Adjuvant treatment of high-risk endometrial cancers

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Adjuvant treatment of high-risk endometrial cancers

Authors: Gini Fleming, MD, Paul A DiSilvestro, 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: Sep 22, 2016.

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

developed countries and the second most common in developing countries. Among the different histologic types

of adenocarcinomas, grade 1 and 2 endometrioid uterine cancers have a favorable prognosis and typically

present at an early stage. Other histologic types of uterine adenocarcinoma (eg, serous, clear cell) are

associated with a poorer prognosis.

The American Joint Committee on Cancer (AJCC) and International Federation of Gynecology and Obstetrics

(FIGO) combined staging system is used to designate cancer stage (table 1). In addition to stage, other

pathologic factors are used to assign risk for recurrent or persistent disease into low, intermediate, and high risk.

Women with high-risk endometrial cancer have a poor prognosis following surgery alone. Therefore, adjuvant

treatment is often administered, although the effect of any therapy following surgery on overall survival is unclear.

This review will focus on treatment of high-risk endometrial cancer.

An overview of endometrial cancer, including clinical features and an approach to diagnosis, the approach to

adjuvant treatment, and treatment of both low- and intermediate-risk endometrial cancer are discussed

separately.

®

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● (See "Overview of endometrial carcinoma".)

● (See "Endometrial carcinoma: Clinical features and diagnosis".)

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

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

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

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DEFINITION OF HIGH RISK — Patients are classified as having high-risk endometrial cancer if they have

serous or clear cell adenocarcinoma (any stage) or pathologic stages III/IV disease (table 1).

Some experts also include the presence of specific risk factors for women with early-stage endometrial cancer

(ie, deep myometrial invasion, grade 3 disease, tumor lymphovascular space invasion [LVSI]) (see 'High

intermediate-risk disease' below and "Adjuvant treatment of intermediate-risk endometrial cancer"). Results of

The Cancer Genome Atlas (TCGA) analysis suggest that a subset of grade 3 endometrioid cancers are

biologically similar to serous carcinomas, but this subgroup has not been well defined using conventional

clinicopathologic factors [1].

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

Uterine serous or clear cell carcinoma — Compared with endometrioid adenocarcinomas, uterine serous and

clear cell carcinomas are more aggressive histologic types [2]. This was demonstrated in a Surveillance,

Epidemiology, and End Results (SEER) study of cases diagnosed from 1998 to 2001 [2]. The five-year survival

rate stratified by histologic type was 45, 65, and 91 percent for serous, clear cell, and endometrioid

adenocarcinomas, respectively.

This poorer prognosis was also seen when stratified by stage at presentation [2]:

Stage III disease — Compared with women with early-stage I or II endometrial cancer (table 1), patients with

surgical and pathologic stage III endometrial cancer have a lower five-year survival rate (60 versus 97 and 80

percent for stage I and II, respectively) [2]. However, outcomes appear to differ based on grade. Among women

with stage III disease, those with grade 1 adenocarcinoma have a higher five-year survival rate (83 versus 68

and 48 percent for women with grade 2 or 3 tumors, respectively).

High intermediate-risk disease — Individual experts and cooperative groups may also include women with

intermediate-risk endometrial cancer in clinical trials of high-risk endometrial cancer based on three tumorassociated

risk factors: grade 2 or 3 histology, outer-third myometrial invasion, or LVSI. The Gynecologic

Oncology Group (GOG) has used these factors to include women in clinical trials for high-risk endometrial cancer

as below:

● (See "Treatment of recurrent or metastatic endometrial cancer".)

Among women diagnosed with stage I serous, clear cell, or endometrioid cancers, the five-year survival rate

was 74, 88, and 95 percent.

●

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

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

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

● Patients of any age with all three risk factors

● Patients 50 to 69 years old with at least two factors

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A discussion on the approach to women with high intermediate-risk endometrial cancer is covered separately.

(See "Adjuvant treatment of intermediate-risk endometrial cancer", section on 'High intermediate-risk disease'.)

TREATMENT APPROACH — Given the lack of high-quality data to help guide recommendations, there is no

uniform approach to the treatment of women with high-risk endometrial cancer. For women with surgically and

pathologically defined high-risk endometrial cancer, we take into account whether disease is confined to the

uterus (stage I/II) or whether disease extends outside of the uterus (stage III) (table 1).

Women with bulky stage III disease not amenable to surgery cannot be cured by nonsurgical therapy alone, and

these patients are treated similarly to women with recurrent or metastatic endometrial cancer. (See "Treatment of

recurrent or metastatic endometrial cancer".)

Serous carcinoma — The risk of recurrence and death for women with serous carcinoma is dependent on the

extent of tumor involvement. For women with early-stage disease (stage I to II), our approach is discussed

below. The approach to women with fully resected stage III disease is discussed separately. (See 'Stage III

disease, regardless of histology' below.)

Stage IA disease without myometrial invasion — Although the data are limited, women with endometrial

serous carcinoma without myometrial invasion (subset of stage IA) are at a lower risk of recurrence compared

with women with myometrial invasion (9 versus 29 percent) [3]. Therefore, we prefer to treat these patients with

vaginal brachytherapy (VBT) alone (with or without radiation therapy [RT]). However, given the overall low risk of

recurrence, observation may be a reasonable alternative. A review of cases of stage IA polyp- or endometriumlimited

endometrial cancers of clear cell, serous, or mixed histology who received a variety of adjuvant therapies

showed a three-year progression-free survival (PFS) rate of 94.9 percent and no impact of histologic subtype on

adjuvant treatment [4].

An analysis of stage IA noninvasive serous carcinomas showed that adjuvant chemotherapy or pelvic radiation

had no impact on outcome in patients who had undergone lymphadenectomy. There was an improved outcome

for unstaged patients, but this effect was likely due to occult spread to lymph nodes in a number of these

patients. The overall risk of recurrence in staged patients with no adjuvant therapy was 23.5 percent with a

median follow-up time of 52 months [5]. Surgical staging, including lymph node assessment, for patients with

endometrial cancer is discussed elsewhere. (See "Endometrial carcinoma: Pretreatment evaluation, staging, and

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

Stage IA or IB disease — For women with early-stage serous carcinoma with myometrial invasion (stage IA

or IB), we suggest adjuvant chemotherapy plus RT [3,6-9], although the evidence for use of RT is not as strong

as the evidence for the use of chemotherapy. The largest dataset supporting the adjuvant use of chemotherapy

in stage I serous carcinomas comes from the Uterine Papillary Serous Carcinoma Consortium study that

included 142 women with stage I serous cancers [6]. Following surgery, 23 percent received no further treatment,

while 14 and 63 percent were treated with adjuvant RT alone or adjuvant chemotherapy, respectively. Of those

receiving chemotherapy (primarily carboplatin and paclitaxel administered for three or more cycles), 37 percent

also received RT. Adjuvant chemotherapy was associated with:

● Patients who are 70 years or older with at least one factor

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As with most retrospective studies, there is the possibility of bias in the selection of treatments and particularly, in

who did or did not receive chemotherapy.

Stage II disease — For women with stage II serous carcinoma, we suggest adjuvant chemotherapy plus RT.

The largest report on outcomes for women with stage II serous carcinoma comes from the Uterine Papillary

Serous Carcinoma Consortium and included 55 women (20 and 35 with stage IIA and IIB disease, respectively)

[10]. Of these, 10 (18 percent) underwent observation following surgery, 19 (34.5 percent) were treated with

chemotherapy (18 of whom were treated with carboplatin plus paclitaxel), and 26 (47.3 percent) underwent RT

(though it is unclear if pelvic and/or VBT was administered). Of those treated with chemotherapy (n = 19), the

median number of cycles was five (range, three to six). Of the 38 total patients treated with RT (with or without

chemotherapy), 34, 50, and 16 percent were treated with VBT, whole-pelvic RT plus VBT, and whole-abdominal

RT (alone or in combination with pelvic RT or VBT), respectively.

Patients who received adjuvant chemotherapy (with or without RT) had:

This recommendation is supported by a report from the Canadian high-risk endometrial cancer consortium

(CHREC) [11]. They analyzed data on patients treated between 2000 and 2012 from seven centers. A

multivariable analysis including only surgically staged stage I and II serous carcinoma showed that the use of

chemotherapy was associated with an improvement in OS, while the use of adjuvant radiotherapy was not.

Clear cell carcinoma — There are no prospective data to help define the optimal management of women with

clear cell carcinoma. In the absence of high-quality data, some UpToDate contributors favor treating clear cell

carcinomas with chemotherapy and radiation, along the lines of serous carcinoma. If such an approach is

adopted, it is preferable to treat clear cell carcinoma initially with chemoradiation followed by chemotherapy,

given that this histology is likely to be more chemoresistant than other histologies. Other UpToDate contributors

utilize radiation alone for clear cell carcinoma (vaginal brachytherapy, with or without pelvic RT), given that the

limited data that exist support an improvement in survival with radiation but not chemotherapy. In a study by the

CHREC, among patients with stage I to III clear cell carcinoma, adjuvant radiotherapy was associated with an

improvement in overall survival, while adjuvant chemotherapy was not [11].

A statistically significant reduction in the recurrence rate (11 versus 30 and 25 percent with surgery alone or

surgery followed by RT, respectively).

●

A statistically significant improvement in five-year progression-free survival (PFS, 82, 64, and 65 percent,

respectively).

●

An improvement in five-year cancer-specific survival (88, 60, and 70 percent, respectively) that was

statistically nonsignificant.

●

A statistically significant reduction in the recurrence rate compared with those not treated with chemotherapy

(10 versus 50 percent, respectively).

●

● A statistically significant improvement in PFS at five years (86 versus 41 percent, respectively).

● An improvement in overall survival (OS, 88 versus 64 percent), although it was not statistically significant.

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Stage III disease, regardless of histology — Patients with extrauterine disease confined to the pelvis or vagina

(stage III) are treated with chemotherapy. Adjuvant chemotherapy is associated with improvement in both PFS

and OS, regardless of whether RT is used. Although there are more prospective randomized data supporting the

use of chemotherapy than exist for radiotherapy in stage III disease, we agree with the current American Society

for Radiation Oncology (ASTRO) guidelines and suggest use of radiotherapy in addition to chemotherapy,

particularly in women with a good performance status. (See 'Timing of radiation with chemotherapy' below.)

As a possible exception to this approach, some UpToDate contributors treat clear cell carcinoma as well as

grade 1 endometrioid carcinomas with limited nodal involvement (1 to 2 nodes) with radiation alone, although

others also utilize chemotherapy, as for other histologies. (See 'Clear cell carcinoma' above.)

The benefit of adjuvant chemotherapy for women with stage III endometrial cancer is supported by a 2013 metaanalysis

(updated in May 2014) that included the data from two Gynecologic Oncology Group (GOG) randomized

trials (n = 620) [12]:

Compared with RT, the administration of platinum-based combination chemotherapy resulted in:

While prospective randomized data of chemotherapy versus chemotherapy and radiation are not yet available, a

phase 2 study of combined-modality treatment suggested favorable outcomes compared with historic results of

chemotherapy only. In the Radiation Therapy Oncology Group (RTOG) 9708 phase 2 trial of pelvic radiation with

concurrent cisplatin followed by four cycles of paclitaxel and cisplatin, the pelvic failure rate was 2 percent [13],

whereas it was 18 percent among patients treated with chemotherapy only in GOG 122 [14]. Retrospective data

of patients with optimally resected stage IIIC disease also suggest improved outcomes with chemotherapy and

radiation compared with chemotherapy alone [15,16]. For example, in a registry study including over 21,000

patients with stage III endometrial cancer, patients receiving adjuvant chemoradiotherapy experienced a

decreased risk of death on multivariate analysis relative to those receiving adjuvant RT or chemotherapy only

(HR 0.62, 95% CI 0.56-0.70) [16]. Retrospective data also specifically support the use of RT in stage IIIC serous

carcinomas [17].

We await reporting of GOG 258, a prospective trial in which women with stage III disease were randomly

assigned to chemotherapy alone or chemotherapy with pelvic radiotherapy, to further inform our approach.

Choice of chemotherapy regimen — For most women with high-risk endometrial cancer, we suggest

carboplatin and paclitaxel in the adjuvant setting. This is based on the results of GOG 209, which were presented

at the 2012 Society of Gynecologic Oncology Annual Meeting [18]. This trial compared carboplatin plus paclitaxel

GOG 122 – A comparison of whole-abdominal RT versus chemotherapy (doxorubicin plus cisplatin) in

women with cytoreduced stage III or IV endometrial cancer.

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