Approach to Adjuvant Treatment of Endometrial Cancer

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Approach to adjuvant treatment of endometrial cancer

Authors: Steven C Plaxe, MD, Arno J Mundt, MD

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

Deputy Editor: Sadhna R Vora, MD

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: Jan 04, 2016.

INTRODUCTION — The treatment of endometrial cancer following surgical staging is based on the risk of

relapse and persistent disease, which is defined by the cancer stage at diagnosis and presence of prognostic

factors. This topic will cover the risk stratification criteria for newly diagnosed endometrial cancer. The treatment

by risk category is covered separately.

DEFINITION OF RISK BASED ON HISTOLOGY AND STAGE — For women with newly diagnosed endometrial

cancer, treatment is stratified based on the risk of disease recurrence, which is characterized using the stage of

disease (table 1), histology of the tumor, and other pathologic factors:

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

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

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

Low-risk endometrial cancer includes women with grade 1 endometrial cancer of endometrioid histology

that is confined to the endometrium (a subset of stage IA disease). The overall probability of recurrence in

these groups is very low following surgical treatment alone.

●

Intermediate-risk endometrial cancer includes women with uterine-limited cancer that invades the

myometrium (stage IA or IB) or demonstrates occult cervical stromal invasion (stage II). These groups have

a higher risk of recurrence than do patients whose tumors are confined to the endometrium (which defines

patients with low-risk endometrial cancer).

Among this subgroup, there are other adverse prognostic factors used to stratify women into high and lowintermediate-

risk. These include outer one-third myometrial invasion, grade 2 or 3 differentiation, or the

presence of lymphovascular invasion within the cancer. (See "Adjuvant treatment of intermediate-risk

●

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Staging evaluations and discussion of the role of the sentinel lymph node biopsy are discussed in detail

elsewhere. (See "Endometrial carcinoma: Pretreatment evaluation, staging, and surgical treatment", section on

'Pretreatment evaluation' and "Endometrial carcinoma: Pretreatment evaluation, staging, and surgical

treatment".)

OTHER PROGNOSTIC FACTORS — Beyond histology and stage, other factors may be used to inform the role

of adjuvant therapy beyond the risk-stratified approach described above. These include:

Lower uterine segment involvement — Women with otherwise low-risk disease who have involvement of the

lower uterine segment may be at a greater risk for nodal involvement. However, it is not clear if involvement of

the lower uterine segment represents an independent risk factor for survival. This topic is discussed in detail

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

Positive peritoneal cytology — Approximately 11 percent of patients undergoing surgical staging have positive

peritoneal cytology, most commonly in the setting of advanced (extrauterine) disease [1]. However, positive

peritoneal cytology is no longer considered in the staging system for endometrial carcinoma to assign tumor (T)

stage (table 1) [2]. Despite this, the prognostic significance of isolated positive peritoneal washings in the

absence of extrauterine spread remains controversial, as illustrated in the following studies:

endometrial cancer", section on 'Definition of intermediate-risk'.)

High-risk endometrial cancer includes women with stage III or higher endometrial cancer, regardless of

histology or grade. However, women with a serous (USC) or clear cell (CC) carcinoma are deemed at high

risk, regardless of stage. These women are at a high risk of relapse and death.

●

A 2009 systematic review that included over 50 studies reported that the prognosis associated with a

positive peritoneal cytology varied according to the presence of other factors [3]. Women with positive

peritoneal cytology, but otherwise low-risk disease (grade 1 or 2, myometrial invasion <50 percent, no

cervical involvement, no lymphovascular space invasion) had a significantly lower rate of recurrence

compared with other women (4.1 versus 32 percent).

●

However, a 2012 analysis of 14,704 patients identified from the Surveillance, Epidemiology, and End

Results (SEER) registry reported that positive peritoneal cytology was an independent predictor of mortality,

regardless of histologic subtype, among women with early-stage (stage I to II) endometrial carcinoma [4].

The main results were:

●

Patients with high-risk factors (eg, grade 3 disease, clear cell or serous histology) were more likely to

have positive peritoneal cytology than those without high-risk factors (17.5 versus 7.5 percent,

respectively, p <0.0001).

•

The presence of positive peritoneal cytology predicted significantly poorer survival regardless of

histology and tumor grade compared with those with negative cytologic results.

•

The risk of death was significantly higher among women with positive peritoneal cytology compared

with those with negative peritoneal cytology and stage IA disease (hazard ratio [HR] 4.6, 95% CI 3.79-

5.66).

•

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We do not routinely consider peritoneal cytology results by themselves in the formulation of a treatment plan for

patients with endometrial cancer and continue to make treatment decisions primarily based on extent of disease

(determined at staging) and final pathologic features. We agree with the 2009 International Federation of

Gynecology and Obstetrics (FIGO) staging guidelines for endometrial cancer and report cytology results

separately without adjustment to the T-stage [5]. (See "Endometrial carcinoma: Pretreatment evaluation, staging,

and surgical treatment", section on 'Staging and primary surgical treatment'.)

Older age — Older age has been associated with higher rates of clinical failure and survival in several [6-11] (but

not all [12]) studies. The association between age and prognosis can be illustrated by data from the Gynecologic

Oncology Group (GOG) protocol 33, in which five-year relative survival rates for women with clinical stage I and

II endometrial cancer stratified by age were as follows:

Whether age represents an independent prognostic factor is controversial. Women over the age of 65 have more

frequent deep myometrial invasion, high tumor grade, and advanced tumor stage [7,12-15]. Furthermore, less

aggressive therapy could also account for some of the poor outcomes seen in older patients [12,14,15]. As noted

above, age is used to categorize women with intermediate-risk disease into either a high or low-intermediate risk

group, which may influence treatment decisions. However, even when treated in uniform fashion, older women

seem to have higher recurrence rates and inferior survival compared with their younger counterparts. (See

'Definition of risk based on histology and stage' above.)

Black women — Race also factors into prognosis. Black women have a consistently poorer outcome than

Caucasians, an effect that is incompletely explained by imbalances in psychosocial, clinicopathologic, and

treatment factors [16-22]. Some of the racial disparity in survival has been attributed to a lower incidence of

good-prognosis (low-grade endometrioid) cancers in blacks and a higher incidence of high-risk (grade 3 and nonendometrioid)

tumors [23,24]. However, an alternative explanation for the worse survival is provided by emerging

data suggesting that at least in uterine serous cancers, blacks have a higher frequency of overexpressed or

amplified human epidermal growth factor receptor 2 (HER2) [25,26].

In contrast to Black women, Asian women appear to have a better survival relative to other populations, an effect

that is attributed at least in part to younger age at diagnosis. In data from the SEER of the National Cancer

Institute, 1 in 50 Asian women with uterine cancer was diagnosed before age 35 as compared with 1 in 150 white

women [27].

Molecular prognostic factors — A number of molecular factors hold promise for determining the prognostic

value of routine surgical and histologic characteristics. These include p53 and p16 overexpression, phosphatase

and tensin homolog (PTEN) mutations, markers of proliferation, microsatellite instability, tumor expression of

estrogen (ER) and/or progesterone (PR) receptors, or proteins involved in the phosphoinositide 3-kinase

● ≤40 years old – 96 percent

● 41 to 50 years old – 94 percent

● 51 to 60 years old – 87 percent

● 61 to 70 years old – 78 percent

● 71 to 80 years old – 71 percent

● ≥80 years old – 54 percent

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(PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway [28-41].

Until more data become available, however, they remain investigational and should not be incorporated into

clinical decision making. As examples:

OVERVIEW OF TREATMENT — All women with endometrial cancer should undergo surgical staging, especially

if the disease is not suspected to be metastatic. For these women, the treatment approach is based on final

pathology and the histologic type of cancer, which are used to define risk (see 'Definition of risk based on

histology and stage' above):

Low-risk endometrial cancer — For women with low-risk endometrial cancer, no adjuvant treatment is

indicated following surgery. However, some women may wish to preserve future fertility, despite a biopsy-proven

diagnosis of grade 1 endometrial cancer. These patients may be candidates for conservative treatment using

progestin therapy (eg, megestrol acetate), although careful selection of appropriate patients is necessary. (See

"Treatment of low-risk endometrial cancer".)

Intermediate-risk endometrial cancer — Women with intermediate-risk endometrial cancer benefit most from

postoperative radiation therapy (RT). However, some clinicians may offer adjuvant chemotherapy (with or without

In a report of 134 women who underwent complete surgical staging, p53 overexpression and high S phase

fraction (≥9 percent) in preoperative endometrial curettage specimens were independent, significant,

presurgical molecular determinants of outcome. The presence of both factors increased the risk of

recurrence sevenfold, and the risk of cancer-related death almost 10-fold when compared with women with

neither factor [29].

●

The absence of PR expression has been correlated with the presence of lymph node metastases and

inferior survival in some reports [31,32]. Absence of ER expression appears to have some prognostic value,

but less than PR expression [33].

●

Many series report a more favorable outcome for women whose endometrial cancers arise in the setting of

Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), but there may be subsets with a

poorer prognosis. Within the subgroup of endometrioid endometrial tumors with high-level microsatellite

instability (MSI-H), tumors that harbor mutations in the cell cycle checkpoint gene, ATR have a significantly

worse prognosis than those with a wild-type ATR gene [39]. (See "Endometrial and ovarian cancer

screening and prevention in women with Lynch syndrome (hereditary nonpolyposis colorectal cancer)".)

●

Mutations involving the PI3K/AKT/mTOR pathway appear to be associated with prognosis. For example, in

one report, amplifications of the catalytic subunits of PI3K (PI3KCA) were significantly associated with

poorer recurrence-free survival compared with those without amplification [42]. Therefore, targeting of this

pathway appears to be a promising approach to patients with endometrial cancer.

Strategies directed at targeting aberrations in the PI3K/AKT/mTOR pathway include rapalogs, inhibitors of

either PI3K or mTOR individually or together, and inhibition of AKT [40]. However, one retrospective review

of patients treated with mTOR inhibitors in phase II studies did not identify a predictive biomarker for

sensitivity to mTOR inhibition [41].

●

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RT) to women with higher risk intermediate-risk endometrial cancer, although the benefit of this approach is not

clear. Therefore, whenever possible, we prefer to offer treatment on clinical trials. (See "Adjuvant treatment of

intermediate-risk endometrial cancer".)

High-risk endometrial cancer — Women with high-risk endometrial cancers undergoing surgery should be

offered adjuvant chemotherapy. Whether there is an additional benefit to RT is not entirely clear. Therefore, we

believe these patients should be offered participation in appropriate clinical trials, such as Gynecologic Oncology

Group (GOG) 258, a phase III trial of chemotherapy (carboplatin and paclitaxel) with or without cisplatin and RT.

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

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and

"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond

the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10 to 12 grade reading level and are best for patients who want in-depth information and are

comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

"patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis and staging (Beyond the

Basics)" and "Patient education: Endometrial cancer treatment after surgery (Beyond the Basics)")

●

For women with newly diagnosed endometrial cancer, the risk of recurrence is used to categorize women as

having low, intermediate, or high-risk endometrial cancer. In general, this is based on tumor histology and

pathologic stage. (See 'Definition of risk based on histology and stage' above.)

●

Beyond stage and tumor histology, other factors may be used to individualize risk further. These include

lower uterine segment involvement, older age, and race. (See 'Other prognostic factors' above.)

●

While molecular characterization of the tumor can help distinguish risk, more data are needed before we

utilize this information for tailoring adjuvant treatment. (See 'Molecular prognostic factors' above.)

●

Women with low-grade (grade 1 or 2) endometrioid cancers confined to the endometrium (a subset of stage

IA disease) are classified as having low-risk endometrial cancer. Because their prognosis following surgery

is excellent, no adjuvant treatment is required. (See 'Low-risk endometrial cancer' above.)

●

Women with endometrial cancer that invades the myometrium (stage IA or IB) or demonstrates occult

cervical stromal invasion (stage II) have intermediate-risk disease. These patients are candidates for

adjuvant radiation therapy (RT). Although there is no clear role for chemotherapy as part of an adjuvant

treatment strategy, some clinicians recommend chemotherapy to women with high intermediate-risk

disease. (See 'Intermediate-risk endometrial cancer' above.)

●

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●

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Topic 16742 Version 13.0

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GRAPHICS

Staging uterine carcinoma* (TNM and International Federation of Gynecology and

Obstetrics [FIGO])

Primary tumor (T) (surgical-pathologic findings)

TNM

CSN

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Approach to Adjuvant Treatment of Endometrial Cancer