhna R Vora, MD, Sandy J Falk, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2017. | This topic last updated: Jun 15, 2015.

INTRODUCTION — Adenocarcinomas of the endometrium are the most common gynecologic malignancy in

developed countries and the second most common in developing countries (cervical cancer is the most common

gynecologic malignancy in developing countries). Among the different histologic types of adenocarcinomas,

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.

This topic will review the approach and treatment options for women with recurrent or metastatic endometrial

cancer. The initial treatment of low-risk, intermediate-risk, and high-risk endometrial cancers (which includes

women who present with locally advanced disease) are covered separately. In addition, chemotherapy protocols

used in the treatment of endometrial cancer is available separately.

CLINICAL PRESENTATION — Most women who relapse will do so within three years of the initial diagnosis.

Although the symptoms that herald recurrent or metastatic endometrial cancer are non-specific, most women will

have symptoms, with the most common consisting of bleeding (which emanates from the vagina, bladder, or

rectum), anorexia, weight loss, bone or pelvic pain, cough, shortness of breath, or lower abdominal or extremity

swelling [1].

However, recurrent endometrial cancer presents with different patterns, including disease localized to the vagina,

®

®

● (See "Approach to adjuvant treatment of endometrial cancer".)

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

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

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

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

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limited to the pelvis, or as metastatic disease involving the abdominal cavity or other organs. In addition, some

women may initially present with de novo metastatic disease (ie, stage IVB). For women suspected of recurrent

or metastatic disease, confirmation of this diagnosis is important, particularly if the diagnosis is being considered

for the first time.

DIAGNOSTIC EVALUATION — For women suspected of recurrent or metastatic endometrial cancer, the

diagnostic work-up should include the following:

Additional studies may include testing the tumor for estrogen (ER) and progesterone (PR) receptor expression,

especially in endometrioid cancer. In addition, overexpression of human epidermal growth factor 2 (HER2) is

performed at some centers, particularly in patients with uterine serous cancer.

OVERVIEW OF TREATMENT — Most women with a diagnosis of recurrent or metastatic disease have a poor

prognosis, regardless of treatment. In addition, unlike in the setting of a new diagnosis, data suggest that

histology does not predict treatment response in these patients. This was shown in a retrospective study of over

1200 women who participated in first-line chemotherapy trials (all of which tested an anthracycline-containing

combination) conducted by the Gynecologic Oncology Group (GOG) [2]. The main finding was that histologic

subtype did not predict response to first-line chemotherapy. However, specific histology subtypes were

associated with outcome:

Despite these data, it is still possible to cure selected patients with isolated disease with an aggressive local or

regional approach. Therefore, our approach to treatment varies by the clinical scenario:

● Pelvic examination with biopsies of areas suspected of recurrent disease

● Physical exam, with attention to nodal regions

Whole body imaging to evaluate for metastatic disease – Imaging of the chest, abdomen and pelvis can be

performed using computerized tomography (CT), magnetic resonance imaging (MRI), positron emissions

tomography (PET) scan, or a combined PET-CT scan. In general, computerized tomography (CT) is usually

the initial study. If CT results are equivocal, further evaluation using positron emissions tomography (PET)

scan or a combined PET-CT scan may be indicated. Ultimately, the choice between these imaging

modalities is dependent on institutional practice.

Measurement of cancer antigen 125 (CA-125) – Measurement of serum CA-125 may be useful in the

diagnostic work-up of a suspected recurrence, particularly in women that had an associated elevation in

their CA-125 at the initial diagnosis. However, the level of CA-125 alone should not influence treatment

decisions.

● Clear cell carcinoma was an independent predictor of poorer progression-free survival

● Serous and clear cell histologies were significant predictors of overall survival

Women with recurrent disease isolated to the vaginal vault are potentially curable. Choices for treatment

depend on whether radiation therapy (RT) was previously administered. (See 'Isolated vaginal recurrence'

below.)

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The posttreatment surveillance of women with endometrial cancer is discussed separately. (See "Overview of

endometrial carcinoma", section on 'Posttreatment surveillance'.)

ISOLATED VAGINAL RECURRENCE — Women who have undergone a hysterectomy for endometrial cancer

are at risk for a recurrence at the vaginal vault, although treatment with adjuvant radiation therapy (RT)

decreases this risk.

This was demonstrated in the Postoperative Radiation Therapy after Endometrial Cancer (PORTEC) randomized

trial that included 715 women with stage I endometrial cancer who underwent total hysterectomy and bilateral

salpingo-oophorectomy without lymphadenectomy, and were then assigned to adjuvant RT or no further

treatment [3]. Women treated with adjuvant RT had a lower incidence of vaginal recurrence at eight-year followup

(2 versus 8 percent), without a difference in overall survival. Further results of the PORTEC trial are discussed

separately.

For those who develop an isolated vaginal recurrence, the local treatment approach takes into account whether

or not prior RT was administered:

No prior radiation — For women with an isolated vaginal recurrence of endometrial cancer who were not

previously treated with RT, we suggest RT rather than surgery. However, surgery alone can be a curative and

reasonable alternative to RT in carefully selected patients, including those women who decline RT or are not

candidates for RT. (See 'Operative candidates' below.)

Radiation therapy — Data regarding treatment of an isolated vaginal recurrence are limited, but outcomes

appear favorable based on observational studies and the few studies of surgical treatment for this patient

population. Two retrospective case series (n = 50 and 69) evaluated women with endometrial cancer, nearly all of

whom had not received prior RT, following an isolated vaginal recurrence [3,4]. Treatment with RT was

associated with a five-year overall survival rate (OS) of 53 to 75 percent.

In addition, in the PORTEC I trial described above, 30 women who were not initially treated with RT had a

vaginal recurrence and were subsequently treated with curative intent; most received whole pelvic RT with or

without brachytherapy (28, although three women were treated with RT and surgery or RT and hormonal

therapy) [3]. The complete response rate for all women treated with curative intent was 87 percent.

The role of concurrent chemotherapy with RT is investigational and, in our practice, we do not offer combined

modality treatment. We encourage women in this situation to enroll in a randomized trial being conducted by the

Women with locally recurrent disease limited to the pelvis are also potentially curable. Treatment options

include surgery and/or RT, provided they are appropriate candidates for this. For women who are not

candidates for a local therapeutic approach, we proceed with medical treatment as we would for women with

metastatic disease. (See 'Recurrence limited to the pelvis' below and 'Patients who develop metastatic

disease' below.)

Women with disease outside of the pelvis either at their initial presentation or at the time of recurrence have

metastatic endometrial cancer. In most cases, treatment is not curative. Therefore, the approach should be

individualized. (See 'Metastatic disease' below.)

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Gynecologic Oncology Group (GOG 238), which randomly assigns these patients to RT with or without

concurrent sensitizing cisplatin.

Prior radiation — Although vaginal recurrences are less common in women treated with prior RT, they are

associated with a poor prognosis. In the PORTEC trial, there were only seven vaginal recurrences out of 354

women treated with RT (eight-year recurrence rate, 2 percent) [3]. However, the actuarial OS rate at three years

among these patients was 43 percent.

Treatment options among these women depend on whether or not they are candidates for surgery:

Operative candidates — For women with a vaginal recurrence who have been previously treated with RT

and who are operative candidates (complete resection is technically feasible and can tolerate surgery), we

suggest surgical resection rather than additional RT or medical therapy. Pelvic exenteration is the mainstay of

surgical therapy for a vaginal recurrence. Although a radical resection of locally recurrent disease (eg,

vaginectomy) may be a less morbid alternative to a pelvic exenteration, it should only be offered to carefully

selected patients in whom the chances of cure will not be compromised.

Pelvic exenteration is an extensive procedure with a substantial risk of short- and long-term morbidity, including

urinary and bowel dysfunction and sexual dysfunction. Urinary and/or colonic diversions are typically required. In

general, we restrict surgery to women in whom a complete resection of disease is technically feasible and who

are able to tolerate surgery and are willing to accept the functional postoperative changes. Patients who are

candidates for surgery should be thoroughly counseled about the details of the procedure, risks, recovery, and

future changes in functioning. (See "Exenteration for gynecologic cancer", section on 'Patient selection'.)

Data on the outcomes of women following pelvic exenteration for recurrent endometrial cancer are limited. No

studies have compared surgery with additional RT or chemotherapy, although use of these options in this patient

population has not been well studied and these are regarded as options of last resort. In many case series,

women with pelvic sidewall disease and/or positive pelvic or paraaortic lymph nodes were included [5-8]. As a

result, the reported five-year OS rates range from 14 to 50 percent. The largest series included 44 women with

recurrent endometrial cancer; the median OS after pelvic exenteration was 10.2 months and five-year OS was 20

percent [6]. Details of the procedure of pelvic exenteration for gynecologic cancer are discussed in detail

separately. (See "Exenteration for gynecologic cancer".)

Following surgery for an isolated vaginal recurrence, we initiate surveillance rather than offering further

treatment, provided there was no evidence of metastatic disease identified at surgery or by postoperative

imaging. Women with evidence of metastatic disease should receive further treatment. (See 'Metastatic disease'

below.)

Non-operative candidates — For patients with an isolated vaginal recurrence who are not candidates for

surgery for whatever reason, medical treatment is usually the only treatment option. In general, reirradiation is

not an option for women with a vaginal recurrence, particularly after pelvic radiation, given the risks to the normal

surrounding tissue. However, if the technical skills are available, the administration of tailored RT into a

previously irradiated area may be reasonable [9]. This approach should take into account the increased

complexity associated with designing the field of treatment and the possible risks to surrounding normal tissue

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[9-13].

In a case series of 27 patients treated with stereotactic RT after conventional RT, there were no serious (grade 3,

4, or 5) toxicities associated with re-treatment, and a 96 percent symptomatic response (measured by reduced

tumor size, decrease in pain, or decrease in bleeding) was reported [9]. Unfortunately, the experience with

tailored RT approaches is limited and expertise may not be available in many places to allow consideration of

this approach.

For women who are not candidates for either a surgical or RT approach, we offer medical treatment using a

similar approach to women who develop metastatic disease. For women who maintain a good performance

status, we encourage the participation in clinical trials. (See 'Patients who develop metastatic disease' below.)

RECURRENCE LIMITED TO THE PELVIS — The approach to women with recurrent disease involving the

pelvic structures (vagina, lower urinary tract, rectosigmoid colon, pelvic sidewall) is the same as outlined above

for women presenting with an isolated vaginal recurrence. (See 'Operative candidates' above and 'Isolated

vaginal recurrence' above.)

Despite surgery for a pelvic recurrence, these patients remain at a high risk for relapse. Therefore, as opposed to

patients who undergo a successful resection of a local vaginal recurrence, those who undergo resection for a

pelvic recurrence should be offered adjuvant chemotherapy. Based upon the results of the Gynecologic

Oncology Group 209 (GOG 209) trial, our preferred regimen is six cycles of carboplatin and paclitaxel. The

results of this study are discussed below. (See 'Carboplatin plus paclitaxel' below and "Adjuvant treatment of

high-risk endometrial cancers", section on 'Stage III disease, regardless of histology'.)

Patients who are not surgical candidates should be offered medical therapy, provided that they are candidates for

treatment. (See 'Patients who develop metastatic disease' below.)

METASTATIC DISEASE

Newly diagnosed patients — For women with metastatic endometrial cancer (stage IVB), surgical

cytoreduction is a reasonable treatment option, particularly if they are newly diagnosed and a complete resection

appears feasible. Unfortunately, high quality data are lacking for cytoreduction for endometrial cancer. This is

discussed in detail separately. (See "Endometrial carcinoma: Pretreatment evaluation, staging, and surgical

treatment", section on 'Cytoreduction'.)

For women who undergo surgical cytoreduction of metastatic disease, we administer first-line chemotherapy in

the postoperative (or "adjuvant") setting. The administration of postoperative chemotherapy in this setting is

extrapolated from the benefits of treatment for women with newly diagnosed, high-risk endometrial cancer.

Based on the results of the Gynecologic Oncology Group 209 (GOG 209) trial, our preferred regimen is six

For women who were not previously treated with radiation therapy (RT), we suggest RT rather than surgery.

For women who decline RT or are not candidates for RT, surgical resection is a reasonable alternative.

For women with a pelvic recurrence and no distant metastases who have been previously treated with RT

and who are operative candidates (complete resection is technically feasible and can tolerate surgery), we

suggest surgical treatment.

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cycles of carboplatin and paclitaxel. The results of this study are discussed below. (See 'Carboplatin plus

paclitaxel' below and "Adjuvant treatment of high-risk endometrial cancers", section on 'Stage III disease,

regardless of histology'.)

Patients who are not surgical candidates should be offered medical therapy, provided that they are candidates for

treatment. (See 'Patients who develop metastatic disease' below.)

Patients with stage IVB disease who are not surgical candidates have a poor prognosis; in the Surveillance,

Epidemiology and End Results database, the reported five-year relative survival for women presenting with

distant disease (which encompasses stage IVB disease) is less than 20 percent [14]. Therefore, the intent of

treatment is generally palliative rather than curative.

Patients who develop metastatic disease

First-line chemotherapy — For women who develop metastatic endometrial cancer we typically administer a

platinum-based combination regimen, provided patients are candidates for a combination regimen and

understand the risks associated with treatment. The two most commonly used regimens to treat metastatic

endometrial cancer are carboplatin plus paclitaxel or the triple drug combination of cisplatin, doxorubicin, plus

paclitaxel (TAP) [15,16]. Of these, we prefer carboplatin and paclitaxel because it has similar activity to TAP but

is associated with less toxicity [15].

The benefit of multi-agent chemotherapy for advanced, recurrent, or metastatic endometrial cancer was shown in

a 2012 meta-analysis of trials that compared administration of multi-agent combinations ("more intensive"

regimens) with less intensive combinations (eg, three versus two-agent combinations, or two agents versus one

agent) [17]. Major findings include:

Although the data from this meta-analysis support the use of multi-agent 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.

Carboplatin plus paclitaxel — Because of the toxicity associated with cisplatin-based combinations,

carboplatin and paclitaxel is the preferred regimen for the first-line treatment of chemotherapy-naive recurrent

metastatic endometrial cancer. The data to support carboplatin plus paclitaxel come from GOG 209 [15], 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 non-inferiority of the

experimental chemotherapy regiment over the standard regimen), 1300 women with chemotherapy naive stage

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 to seven months,

hazard ratio [HR] 0.82, 95% CI 0.74-0.90) and overall survival (OS, from 9 to 10.5 months, HR 0.86, 95% CI

0.77-0.96). Trials that compared doxorubicin (or doxorubicin plus cisplatin) with or without additional drugs

favored the arms incorporating additional chemotherapy.

The administration of "more intensive" chemotherapy significantly 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).

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III, IV, or recurrent endometrial carcinoma were randomly assigned to treatment with carboplatin plus paclitaxel

or cisplatin, doxorubicin, and paclitaxel (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 Oncologists

Annual Meeting, carboplatin plus paclitaxel resulted in:

Cisplatin, doxorubicin, plus paclitaxel — GOG 177 demonstrated the benefit of TAP, which enrolled 273

women with previously untreated stage III/IV or recurrent endometrial cancer and randomly assigned them to

treatment with AP (cisplatin [50 mg/m ] plus doxorubicin [60 mg/m ] administered on day 1 every three weeks) or

TAP (doxorubicin [45 mg/m on day 1], cisplatin [50 mg/m on day 1] plus paclitaxel [160 mg/m over three hours

on day 2] every three weeks) [18]. Of note, patients assigned to TAP received prophylactic growth-factor support

using filgrastim. Compared with AP, TAP resulted in:

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

Endocrine therapy — We suggest endocrine therapy as initial treatment for patients in whom secondary

cytoreduction or cytotoxic chemotherapy is not planned for whatever reason. Response to endocrine therapy is

expected to be more favorable in patients with any of the following characteristics:

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 lowgrade

tumors [19]. While most remissions are partial and relatively brief in duration, some patients may remain

progression-free for extended periods of time (>2 years) [23].

If endocrine therapy is administered, we typically use megestrol acetate alternating in sequence with tamoxifen.

● 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)

2 2

2 2 2

● A significant improvement in the ORR (57 versus 34 percent).

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

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

● Grade 1 or 2 endometrioid endometrial cancer.

Positive expression of estrogen (ER) and progesterone (PR) receptors. Several studies suggest that

hormone receptor positive cancers are more likely to respond to endocrine treatment, though the data are

not consistent [19-22].

● Asymptomatic or minimally symptomatic disease.

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The benefit of sequential therapy was demonstrated in a phase II study conducted by the GOG that enrolled 56

women assigned treatment with megestrol acetate (160 mg orally for three weeks), alternating with tamoxifen (40

mg daily for three weeks) [24]. Treatment resulted in an overall response rate of 27 percent with a median

progression-free survival of 2.7 months and median overall survival of 14 months [24]. Interestingly, the response

rate among women with grade 3 tumors was 22 percent, presumably due to tamoxifen induction of progesterone

receptors.

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:

The aromatase inhibitors appear to have little activity in endometrial cancer. Both letrozole and anastrazole were

tested in phase II clinical trials of women with advanced, recurrent, or persistent endometrial cancer and had

response rates of less than 10 percent [36,37]. 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 [36]. Among 22 patients with available tissue, the

majority were positive for progesterone receptors (86 percent) and estrogen receptors (86 percent).

Second-line therapy — Women who progress despite first-line chemotherapy have a poor prognosis.

Therefore, we offer supportive care and encourage a referral for palliative care services regardless of whether

second-line treatment is administered. For women who desire subsequent treatment, the choice of second-line

therapy depends on the type of treatment administered in the first-line setting. (See "Benefits, services, and

models of subspecialty palliative care".)

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 [25-31]. 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).

Tamoxifen – Tamoxifen is the only selective estrogen receptor 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 [20,32-35].

Women who progress following endocrine therapy as their first-line treatment are chemotherapy naive.

These women should be offered a platinum-based combination regimen, provided they are candidates for a

combination treatment and accept the higher risks for toxicity (compared with a single agent therapy).

Because treatment is palliative, single-agent chemotherapy is also reasonable. A choice between these

options should be individualized based on the patient’s wishes, clinical status, and her preferences for

therapy. (See 'First-line chemotherapy' above.)

For women who progress after receiving adjuvant chemotherapy, there is limited evidence that the interval

between the end of adjuvant treatment and the diagnosis of relapse (ie, treatment-free interval) predicts

response to second-line treatment [38,39]. In the largest study conducted by the GOG, a treatment-free

interval of six months or longer was associated with a significant reduction in the risk of death after secondline

chemotherapy (HR 0.70, 95% CI 0.59-0.84) [39]. However, the treatment-free interval did not predict

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Commonly used agents administered to women with recurrent endometrial cancer include:

Doxorubicin — There are no published, prospective data to inform the benefit of doxorubicin (60 mg/m

every three weeks) as a second-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 [40]. In

addition to treatment every three weeks, weekly dose doxorubicin (20 mg fixed dose) is sometimes administered

based on low quality data in the treatment of advanced breast cancer showing it results in an ORR of 19 percent

and lacked serious side effects [41].

Paclitaxel — Paclitaxel (175 mg/m every three weeks) is an option in the second-line setting, particularly

in patients who were not previously treated with this agent in the first-line setting. In one study, paclitaxel resulted

in a 25 percent ORR among 48 paclitaxel-naive patients [42]. However, weekly administration (80 mg/m ) 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 [43].

Bevacizumab — The anti-VEGF monoclonal antibody bevacizumab (15 mg/kg IV every three weeks)

appears to be an active agent in endometrial cancer. This was shown in a GOG trial that enrolled 53 women who

had received up to two prior treatments for endometrial cancer [44]. The ORR was 15 percent with 36 percent

progression-free at six months. The median PFS and OS were 4 and 11 months, respectively. There were no

episodes of gastrointestinal perforation.

subsequent treatment response.

On the basis of these data, our approach to second-line treatment takes in to account this interval:

For women with a long treatment-free interval following platinum-based combination chemotherapy (ie,

six months or longer), we suggest repeat treatment with a platinum-based combination. Although there

are no prospective data that a platinum-based combination improves outcomes compared with singleagent

therapy in this context, the use of a platinum-based combination in the second-line treatment in

this population is extrapolated from the treatment of platinum-sensitive recurrent ovarian cancer. (See

"Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinumsensitive

disease".)

Women who experience a short treatment-free interval (<6 months) have a poor prognosis. The limited

data suggest that the most likely response to second line treatment is stable disease at best and overall

survival is less than a year [38]. Therefore, the role of subsequent treatment is of unclear benefit. For

women who desire further treatment, accept the risks associated with cytotoxic chemotherapy, and

acknowledge the lack of data to suggest a benefit to subsequent treatment, second-line therapy is

reasonable.

For women who experience disease progression after first-line chemotherapy for metastatic disease, we

suggest single agent chemotherapy. While responses are observed with single agent therapy in these

patients, these are often short-lived and median overall survival across studies is typically less than one

year. For women who prefer not to receive cytotoxic therapy but desire further treatment, endocrine therapy

can be administered. (See 'Endocrine therapy' above.)

2

2

2

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The benefit of bevacizumab as first-line treatment for advanced, metastatic, or recurrent endometrial cancer was

evaluated in the three-arm randomized phase II NRG Oncology/Gynecologic Oncology Group (GOG) 86P trial,

which randomly assigned 349 patients (over 80 percent of whom had received prior radiation therapy [RT]) to

treatment on one of three arms using: carboplatin and paclitaxel plus bevacizumab (arm 1); carboplatin and

paclitaxel plus temsirolimus (an mTOR inhibitor, arm 2); or carboplatin and ixabepilone plus bevacizumab (arm

3). The main results were compared with a historical reference using the data from GOG 209, which are

discussed above.

As presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, the main results were

[45]:

In addition to these results, a second study presented at the 2015 ASCO Meeting also suggests bevacizumab

has activity as a second-line treatment. In the Multicenter Italian Trials in Ovarian Cancer (MITO) Group END-2

trial, 108 patients who had received ≤1 prior platinum-based regimens 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 [46]. Compared with carboplatin plus paclitaxel, the addition of bevacizumab

resulted in:

These results suggest bevacizumab has activity in combination with chemotherapy for women with recurrent or

metastatic endometrial cancer. However, definitive data from phase III randomized trials are needed before

adopting it as a standard treatment option.

Other agents

● There was no difference in PFS. Compared with historical reference:

• Arm 1 – HR 0.81 (95% CI 0.63-1.02)

• Arm 2 – HR 1.22 (95% CI 0.96-1.55)

• Arm 3 – HR 0.87 (95% CI 0.69-1.11)

● The ORR was 59.5, 55.3, and 52.9 percent in arms 1, 2, and 3, respectively.

Median OS was significantly improved in arm 1 compared with historical reference (34 versus 23 months),

but was not different in arms 2 or 3 (median, 25 months in both).

● Higher ORR (71.7 versus 54.3 percent)

● A significant improvement in PFS (median, 13 versus 8.7 months; HR 0.59, 95% CI 0.35-0.98)

● No significant difference in OS (median, 23.5 versus 18 months; HR 0.65, 95% CI 0.31-1.36)

Ifosfamide – Ifosfamide (1.2 g/m /day for five days, repeated every four weeks) resulted in an ORR of 15

percent in a study involving 52 women [47]. Serious (grade 3/4) toxicity was limited to neutropenia in 53

percent and neuropathy in 11 percent.

● 2

● Ixabepilone – Ixabepilone is an epothilone B analogue approved for treatment of metastatic breast cancer.

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Third or later line treatment — 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. Among the available options, endocrine therapy is a

reasonable alternative to chemotherapy, particularly for patients who did not receive them as prior therapy for

recurrence (eg, as primary prevention for breast cancer). (See 'Endocrine therapy' above and 'Second-line

therapy' above.)

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 overall survival in clinical trials after first- or second-line agents is generally 12 months or less.

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 the participation in clinical

In GOG 129P, 50 women (majority previously treated with paclitaxel) were treated with ixabepilone (40

mg/m every three weeks) [48]. The ORR was 12 percent and the median PFS was three months. Serious

(grade 3) toxicities included neutropenia, leukopenia, gastrointestinal, neurologic, constitutional, and

infection. However, compared with historical reference, the addition of ixabepilone to chemotherapy in GOG

86P was not associated with an improvement in PFS or OS [45].

2

Docetaxel – Weekly docetaxel (36 mg/m IV on days 1, 8, and 15 every 28 days) resulted in an ORR of 7.7

percent in a phase II GOG study involving 27 women (the majority of whom previously received paclitaxel)

[49]. The most frequently reported adverse events were leucopenia, neutropenia, gastrointestinal,

constitutional, and peripheral neuropathy. Given the low response rate, the study was terminated early.

● 2

Topotecan – A prospective, phase II clinical trial of topotecan suspended because of unexpected toxicities

(ie, sepsis and bleeding), but was reopened using lower doses of (1.0 mg/m or 0.8 mg/m days one

through five for patients with prior radiation therapy). The ORR among 44 patients was 20 percent [50]. The

median OS was 6.5 months. The major toxicities were hematologic and gastrointestinal.

2 2

Oxaliplatin – Oxaliplatin (130 mg/m every three weeks) resulted in an ORR of 14 percent in a study

involving 50 women [51]. Major toxicities were nausea, vomiting, and neurotoxicity.

● 2

Etoposide – Oral etoposide (50 mg daily on days 1 through 21 on a 28-day schedule) was evaluated in a

GOG trial that included 44 women [52]. The ORR was 14 percent (including one complete remission).

Toxicity included neutropenia, anemia, and nausea.

Pegylated liposomal doxorubicin – Pegylated 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/m on

a four-week schedule, the ORR was 9.5 percent [53]. 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 endometrial cancer, a dose of 40 mg/m is generally

administered to reduce the treatment-related toxicities, particularly in those patients previously treated with a

platinum agent.

2

2

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trials.

SPECIAL POPULATIONS

Older women — While age is used to stratify women with either high- versus low- intermediate-risk endometrial

cancer, 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 chemotherapy, 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

"Approach to adjuvant treatment of endometrial cancer", section on 'Older age' and "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

(ASCO) [54]. One exception to this is the dosing of carboplatin, where we continue to use fixed dosing based on

AUC 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 [54]. (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/m . 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, monitoring, and diagnosis of anthracyclineinduced

cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

Novel agents — A number of agents are being evaluated in clinical trials with the aim of increasing the treatment

options for women with endometrial carcinoma. However, the agents below are investigational and only available

in clinical trials. Agents being specifically evaluated in endometrial carcinoma include:

2

Angiokinase inhibitors – New drugs that target angiogenesis and other pathways are in phase II clinical

trials for this population of patients with previously treated endometrial cancer:

Brivanib is a dual tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR2 and

VEGFR3) and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). It was evaluated as a

single agent among 43 evaluable patients in a phase II trial conducted by the GOG and resulted in a

response rate of 19 percent [55]. In addition, 30 percent of patients were progression-free at six

months.

Nintedanib is an angiokinase inhibitor of VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), platelet

derived growth factor receptors (PDGFR alpha and beta), and FGF receptors (FGFR1, FGFR3). It has

also been evaluated in a phase II single-agent trial conducted by the GOG that enrolled 32 eligible

patients [56]. The overall response rate was 9 percent (three partial and no complete responders), and

event-free survival at six months was 22 percent.

● HER2-directed agents – Human epidermal growth factor 2 (HER2) overexpression predicts patients with

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The anti-HER2 monoclonal antibody trastuzumab was evaluated in a GOG trial of 34 women with advanced or

recurrent endometrial cancer who had confirmed amplification of HER2 [57]. Although no responses were seen,

12 had stable disease. Despite these less than encouraging results, an ongoing clinical trial is evaluating

trastuzumab in combination with chemotherapy, specifically in patients with serous histologies.

Lapatinib is another HER2-directed agent that also inhibits the EGFR, known as HER1. It has shown some

activity as evidenced in one trial of 30 patients treated with single-agent lapatinib [58]. Three patients were

progression-free after six months and one patient had a partial response.

DEFINITION OF DISEASE PROGRESSION — There is no precise definition of disease progression in routine

clinical practice. In clinical trials, the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria are used

to define the parameters for response and disease progression (table 1) [64]. According to RECIST, disease

breast cancer who will respond to HER2-directed agents. Some data suggest that HER2 is a relevant target,

especially in patients with uterine serous carcinomas. However, the role of HER2-directed therapy is

investigational and patients should only be treated with these agents as part of a clinical trial.

P13K/PTEN/AKT/mTOR pathway inhibitors – The phosphoinositide-3 kinase (PI3K), phosphatase and

tensin homolog (PTEN), the protein kinase AKT, and mechanistic Target of Rapamycin (mTOR, formerly

mammalian target of rapamycin) are all involved in a key pathway that regulates metabolism, cellular

growth, and survival [59]. Multiple agents have been evaluated and show promise for women with

endometrial cancer. These include:

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 endometrial

carcinoma were treated with this agent in a single-arm phase II trial [60]. The overall response rate was

seven 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 [61]. 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 endometrial cancer not previously

treated with chemotherapy. However, compared with historical reference, the addition of temsirolimus

was not associated with an improvement in progression-free survival (PFS) or overall survival (OS) [45].

Other mTOR inhibitors that have been evaluated include deforolimus [62] and everolimus [63].

However, none of these agents are available off of a clinical trial.

GDC0980 – GDC-0980 is a novel inhibitor of both PI3K and mTOR. It is in evaluation in a multicenter,

single-arm, open-label phase II study in this population.

MK2206 – MK2206 is an allosteric inhibitor of AKT. It is currently being studied in endometrial cancer in

a single-arm phase II trial.

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progression is defined as:

The primary role of RECIST 1.1 criteria is to standardize the reporting of results on clinical trials. In clinical

practice, however, RECIST is seldom used because it is a cumbersome system. In addition, it does not consider

clinical deterioration as a criterion for disease progression, although many oncologists do. Therefore, the

determination of disease progression requires close communication between radiologists, oncologists, and

patients.

In our own practice, we monitor for disease progression by taking into account the tempo of disease progression

(based on CT imaging performed every two to three cycles) and the clinical status of the patient. Some criteria

that we use to define disease progression include any of the following:

Role of CA-125 monitoring — As in the adjuvant setting, the data do not support the routine monitoring of

serum CA-125 for women with recurrent or metastatic endometrial cancer. 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'.)

SUMMARY AND RECOMMENDATIONS

Isolated vaginal recurrence

A 20 percent or more increase in the sum of measurable lesions compared with the smallest sum previously

recorded

● The evolution of any new lesions

Worsening of the overall tumor burden (even if the sum of measurable lesions alone meets criteria for a

partial response or stable disease)

Clinical deterioration during treatment (ie, increasing disease related symptoms, declining performance

status)

● Evolution of new metastases

● Increasing size of previously documented metastatic lesions

Recurrent endometrial cancer presents with different patterns, including disease localized to the vagina,

pelvis, or as metastatic disease. In addition, some women may present with de novo (stage IV) metastatic

disease. Although the prognosis for the vast majority is poor, carefully selected patients can be cured with

an aggressive locoregional approach. (See 'Introduction' above.)

For women with an isolated vaginal recurrence who were not previously treated with RT, we suggest RT

rather than surgery (Grade 2C). For women who decline RT or are not candidates for RT, surgical resection

is a reasonable alternative. (See 'No prior radiation' above.)

● For women with an isolated vaginal recurrence who have been previously treated with RT and who are

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Recurrence limited to the pelvis

Metastatic disease

operative candidates (complete resection is technically feasible and can tolerate surgery), we suggest

surgical resection rather than additional RT or medical therapy (Grade 2C). Pelvic exenteration is the

mainstay of surgical therapy for a vaginal recurrence. Additional RT is an option for women who are not

operative candidates. (See 'Prior radiation' above.)

For women who are not candidates for either surgical resection or RT, we offer medical treatment. The

approach mirrors that for women who develop metastatic disease. (See 'Patients who develop metastatic

disease' above.)

● Following completion of local treatment, we suggest surveillance rather than further therapy (Grade 2C).

For women with a pelvic recurrence and no distant metastases who were not previously treated with RT, we

suggest RT rather than surgery (Grade 2C). For women who decline RT or are not candidates for RT,

surgical resection is a reasonable alternative. (See 'Recurrence limited to the pelvis' above.)

For women with a pelvic recurrence and no distant metastases who have been previously treated with RT

and who are operative candidates (complete resection is technically feasible and can tolerate surgery), we

suggest surgical treatment (Grade 2C). Following surgery, we suggest adjuvant chemotherapy rather than

observation (Grade 2C). We suggest carboplatin and paclitaxel for these patients rather than other

regimens (Grade 2C). (See 'First-line chemotherapy' above.)

Women who have been previously treated with RT and who are not surgical candidates should be offered

medical treatment. The treatment approach mirrors that for women with metastatic disease. (See 'Patients

who develop metastatic disease' above.)

For women with newly-diagnosed, metastatic endometrial cancer (stage IVB) that are felt to have operable

disease, we suggest surgical cytoreduction (Grade 2C). For those who undergo surgery, we suggest the

administration of adjuvant chemotherapy following surgery (Grade 2C). We suggest carboplatin and

paclitaxel as an adjuvant regimen for these patients (Grade 2C). (See 'Newly diagnosed patients' above.)

For women with metastatic endometrial cancer, we suggest carboplatin and paclitaxel rather than another

cisplatin-based combination in the first-line setting (Grade 2B). (See 'Carboplatin plus paclitaxel' above.)

For some women with metastatic endometrial cancer, endocrine therapy is a reasonable alternative to

combination chemotherapy if any of the following factors are present: grade 1 or 2 endometrial cancer,

tumors positive for estrogen (ER) and progesterone (PR) receptors, and women without (or with minimal)

cancer-related symptoms. If endocrine therapy is administered, we suggest megestrol acetate alternating

with tamoxifen (Grade 2C). (See 'Endocrine therapy' above.)

For women who progress following endocrine therapy and are chemotherapy naive, we suggest platinumbased

combination chemotherapy (Grade 2C). However, because treatment is palliative, single-agent

chemotherapy is a reasonable alternative. (See 'Carboplatin plus paclitaxel' above.)

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Topic 3186 Version 36.0

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GRAPHICS

Revised Response Evaluation Criteria in Solid Tumors (RECIST) for assessing

clinical tumor response

Response

assessment

RECIST guideline, version 1.1

Target lesions

CR Disappearance of all target lesions and reduction in the short axis measurement of all pathologic

lymph nodes to ≤10 mm

PR ≥30 percent decrease in the sum of the longest diameter of the target lesions compared with

baseline

PD ≥20 percent increase of at least 5 mm in the sum of the longest diameters of the target lesions

compared with the smallest sum of the longest diameter recorded

OR

The appearance of new lesions including those detected by FDG-PET

SD Neither PR nor PD

Non-target lesions

CR Disappearance of all non-target lesions and normalization of tumor marker levels

IR, SD Persistence of one or more non-target lesions and/or the maintenance of tumor marker levels

above normal limits

PD The appearance of one of more new lesions or unequivocal progression.

If patient has measurable disease, an increase in the overall level, or substantial worsening in

non-target lesions, such that tumor burden has increased, even if there is a SD or PR in target

lesions.

If no measurable disease, an increase in the overall tumor burden comparable in magnitude to

the increase that would be required to declare PD in measurable disease (eg, an increase in

pleural effusions from trace to large, or an increase in lymphangitic disease from localized to

widespread).

CR: complete response; IR: incomplete response; PD: progressive disease; SD: stable disease.

Reference:

1. Eisenhauer E, et al. Eur J Cancer 2009; 45:228.

Graphic 57181 Version 2.0

[1]

Treatment of recurrent or metastatic endometrial cancer - UpToDate 3/14/17, 1:11 PM

https://www.uptodate.com/contents/treatment-of-recurrent-or-meta…=see_link&sectionName=First-line%20chemotherapy&anchor=H8007524 Page 22 of 22

Contributor Disclosures

Susana M Campos, MD Consultant/Advisory Boards: Genentech [Ovary (bevacizumab)]; AstraZeneca [Ovary];

Clovis [parp inhibitors]. David E Cohn, MD Consultant/Advisory Boards: Oncology Analytics [Medical Advisory

Board]. Other Financial Interest: Gynecologic Oncology [journal Deputy Editor]. Barbara Goff,

MD Consultant/Advisory Boards: Roche Diagnostics [Biomarkers for ovarian cancer (HE4)]. Employment

(Spouse): Lilly [General oncology (Gemcitabine, pemetrexed)] - No relevant conflict on topics. Don S Dizon,

MD, FACP Consultant/Advisory Boards: Pfizer [Chemotherapy (Biosimilars)]. Sadhna R Vora, MD Nothing to

disclose Sandy J Falk, MD, FACOG Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are

addressed by vetting through a multi-level review process, and through requirements for references to be

provided to support the content. Appropriately referenced content is required of all authors and must conform

to UpToDate standards of evidence.

 

Conflict of interest policy

Kvdyson's picture
Kvdyson
Posts: 789
Joined: Jan 2016

Thank you, Cindy! I believe that UptoDate is a paid service so it's super nice of you to post these for us!

cindy0519
Posts: 173
Joined: Nov 2015

UpToDate is a paid Subscription but I'm happy to share!

derMaus's picture
derMaus
Posts: 561
Joined: Nov 2016

This is a lot to read and it took me awhile to get my mind around it but, when I did, I realized why you posted it in toto. Thank you very much for taking the time to do so and sharing such an in depth resource.

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