International Journal of Gynecology and Obstetrics 131 (2015) S96S104

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International Journal of Gynecology and Obstetrics

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FIGO CANCER REPORT 2015

Cancer of the corpus uteri

Frdric Amant a, Mansoor Raza Mirza b, Martin Koskas c, Carien L. Creutzberg d
a
Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium
b
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
c
Division of Gynecologic Oncology, Bichat University Hospital, Paris, France
d
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

1. Staging Serous adenocarcinoma.

Clear cell adenocarcinoma.
1.1. Anatomy Undifferentiated carcinoma.
Mixed carcinoma (carcinoma composed of more than one type, with
1.1.1. Primary site at least 10% of each component).
The upper two-thirds of the uterus above the level of the internal
cervical os is called the corpus. The fallopian tubes enter at the upper lat-
eral corners of a pear-shaped body. The portion of the muscular organ Endometrial cancers are usually classied in one of the following
that is above a line joining the tubo-uterine orices is often referred to two categories:
as the fundus. Type 1 (grade 1 and 2 endometrioid carcinoma) may arise from
complex atypical hyperplasia and is linked to unopposed estro-
1.1.2. Nodal stations genic stimulation.
The major lymphatic trunks are the utero-ovarian (infundibu- Type 2 includes grade 3 endometrioid tumors as well as tumors of non-
lopelvic), parametrial, and presacral, which drain into the hypogastric, endometrioid histology and develops from atrophic endometrium.
external iliac, common iliac, presacral, and para-aortic nodes. Although
a direct route of lymphatic spread from the corpus uteri to the para-
aortic nodes through the infundibulopelvic ligament has been sug-
1.3.2. Histopathologic grades (G)
gested from anatomical and sentinel lymph node studies, direct metas-
tases to the para-aortic lymph nodes are uncommon. GX: Grade cannot be assessed.
G1: Well differentiated.
1.1.3. Metastatic sites G2: Moderately differentiated.
The vagina and lungs are the common metastatic sites. G3: Poorly or undifferentiated.

1.2. Rules for classication

The FIGO Committee on Gynecologic Oncology, following its
meeting in 1988, recommended that endometrial cancer be surgically
staged. There should be histologic verication of grading and extent of
the tumor.
1.3. Histopathology
Cases of carcinoma of the corpus should be grouped with regard to
the degree of differentiation of the adenocarcinoma as follows:
G1: less than 5% of a nonsquamous or nonmorular solid growth pattern.
G2: 6%50% of a nonsquamous or nonmorular solid growth pattern.
G3: greater than 50% of a nonsquamous or nonmorular solid
growth pattern.

1.3.1. Histopathologic types (according to World Health Organization/
International Society of Gynecological Pathology classication)
All tumors are to be microscopically veried.
The histopathologic types are:
Endometrioid carcinoma: adenocarcinoma; adenoacanthoma (adeno-
carcinoma with squamous metaplasia); and adenosquamous carcino-
ma (mixed adenocarcinoma and squamous cell carcinoma).
Mucinous adenocarcinoma.
1.3.3. Pathologic grading notes
Notable nuclear atypia (pleomorphism and prominent nucleoli), in-
appropriate for the architectural grade, raises the grade of a grade 1 or
grade 2 tumor by 1.
In serous and clear cell adenocarcinomas, nuclear grading takes pre-
cedent. Most authors consider serous and clear cell carcinomas high
grade by denition.
Adenocarcinomas with squamous differentiation are graded accord-
ing to the nuclear grade of the glandular component.

http://dx.doi.org/10.1016/j.ijgo.2015.06.005
0020-7292/ 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104 S97

1.4. FIGO staging classication Table 2

Cancer of the corpus uteri: FIGO staging compared with the TNM classication.a

The current FIGO staging classication for cancer of the corpus uteri FIGO Stage Union for International Cancer Control (UICC)
is given in Table 1. Comparison of the stage groupings with the TNM T N M
classication is given in Table 2. (tumor) (lymph nodes) (metastasis)

I T1 N0 M0
1.4.1. Regional lymph nodes (N) IA T1a N0 M0
IB T1b N0 M0
NX: Regional lymph nodes cannot be assessed.
II T2 N0 M0
N0: No regional lymph node metastasis. III T3 N0N1 M0
N1: Regional lymph node metastasis to pelvic lymph nodes. IIIA T3a N0 M0
N2: Regional lymph node metastasis to para-aortic lymph nodes, with IIIB T3b N0 M0
or without positive pelvic lymph nodes. IIIC1 T1T3 N1 M0
IIIC2 T1T3 N1 M0
IVA T4 Any N M0
IVB Any T Any N M1
a
1.4.2. Distant metastasis (M) Carcinosarcomas should be staged as carcinoma.

MX: Distant metastasis cannot be assessed.

2. Introduction
M0: No distant metastasis.
M1: Distant metastasis (includes metastasis to inguinal lymph nodes
Worldwide, endometrial cancer is the sixth most common malig-
or intraperitoneal disease).
nant disorder with approximately 290 000 new cases annually. The
incidence is higher in high-income countries (5.5%) compared with
low-income countries (4.2%), although specic mortality is higher in
1.4.3. Rules related to staging the latter. The cumulative risk of endometrial cancer up to the age of
Corpus cancer is surgically staged, therefore procedures previously 75 years has been estimated as 1.6% for high-income regions and 0.7%
used for determination of stage are no longer applicable (e.g. the nd- for low-income countries [3]. This difference has been associated with
ings of fractional curettage to differentiate between Stage I and Stage II). an epidemic of obesity and physical inactivity, two important risk fac-
There may be a small number of patients with corpus cancer who tors, in high-income countries. Moreover, endometrial cancer patients
will be treated primarily with radiation therapy. In these cases, the clin- with obesity also tend to have a poorer outcome [4]. On the other
ical staging adopted by FIGO in 1971 would still apply, but designation hand, physical activity and long-term use of continuous combined
of that staging system should be noted. estrogenprogestin therapy is associated with a reduced risk of endo-
Ideally, distance from tumor to serosa should be measured. The metrial cancer [4,5]. Obesity is associated with earlier age at diagnosis,
presence of lymphovascular space invasion (LVSI) should also be re- and with endometrioid-type endometrial cancers. Similar associations
ported in the pathological report of the hysterectomy specimen. A were not observed with nonendometrioid cancers, consistent with dif-
LVSI-positive status has a signicantly worse prognosis, especially if ex- ferent pathways of tumorigenesis [6].
tensive LVSI is found [1]. The distinction by LVSI status could be more In North America and Europe, endometrial cancer is the most
relevant than the distinction between Stages IA and IB for predicting frequent cancer of the female genital tract and the fourth most common
survival in Stage I endometrial cancer [2]. site after breast, lung, and colorectal cancer [3]. The incidence is rising as
As a minimum, any enlarged or suspicious lymph nodes should life expectancy increases. Furthermore, an estimated 23 700 European
be removed in all patients. For high-risk patients (grade 3, deep women died of endometrial cancer in 2012, which is the eighth most
myometrial invasion, cervical extension, serous or clear cell histology), common cause of death from cancer in women [7]. Importantly, the
complete pelvic lymphadenectomy and resection of any enlarged corrected corpus uteri cancer mortality rates showed a decrease in
para-aortic nodes is recommended. most European Union member states among women born before
1940 [8].
In North America, it is the seventh most frequent cause of death,
Table 1 with approximately 55 000 new cases and 10 000 estimated new deaths
Cancer of the corpus uteri.
each year [3]. The increase in endometrial cancer incidence rates
FIGO after 2002 may be related to the widespread decrease in estrogen
Stage plus progestin menopausal hormone therapy use, which has been
Ia Tumor conned to the corpus uteri reported to lower endometrial cancer risk in overweight and obese
IAa No or less than half myometrial invasion women [9]. However, the main reasons underlying the increase in en-
IBa Invasion equal to or more than half of the myometrium
dometrial cancer incidence in high-income countries remain the
IIa Tumor invades cervical stroma, but does not extend beyond the
uterus b increasing prevalence of obesity in postmenopausal as well as the in-
IIIa Local and/or regional spread of the tumor creased life expectancy.
IIIAa Tumor invades the serosa of the corpus uteri and/or adnexaec Endometrioid adenocarcinoma progresses through a premalignant
IIIBa Vaginal involvement and/ or parametrial involvementc phase of intraepithelial endometrial neoplasia in a large proportion of
IIICa Metastases to pelvic and/or para-aortic lymph nodesc
cases [10]. Other forms such as serous and clear cell carcinoma arise as
IIIC1a Positive pelvic nodes
IIIC2a Positive para-aortic nodes with or without positive pelvic lymph nodes a result of a sequence of genetic mutations. In serous endometrial can-
IVa Tumor invades bladder and/or bowel mucosa, and/or distant cer, the mutant p53 plays a pivotal role [11]. Endometrial cancer re-
metastases search has gained some momentum in recent years and now provides
IVAa Tumor invasion of bladder and/or bowel mucosa
better information for clinical practice. Its early presentation following
IVBa Distant metastasis, including intra-abdominal metastases and/or
inguinal nodes) postmenopausal bleeding results in a generally good prognosis, but it
a
should be treated using evidence-based protocols, and where appropri-
Either G1, G2, or G3.
b
Endocervical glandular involvement only should be considered as Stage I and no lon-
ate, by expert multidisciplinary teams.
ger as Stage II. The role of population screening for endometrial cancer remains low
c
Positive cytology has to be reported separately without changing the stage. [12], although certain high-risk groups such as those with Lynch type 2
S98 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
syndrome can undergo endometrial surveillance by biopsy, or trans-
vaginal ultrasonography if post menopausal. Transvaginal ultrasound
is reasonably sensitive and specic but screening of asymptomatic
women has in general been recommended only for those with Lynch
syndrome [13].
Following presentation, ultrasound is an effective rst test with a
high negative predictive value when the endometrial thickness is less
than 5 mm. In one of the largest studies undertaken, there was a nega-
tive predictive value of 96% among 1168 women in whom the results of
transvaginal ultrasound were correlated with an endometrial biopsy
obtained by curettage [14]. When a biopsy is required, this can be ob-
tained usually as an ofce procedure using a number of disposable in-
struments developed for this purpose. In certain cases, hysteroscopy
may be helpful, and with exible instruments can also be done without
recourse to general anesthesia. However, the biological role of cells that
are transtubally ushed during hysteroscopy remains uncertain. If cer-
vical stenosis or patient tolerance does not permit an ofce procedure,
hysteroscopy and curettage under anesthesia may be necessary. Indi-
viduals whose pelvic examination is unsatisfactory may also be evaluat-
ed with transvaginal or abdominal ultrasound to rule out concomitant
adnexal pathology.
Following a histopathologic diagnosis of endometrial adenocar-
cinoma, the local extent of the tumor, and evidence of metastatic dis-
ease should be determined. In addition, the perioperative risk should
be assessed.
As a minimum, the pathology report from endometrial sampling
should indicate the tumor type and grade of the lesion. A chest X-ray,
full biochemistry (renal and liver function tests), and blood count are
routine. A serum CA125 may be of value in advanced disease for
follow-up. Evaluation for metastasis is indicated particularly in patients
with abnormal liver function tests, and clinical ndings such as
parametrial or vaginal tumor extension. In high-risk patients, imaging
of the abdomen and lymph nodes may help determine the surgical
approach. In certain situations, cystoscopy and/or proctoscopy/barium
enema may be helpful if direct extension to the bladder or rectum
is suspected.
3. Prognostic tumor characteristics for high-risk disease
The recommended histopathologic criteria for determining high-
risk disease are:
Tumor grade 3 (poorly differentiated).
More than 50% of myometrial invasion.
Lymphovascular space invasion.
Non-endometrioid histology (serous, clear cell, undifferentiated,
small cell, anaplastic, etc.).
Cervical stromal involvement.
The most accurate means of assessing both depth of myometrial in-
vasion and cervical involvement is MRI scanning and intraoperative
frozen section [1517]. CT and MRI are equivalent in terms of evaluating
nodal metastases, but neither is good enough to replace surgical lymph
node assessment, which provides histological conrmation [18,19]. The
role of PET-CT and PET-MRI is currently being investigated.
Nonsurgical staging for endometrial cancer, where extrauterine dis-
ease exists, is inherently inaccurate, particularly in respect to small
nodal involvement, intraperitoneal implants, and adnexal metastasis.
4. Surgical staging procedure for endometrial cancer
In 1988, the FIGO Cancer Committee changed the ofcial FIGO stag-
ing from clinical to surgical for endometrial cancer. Since that recom-
mendation, considerable debate has ensued as to what constitutes an
internationally acceptable approach. A generally recommended proto-
col would be that the abdomen should be opened with a vertical
midline abdominal incision and peritoneal washings taken immediately
from the pelvis and abdomen, followed by careful exploration of the
intra-abdominal contents. The omentum, liver, peritoneal cul-de-sac,
and adnexal surfaces should be examined and palpated for any possible
metastases, followed by careful palpation for suspicious or enlarged
nodes in the aortic and pelvic areas. The standard surgical procedure
should be an extrafascial total hysterectomy with bilateral salpingo-
oophorectomy. Adnexal removal is recommended even if the tubes
and ovaries appear normal, as they may contain micrometastases.
Vaginal cuff removal is not necessary, nor is there any benet from
excising parametrial tissue in the usual case. Where obvious cervical
stromal involvement is demonstrated preoperatively, a modied radical
hysterectomy has been historically performed. However, there is
consensus (ESMO-ESGO-ESTRO) that simple hysterectomy with free-
margins together with pelvic lymphadenectomy can be sufcient.
There has also been considerable debate on the safety of endoscopic
surgery for the treatment of endometrial cancer. Recent studies have
demonstrated that laparoscopic removal of the uterus and adnexae
(in experienced hands) appears to be safe. Whereas there is no differ-
ence in terms of major complications between abdominal hysterectomy
and laparoscopically assisted vaginal hysterectomy (LAVH) or total lap-
aroscopic hysterectomy (TLH), the laparoscopic approach is associated
with a signicantly decreased risk of major surgical adverse event, a
shorter hospital stay, less pain, and quicker resumption of daily activi-
ties [2022]. Since the oncological safety of the laparoscopic approach
has now been demonstrated in several randomized studies [23,24], hys-
terectomy and bilateral salpingo-oophorectomy should be performed
with laparoscopy in those patients with no contraindications to laparos-
copy (e.g. large-volume uterus). This approach can be accompanied by a
laparoscopic lymphadenectomy, if surgical staging is to be undertaken.
Robotic surgery for the surgical management of the morbidly obese pa-
tient is an option only in experienced hands. In such cases, the surgical
management using robotics has been reported to be safe and have
less perioperative complications compared with open surgery [25].
Retrospective studies have suggested equivalent oncologic outcomes
compared with traditional laparoscopic surgery [26,27].
Although mandated through the staging system, lymphadenectomy
of the pelvic and para-aortic areas remains controversial. Selective node
sampling is of dubious value as a routine and complete lymphadenecto-
my should be reserved for cases with high-risk features. Many individ-
uals with endometrial cancer are obese or elderly, with other medical
problems, and clinical judgment is required to determine if additional
surgery is warranted. Any deeply invasive tumor or radiological sugges-
tion of positive nodes is an indication for retroperitoneal lymph
node evaluation, with removal of any enlarged or suspicious nodes.
Documentation of positive nodes identies a high-risk population and
helps to tailor adjuvant treatment, since patients with Stage III disease
appear to benet from chemotherapy [28].
Indications for aortic node sampling would include suspicious aortic
or common iliac nodes, grossly positive adnexae, grossly positive pelvic
nodes, and high-grade tumors showing full thickness myometrial inva-
sion. Patients with clear cell, papillary serous, or carcinosarcoma histo-
logic subtypes are also candidates for aortic node sampling.
5. Who should perform the surgery?
Low-risk tumors will have positive nodes in less than 5% of cases
(well differentiated and b1/2 myometrial invasion) and do not require
full surgical staging. These women can be safely operated on by a gener-
al gynecologist, but those at greater risk of extrauterine disease, who
may require lymphadenectomy, should be referred to a gynecological
oncologist since care provided by gynecologic oncologists has been as-
sociated with better survival in high-risk cancers [29]. Moreover, prima-
ry management by gynecologic oncologists has been suggested to result
in an efcient use of health care resources and minimization of the po-
tential morbidity associated with adjuvant radiation [30].
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This triaging of women can be done most effectively by a thorough
preoperative assessment, paying particular attention to the pathology
and to radiological features. Triaging for lymphadenectomy is also pos-
sible during surgery. Intraoperative assessment mainly involves assess-
ment of myometrial invasion [15,17,27]. Grading on frozen section is
possible, though suboptimal compared with preoperative grading [17].
6. When should surgery be performed?
The effect of waiting time for surgical staging on survival outcome of
endometrial cancer is controversial. A recent population-based study
concluded that a longer waiting time for surgical staging was associated
with worse survival outcomes in uterine cancer [31]. However, when
focusing on type I endometrial cancer only, the waiting time for surgical
staging was not associated with decreased survival outcome, presum-
ably due to its excellent prognosis anyway [32].
7. Is lymphadenectomy therapeutic?
Although required for accurate staging, a therapeutic benet for
lymphadenectomy is controversial. Historically, one casecontrol
study suggested that it may be therapeutic [33] and another showed a
good prognosis even in node-positive women [34]. Another retrospec-
tive study showed a survival benet of complete lymphadenectomy
for patients with grade 3 tumors [35]. In the UK, the MRC ASTEC trial,
however, which randomized 1400 women undergoing surgery for pre-
sumed Stage I endometrial cancer to pelvic lymphadenectomy or no
lymphadenectomy, showed no therapeutic benet [36]. An Italian ran-
domized trial of pelvic (and in 30% para-aortic) lymphadenectomy
versus no lymphadenectomy in 540 women also did not show any dif-
ference in rates of relapse or survival [37]. Both studies have been criti-
cized because of a limited effort with respect to the extent of dissection
and lymph node evaluation, because of the high proportion of low-risk
patients, and because no direct decision on adjuvant therapy based on
lymphadenectomy was part of the protocols. Lymphadenectomy is pri-
marily used for staging and should be considered in women with high-
risk factors [38]. Although a direct survival benet of lymphadenectomy
has not been documented, the procedure identies node-positive
patients that may benet from adjuvant treatment. An international
trial of the role of lymphadenectomy to direct adjuvant therapy
for high-risk endometrial cancer (STATEC) is planned. The ongoing
ENGOT-EN2-DGCG/EORCT 55102 trial aims to answer this question by
comparing survival in patients with Stage I grade 3 endometrioid endo-
metrial cancer, Stage I and II type 2 endometrial cancer or Stage II
endometrioid endometrial cancer and without metastatic node after
randomization for adjuvant chemotherapy.
In a retrospective study, para-aortic lymphadenectomy resulted
in an improved outcome in intermediate and high-risk patients
when compared with pelvic lymphadenectomy alone [39]. However,
adjuvant therapy was not comparable in the two groups. In patients
who underwent both pelvic and para-aortic lymphadenectomy, 77% re-
ceived chemotherapy whereas this was given to only 45% of patients
who underwent pelvic lymphadenectomy alone. This study suggests
both pelvic and para-aortic lymphadenectomy are benecial in compar-
ison with patients who undergo pelvic lymphadenectomy alone, but it
does not imply that extensive lymphadenectomy improves survival in
comparison with no lymphadenectomy.
8. Adjuvant treatment
Risk factors are used to determine the indication for adjuvant
radiation therapy, as the majority of patients are at low risk of recur-
rence. Low-risk disease (Stage I, grade 1 or 2 with no or supercial
myometrial invasion) does not require adjuvant radiation therapy,
as demonstrated in a Danish cohort study of low-risk women, with
96% ve-year survival after surgery alone [40]. A seminal Norwegian
S99
trial [41], which included 621 women treated after surgery with
vaginal brachytherapy, indicated that overall survival was not improved
by additional external beam radiation therapy (EBRT), although it did
reduce the risk of pelvic recurrence. Three large randomized trials of
pelvic radiation therapy versus no further treatment after surgery
have determined the role of radiation therapy based on risk factors,
and have led to reduced indications for adjuvant radiation therapy:
the PORTEC trial [42], the US GOG#99 trial [43], and the UK MRC
ASTEC trial [44]. All of these trials reported a signicant reduction
in the rates of vaginal and pelvic recurrence with EBRT, but with-
out survival benet. EBRT added to the risk of long-term morbidity.
PORTEC and ASTEC trials had similar recurrence and survival rates
without lymphadenectomy, compared with GOG#99 that included pa-
tients with documented node-negative disease. PORTEC-1 showed
that most pelvic relapses were located in the vaginal vault (75%), and
that salvage rates were high in women who had not had previous radi-
ation therapy [45].
The PORTEC-2 trial randomized 427 women with highintermediate
risk factors to EBRT or vaginal brachytherapy alone [46]. This trial
showed that vaginal brachytherapy had excellent vaginal control rates
(b2% at 5 years for both EBRT and vaginal brachytherapy groups),
with minimal adverse effects and signicantly better quality of life.
Quality of life of patients in the brachytherapy group remained the
same as those of an age-matched normal population [47]. Vaginal
brachytherapy has replaced EBRT as standard adjuvant treatment for
patients with highintermediate risk factors.
That omission of any EBRT or vaginal brachytherapy for
(high)intermediate risk disease increases recurrence rates (22%
for intermediate risk disease, of which 15% locoregional) but without
a difference in survival has been conrmed by a Danish population
study [48]. A patient preference study showed that patients
preferences are biased to a treatment preventing relapse [49].
The seminal NSGO-9501 trial investigated the use of both EBRT
and adjuvant platinum-based chemotherapy compared with EBRT
alone for patients with risk factors (grade 3 or deep invasion or adverse
histologies). This trial was published in a pooled analysis with the Italian
ILIADE trial [50]. While trials comparing adjuvant EBRT alone with
adjuvant cisplatin-based chemotherapy alone have not shown any dif-
ference in overall or relapse-free survival [51,52], the pooled NSGO-
EC9501/EORTC55991 and ILIADE trial analysis reported a signicant
9% improvement in progression-free survival (69% vs 78% at 5 years;
Hazard Ratio [HR] 0.63) with the addition of chemotherapy to EBRT,
and a trend for a 7% improvement in ve-year overall survival (75% vs
82%; HR 0.69, P = 0.07).
Ongoing and recently completed trials are currently investigating
the roles of EBRT or chemotherapy alone or combined EBRT and
chemotherapy for patients with high-risk or advanced stage disease
(GOG#249, GOG#258, PORTEC-3, Danish/EORTC trials). First results of
the randomised GOG-249 trial (601 patients with Stage I II endome-
trial cancer with high intermediate or high-risk factors, comparing
vaginal brachytherapy plus three cycles of carboplatin-paclitaxel
with pelvic EBRT) showed no differences in relapse-free survival (84%
vs 82%) or overall survival (92% vs 93%) between the arms at a median
follow-up of 24 months [53]. About 50% of the trial population had
grade 12 disease with a baseline ve-year survival of 86% 91%. In
the PORTEC-3 trial, patients with high-risk Stage I II or with Stage
III endometrial cancer were randomized to pelvic EBRT alone or EBRT
with two cycles of cisplatin followed by four cycles of carboplatin and
paclitaxel. PORTEC-3 completed accrual (686 patients enrolled) in late
2013 and results are expected in 2016. In the ongoing ENGOT-EN2-
DGCG-trial patients with node-negative endometrial cancer with
high-risk features are randomized to adjuvant chemotherapy (six cycles
of carboplatin-paclitaxel) or observation, with or without brachythera-
py in both arms. These trials will answer many of the questions regard-
ing optimal use and optimal schedules of adjuvant therapy for women
with high-risk endometrial cancer.
S100 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
In summary, adjuvant radiation therapy is not indicated for patients
with grade 12 tumors and no more than 50% myometrial invasion,
or for those with only a single risk factor. For patients with high
intermediate risk factors (at least two of the factors: age N60 years,
deep myometrial invasion, grade 3, serous or clear cell histology,
LVSI), vaginal brachytherapy alone is preferable to EBRT, providing ex-
cellent vaginal control without impacting on quality of life. In patients
with higher-risk disease (3 or more risk factors, Stages II and III), the
role of adjuvant chemotherapy, with or without radiation therapy, is
currently being investigated.
9. Progestogen therapy
This has been widely prescribed in the past, but a meta-analysis of
six randomized trials involving a total of 3339 women has shown no
survival benet for adjuvant progestogen therapy in endometrial cancer
[54]. A subsequently published randomized trial of 1012 women also
failed to demonstrate any survival benet [55].
10. Stage II
10.1. Occult Stage II disease
Patients with clinically occult Stage II disease are generally managed
in a similar way to patients with Stage I disease.
10.2. Clinical overt Stage II disease
Historically, radical hysterectomy, bilateral salpingo-oophorectomy,
bilateral pelvic lymphadenectomy, and selective aortic node dissection
can be used as primary treatment for clinically overt cervical involve-
ment. However, this strategy is poorly supported by the medical litera-
ture. Results from one of the rare retrospective studies could not nd
any survival benet from radical hysterectomy for patients with
suspected gross cervical involvement in comparison with simple or
modied radical hysterectomy [56]. Since radical hysterectomy in-
creases the risk of adverse events, surgical treatment in patients with
suspected gross cervical involvement deserves further prospective eval-
uation. Preoperative MRI scanning is advisable to exclude bladder in-
volvement and ensure local resectability. Studies indicate excellent
results for this approach, with no benet from the addition of radiation
for patients with negative nodes [57,58]. Adjuvant radiotherapy is usu-
ally reserved for patients with involved nodes and/or close or involved
surgical margins.
However, neoadjuvant therapy followed by a less extensive simple
hysterectomy can represent an alternative.
The need for adjuvant radiotherapy has not been studied in a ran-
domized trial, but a SEER study reported improved survival for patients
with Stage II endometrial cancer when adjuvant radiotherapy was used
after radical and simple hysterectomy [59,60].
If surgery is not considered feasible because of tumor extension, full
pelvic radiotherapy and intracavitary brachytherapy, as in cervical
cancer, may be employed.
11. Stage III
Most patients with Stage III endometrial cancer are managed by
complete surgical resection of all metastatic disease, followed by post-
operative EBRT and/or chemotherapy. The randomized GOG#122 trial
included patients with Stages III and IV disease and residual tumor up
to 2 cm, and compared whole abdominal radiation with intensive
adjuvant chemotherapy (eight cycles of doxorubicin and cisplatin). It
showed a survival benet for chemotherapy (42% vs 53% estimated
ve-year survival), although event rates were high in both arms [28].
Adjuvant platin-based chemotherapy (more recently, carboplatin
and paclitaxel) is increasingly used to reduce the risk of metastases.
Retrospective studies have shown substantial pelvic recurrence rates
when EBRT was omitted when using chemotherapy [61,62], and current
ongoing trials are investigating the roles of chemotherapy, and combi-
nations of chemotherapy and radiation therapy.
A recent meta-analysis including four multicenter randomized con-
trolled trials involving 1269 women with primary FIGO Stage III/IV en-
dometrial cancer who received primary cytoreductive surgery showed
that chemotherapy increases survival time after primary surgery by ap-
proximately 25% relative to radiotherapy [63]. Two trials, evaluating
620 women, mainly Stage III compared adjuvant chemotherapy with
adjuvant radiotherapy [52,64], one trial evaluating 552 women mainly
Stage III compared two chemotherapy regimens (cisplatin/doxorubicin/
paclitaxel versus cisplatin/doxorubicin treatment) in women who had
all undergone adjuvant radiotherapy (GOG 184) [65], and one trial con-
tributed no data [51].
Overall and progression-free survivals were longer with adjuvant
chemotherapy compared with adjuvant radiotherapy [63]. In subgroup
analyses, the effects on survival in favor of chemotherapy were not
different for Stage III and IV, or Stage IIIA and IIIC. This evidence was
of moderate quality. Data from one trial showed that women receiving
adjuvant chemotherapy were more likely to experience hematological
and neurological adverse events and alopecia, and more likely to
discontinue treatment, than those receiving adjuvant radiotherapy
[63]. There was no statistically signicant difference in treatment-
related deaths between the chemotherapy and radiotherapy treatment
arms [63]. There was no clear difference in progression free survival be-
tween intervention groups in the one trial that compared cisplatin/
doxorubicin/paclitaxel versus cisplatin/doxorubicin [65].
A large trial evaluating adjuvant chemotherapy alone (six cycles
of carboplatin-paclitaxel) compared with chemotherapy during and
after radiation therapy (same schedule as used in PORTEC-3) for Stage
III IV endometrial cancer (GOG 0258) has recently completed accrual
(804 patients) and results are expected in 2016.
Patients with presumed Stage III disease because of adnexal involve-
ment should have full surgical staging and expert pathologic examina-
tion of the specimen, as primary tumors of both the ovary and the
endometrium may be present. Management should be individualized,
and based on the stage of each tumor.
Patients with clinical Stage III endometrial carcinoma that is not
felt to be resectable by virtue of vaginal or parametrial extension are
best treated primarily by pelvic irradiation, with or without chemother-
apy [66]. Once therapy has been completed, exploratory laparotomy
should be considered for those patients whose disease now appears to
be resectable.
12. Stage IV
Patients with Stage IV disease based on intraperitoneal spread
benet from cytoreductive surgery only if there is no residual tumor
[67]. Neoadjuvant chemotherapy is an option, particularly if ascites is
present, and/or postoperative morbidity is considered likely [68]. After
surgery, platinum-based chemotherapy should be considered, based
on the GOG#122 trial cited above [28].
Patients with evidence of extra-abdominal metastases are usually
managed with systemic platinum-based chemotherapy, or hormonal
therapy if grade 1 and/or receptor positive. Combination chemotherapy
is the treatment of choice in advanced-stage disease as well as in re-
lapsed disease. The combinations of doxorubicin, cisplatin, and paclitax-
el (TAP) [69] and carboplatin and paclitaxel have been shown to be
most effective. The former is much more toxic.
Doxorubicin monotherapy versus doxorubicincisplatin doublet has
been investigated in two randomized trials [70,71]. Both documented
superiority of the combination chemotherapy in terms of progression-
free and overall survival, with manageable toxicity. Doxorubicin
cisplatin doublet versus doxorubicincisplatinpaclitaxel triplet was
tested in a phase III randomized trial [69]. The triplet regimen resulted
 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
in a signicantly superior progression-free survival, though this regi-
men proved to be too toxic, with treatment-related deaths despite the
use of growth factors.
Carboplatinpaclitaxel doublet was tested in several phase II studies
in advanced-stage or relapsed disease, demonstrating a response rate
of 65%75% and progression-free survival of about 14 months [7274].
The interim results of the GOG-0209 trial, a noninferiority trial
comparing the combination of doxorubicin, cisplatin, and paclitaxel
(TAP) and G-CSF versus carboplatin and paclitaxel shows that
carboplatin and paclitaxel is not inferior to TAP [75]. The better tolera-
bility prole of carboplatinpaclitaxel has lent credence to the use of
carboplatin and paclitaxel as the standard for adjuvant treatment in
Stage III and IV disease.
Pelvic radiotherapy in Stage IV disease may be used to provide local
tumor control and/or to treat symptoms such as vaginal bleeding or
pain from a local tumor mass, or leg edema due to lymph node involve-
ment. Palliation of brain or bone metastases can be effectively obtained
with short courses (15 fractions) of radiotherapy.
13. Targeted therapy
While surgery, radiotherapy, and cytotoxic therapy have improved
outcomes for patients with endometrial cancer, insights into pathogen-
esis of cancer have led to the development of drugs targeting molecular
pathways vital to cancer cell survival including angiogenesis, DNA re-
pair, and apoptosis. The tumor suppressor gene PTEN (phosphate and
tensin homolog detected on chromosome 10) is important for normal
cellular function. Mutations in PTEN result in decreased apoptosis and
are found in up to 83% of endometrioid carcinomas of the uterus [76].
Decreased transcription due to the mutation leads to decreased phos-
phatidylinositol 3-kinase (PI3K) inhibition, increased activity of Akt,
and uncontrolled function of mTOR. Elevated activity of mTOR is seen
in a vast majority of endometrial cancers [77]. The mammalian target
of rapamycin (mTOR) is a kinase that regulates cell growth and apopto-
sis [78]. Temsirolimus, deforolimus, and everolimus are mTOR inhibi-
tors that have been tested as single agents in phase II studies. They
have been found to promote stable disease in 44% of patients with met-
astatic or recurrent cancer of the endometrium [79,80].
Development of a new blood supply (angiogenesis) is essential to
the development and maintenance of any tissue [81,82]. Diffusion of
nutrients over small distances is sufcient for cellular function, but in
order for tumor growth to exceed 1 mm3 in volume, new vessels must
be recruited [82]. Tumor cells generate angiogenic factors that promote
new vessel formation and recruit supporting cells. The vessel density
and circulating tumor levels of many proangiogenic proteins such as
vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF) are poor prognostic factors for many solid tumors, includ-
ing endometrial carcinoma [82]. VEGF is one of the best characterized
angiogenesis mediators [83,84]. Increased production of VEGF as well
as other growth factors is frequently observed in regions of hypoxia or
inammation and in the presence of activated oncogenes or down-
regulated tumor suppressor genes [85,86]. Overexpression of VEGF
results in increased endothelial cell proliferation, decreased apoptosis,
and increased fenestration of endothelial cells [8587]. VEGF overex-
pression has been shown to be associated with a poor prognosis in
most gynecologic malignancies including endometrial cancer [87]. The
role of drugs inhibiting angiogenesis pathways, such as bevacizumab
and tyrosine kinase inhibitors, is being studied in endometrial cancer.
In the rst phase II trial evaluating the activity and tolerability of
single-agent bevacizumab in 52 recurrent or persistent endometrial
cancers [88], seven patients (13.5%) had clinical responses and 21
(40.4%) had stable disease for 6 months.
Bevacizumab was added to adjuvant paclitaxel and carboplatin in a
phase II trial in patients with measurable disease [89]. Fourteen of the
15 patients were progression free at 6 months. A combination of
temsirolimus and bevacizumab showed a 24% response at the cost of
S101
signicant toxicity [90]. These rst studies of bevacizumab in advanced
and recurrent endometrial cancer need to be conrmed in another
much larger phase II trial (GOG 86P).
Concerning tyrosine kinase inhibitors, a phase II trial evaluated the
efcacy and safety of getinib in 26 patients with persistent/recurrent
endometrial cancer [91]. This treatment regimen was tolerable but
lacked sufcient efcacy to warrant further evaluation in this setting.
A phase II placebo-controlled randomized trial of chemotherapy plus
nintedanib (ENGOT-EN1) is to be initiated in Europe.
The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregu-
lated in endometrial cancer. Hormonal manipulation leads to response
in some patients, but resistance derived from PI3K pathway activation
has been documented. In a recent phase II trial of everolimus and
letrozole in women with recurrent disease, a clinical benet rate of
40% and objective response rate of 32% was documented [92].
Dysregulation of the cell cycle is one of the dened hallmarks of can-
cer. The cyclin-dependent kinases (CDKs) have a crucial role in the reg-
ulation of the G1/S transition. Palbociclib is a reversible oral inhibitor of
CDK4/6 with acceptable toxicity prole. A phase II randomized trial of
letrozole with and without palbociclib is being initiated in Europe.
Various groups have studied the use of HER2/neu-targeted therapies
in patients with aggressive endometrial cancer subtypes [93]. However,
a phase II study evaluating the efcacy of trastuzumab alone for ad-
vanced or recurrent HER2-positive endometrial carcinoma reported
no major tumor responses among the 34 women nally enrolled [94].
A randomized phase II evaluation of carboplatin/paclitaxel with and
without trastuzumab in HER2/neu + patients with advance/recurrent
uterine serous papillary carcinoma is currently recruiting participants.
14. Special considerations
14.1. Diagnosis post hysterectomy
Diagnosis of endometrial carcinoma post hysterectomy can present
some management problems, particularly if the adnexae have not
been removed. This situation most often arises following vaginal hyster-
ectomy for pelvic prolapse. Recommendations for further postoperative
therapy are based on known risk factors for extrauterine disease related
to the histologic grade and depth of myometrial invasion. Individuals
with grade 3 lesions, deep myometrial invasion, or LVSI are candidates
for additional surgery to remove the adnexae, or adjuvant external
beam pelvic radiation therapy. Patients with a grade 1 or 2 lesion with
minimal myometrial invasion and no LVSI involvement generally re-
quire no further therapy.
14.2. Medically inoperable patients
Morbid obesity and severe cardiopulmonary disease are the general
reasons a patient with endometrial carcinoma may be thought to be
medically inoperable. Uterine brachytherapy can achieve cure rates in
excess of 70% and may be combined with external beam radiotherapy
in the presence of prognostic factors suggesting a high risk of involved
nodes. Primary radiation therapy for clinical Stage I and II endometrial
adenocarcinoma provides disease control, with fewer than 16% of sur-
viving patients experiencing recurrence [95].
For patients with a well-differentiated lesion, contraindications to
general anesthesia, and who are unsuitable for radiotherapy, high-
dose progestins may be used.
14.3. Diagnosis in young women
The diagnosis of endometrial carcinoma during the reproductive
years should be made with caution, since this malignancy is uncommon
in women under 35 years, and grade 1 endometrial carcinoma may be
confused with severe atypical hyperplasia. In these women, consider-
ation should be given to an estrogen-related underlying condition
S102 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104

such as a granulosa cell tumor, polycystic ovaries, or obesity. Progestins Maximum clinical response may not be apparent for 3 or more months
such as megestrol acetate (160 mg/day) or medroxyprogesterone ace- after initiating therapy. Platinum-based chemotherapy (cisplatinum
tate (500 mg/day) may be appropriate in these situations if preservation and doxorubicin, or carboplatin and paclitaxel) has been recommended
of fertility is desired. The safety of such an approach has been reported for patients with advanced or recurrent disease, not amenable to cure
in a large number of studies, for grade 1 endometrial adenocarcinoma by surgery and/or radiotherapy [28,72]. Targeted therapies are being in-
and atypical hyperplasia only [96]. Equivocal lesions should be exam- vestigated in several ongoing trials.
ined by an experienced pathologist. Although the literature describes
successful outcomes, fatal recurrences of endometrial cancer after a 17. Recommendations for practice
conservative approach have been reported, and hysterectomy should
be recommended after childbearing has been completed.
(1) Preoperatively, a denitive tissue diagnosis must be obtained.
Ovarian preservation, in patients with grade 1 intramucosal endo-
This helps to determine the surgical approach, and to differenti-
metrial adenocarcinoma, was not associated with an increase in
ate tumors at low and high risk of lymph node metastasis.
cancer-related mortality in the largest sample available [97].
Imaging can be useful to determine depth of myometrial
invasion, cervical involvement, and lymph node enlargement.
15. Follow-up
Level of Evidence C
(2) Lymphadenectomy in clinical Stage I endometrial cancer has no
The conventional reasons for follow-up of treated cancer patients
impact on overall or relapse-free survival. Level of Evidence A.
involve providing reassurance, diagnosing early recurrence, and
Outside clinical trials, lymphadenectomy should be performed
collecting data. One prospective [98] and several retrospective studies
for staging only in high-risk cases. There is little evidence to sup-
[99101] internationally have addressed follow-up. Overall, about 75%
port a therapeutic benet, but it should be used to select women
of recurrences were symptomatic and 25% asymptomatic, and neither
with positive nodes for adjuvant therapy. Level of Evidence C
recurrence-free nor overall survival were improved in asymptomatic
(3) Adjuvant radiotherapy for women with Stage I endometrial can-
cases compared with those detected at clinical presentation. Most
cer with low, intermediate, or highintermediate risk features
(65%85%) recurrences were diagnosed within 3 years of primary treat-
has no impact on survival, although it reduces the rate of pelvic
ment, and 40% of recurrences were local. The use of routine follow-up
recurrence. Level of Evidence A. Vaginal brachytherapy effec-
Pap smears and chest X-rays is not cost-effective. In nonirradiated pa-
tively reduces the risk of vaginal relapse in patients with risk fac-
tients, a strong case can be made for regular follow-up to detect vaginal
tors. Level of Evidence A. External beam radiotherapy should be
recurrence at the earliest opportunity, given the high salvage rate fol-
considered in patients with positive nodes or advanced stage dis-
lowing radiotherapy [102].
ease to ensure pelvic control. Level of Evidence B
Two systematic reviews [103,104] documented evidence for the
(4) The addition of adjuvant chemotherapy to radiotherapy in pa-
utility of follow-up examinations, and concluded that follow-up should
tients with high-risk factors improves progression-free survival,
be practical and directed by symptoms and pelvic examination, and that
but an overall survival benet is unproven. Level of Evidence A
frequency of follow-up visits may be reduced in low-risk patients. Given
(5) Adjuvant chemotherapy for patients with early stage, high-risk
the low risk of recurrence, vaginal cytology can be omitted, resulting in
disease should only be considered within clinical trials.
reduced healthcare costs [105]. It appears that visual inspection is suf-
(6) Chemotherapy is superior to whole abdominal radiation for pa-
cient, since positive cytology is merely diagnosed in cases of symptom-
tients with Stage III disease and abdominal disease with residual
atic recurrence [100,106,107].
nodules less than 2 cm diameter. Level of Evidence A
Patient counseling and follow-up should also acknowledge that
(7) Targeted therapy in endometrial cancer should only be consid-
these patients are at risk of second cancers following their primary
ered within clinical trials.
endometrial cancer. The estimated incidence rate of Lynch syndrome
(8) There is no evidence to support the use of adjuvant hormonal
in an unselected endometrial cancer population is 3% 6% [108].
therapy (progestogen). Level of Evidence A
Routine pathologic screening of mismatch repair deciencies in the en-
(9) Patients with high-risk and advanced stage endometrial
dometrial cancer specimen, similar to colorectal cancer, has been advo-
cancer should be managed where possible by a gynecological
cated [109]. A recent study showed that survivors of endometrial cancer
oncologist, working within a multidisciplinary team. Level of
have a three-fold increased risk of a second cancer compared with a
Evidence A
matched population, mainly due to lifestyle factors and genetic suscep-
(10) Patients with endometrial cancer are frequently old and frail, and
tibility [110].
this should be taken into account when prescribing adjuvant
therapy. Professional consensus
16. Recurrence

Localized recurrences are managed preferentially by surgery, irradi-

ation, or a combination of the two, depending on the primary therapy.
Screening for distant metastases should be performed before deciding
on curative treatment. With an increasing number of patients managed
by surgery alone, radiotherapy provides an effective salvage treatment
in cases of vaginal or central pelvic recurrence. A combination of EBRT
and brachytherapy, preferably image guided, is usually required. Large
recurrences should be evaluated for excision, followed by radiotherapy.
Additional chemotherapy is being evaluated in an ongoing GOG trial.
Extended surgery may be justied, especially in patients who have
had prior radiation therapy. The results of pelvic exenteration in proper-
ly selected cases are similar to those obtained in cervical cancer.
Patients with non-localized recurrent tumors may be candidates for
progestin therapy (medroxyprogesterone acetate 50100 mg three
times a day or megestrol acetate 80 mg 23 times a day). The progestin
therapy is continued as long as the disease is static or in remission.
Conict of interest
The authors have no conicts of interest to declare.
References
[1] Winer I, Ahmed QF, Mert I, Bandyopadhyay S, Cote M, Munkarah AR, et al. Signi-
cance of lymphovascular space invasion in uterine serous carcinoma: what matters
more; extent or presence? Int J Gynecol Pathol 2015;34(1):4756.
[2] Aristizabal P, Graesslin O, Barranger E, Clavel-Chapelon F, Haddad B, Luton D, et al.
A suggested modication to FIGO stage I endometrial cancer. Gynecol Oncol 2014;
133(2):1926.
[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):
529.
[4] Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on
physical activity and cancer prevention. Eur J Cancer 2010;46(14):2593604.
[5] Cust AE. Physical activity and gynecologic cancer prevention. Recent Results Cancer
Res 2011;186:15985.
 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
[6] Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Levitt J, et al. Obe-
sity and age at diagnosis of endometrial cancer. Obstet Gynecol 2014;124(2 Pt 1):
3006.
[7] Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H,
et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries
in 2012. Eur J Cancer 2013;49(6):1374403.
[8] Weiderpass E, Antoine J, Bray FI, Oh JK, Arbyn M. Trends in corpus uteri cancer
mortality in member states of the European Union. Eur J Cancer 2014;50(9):
167584.
[9] Wartko P, Sherman ME, Yang HP, Felix AS, Brinton LA, Trabert B. Recent changes in
endometrial cancer trends among menopausal-age U.S. women. Cancer Epidemiol
2013;37(4):3747.
[10] Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A
long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56(2):
40312.
[11] Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endo-
metrial cancer. Lancet 2005;366(9484):491505.
[12] Jacobs I, Gentry-Maharaj A, Burnell M, Manchanda R, Singh N, Sharma A, et al.
Sensitivity of transvaginal ultrasound screening for endometrial cancer in post-
menopausal women. a casecontrol study within the UKCTOCS cohort. Lancet
Oncol 2011;12(1):3848.
[13] Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009.
a review of current American Cancer Society guidelines and issues in cancer
screening. CA Cancer J Clin 2009;59(1):2741.
[14] Karlsson B, Granberg S, Wikland M, Ylostalo P, Torvid K, Marsal K, et al. Transvaginal
ultrasonography of the endometrium in women with postmenopausal bleedinga
Nordic multicenter study. Am J Obstet Gynecol 1995;172(5):148894.
[15] Ugaki H, Kimura T, Miyatake T, Ueda Y, Yoshino K, Matsuzaki S, et al. Intraoperative
frozen section assessment of myometrial invasion and histology of endometrial
cancer using the revised FIGO staging system. Int J Gynecol Cancer 2011;21(7):
11804.
[16] Cade TJ, Quinn MA, McNally OM, Neesham D, Pyman J, Dobrotwir A. Predictive
value of magnetic resonance imaging in assessing myometrial invasion in endome-
trial cancer. is radiological staging sufcient for planning conservative treatment?
Int J Gynecol Cancer 2010;20(7):11669.
[17] Ozturk E, Dikensoy E, Balat O, Ugur MG, Aydin A. Intraoperative frozen section is
essential for assessment of myometrial invasion but not for histologic grade conr-
mation in endometrial cancer. a ten-year experience. Arch Gynecol Obstet 2012;
285(5):14159.
[18] DelMaschio A, Vanzulli A, Sironi S, Spagnolo D, Belloni C, Garancini P, et al. Estimat-
ing the depth of myometrial involvement by endometrial carcinoma: efcacy of
transvaginal sonography vs MR imaging. AJR Am J Roentgenol 1993;160(3):5338.
[19] Epstein E, Blomqvist L. Imaging in endometrial cancer. Best Pract Res Clin Obstet
Gynaecol 2014;28(5):72139.
[20] Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al.
Laparoscopy compared with laparotomy for comprehensive surgical staging of
uterine cancer. Gynecol Oncol Group Study LAP2. J Clin Oncol 2009;27(32):53316.
[21] Mourits MJ, Bijen CB, Arts HJ, ter Brugge HG, van der Sijde R, Paulsen L, et al. Safety
of laparoscopy versus laparotomy in early-stage endometrial cancer. a randomised
trial. Lancet Oncol 2010;11(8):76371.
[22] Obermair A, Janda M, Baker J, Kondalsamy-Chennakesavan S, Brand A, Hogg R, et al.
Improved surgical safety after laparoscopic compared to open surgery for apparent
early stage endometrial cancer: results from a randomised controlled trial. Eur J
Cancer 2012;48(8):114753.
[23] Galaal K, Bryant A, Fisher AD, Al-Khaduri M, Kew F, Lopes AD. Laparoscopy versus
laparotomy for the management of early stage endometrial cancer. Cochrane Data-
base Syst Rev 2012;9:CD006655.
[24] Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al.
Recurrence and survival after random assignment to laparoscopy versus laparoto-
my for comprehensive surgical staging of uterine cancer. Gynecologic Oncology
Group LAP2 Study. J Clin Oncol 2012;30(7):695700.
[25] Bernardini MQ, Gien LT, Tipping H, Murphy J, Rosen BP. Surgical outcome of robotic
surgery in morbidly obese patient with endometrial cancer compared to laparoto-
my. Int J Gynecol Cancer 2012;22(1):7681.
[26] Cardenas-Goicoechea J, Shepherd A, Momeni M, Mandeli J, Chuang L, Gretz H, et al.
Survival analysis of robotic versus traditional laparoscopic surgical staging for en-
dometrial cancer. Am J Obstet Gynecol 2014;210(2):160.e1160.e111.
[27] Wright JD, Burke WM, Wilde ET, Lewin SN, Charles AS, Kim JH, et al. Comparative
effectiveness of robotic versus laparoscopic hysterectomy for endometrial cancer.
J Clin Oncol 2012;30(8):78391.
[28] Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, et al. Randomized
phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin
chemotherapy in advanced endometrial carcinoma. a Gynecol Oncol Group
Study. J Clin Oncol 2006;24(1):3644.
[29] Chan JK, Sherman AE, Kapp DS, Zhang R, Osann KE, Maxwell L, et al. Inuence
of gynecologic oncologists on the survival of patients with endometrial cancer.
J Clin Oncol 2011;29(7):8328.
[30] Roland PY, Kelly FJ, Kulwicki CY, Blitzer P, Curcio M, Orr Jr JW. The benets of a gy-
necologic oncologist: a pattern of care study for endometrial cancer treatment.
Gynecol Oncol 2004;93(1):12530.
[31] Elit LM, O'Leary EM, Pond GR, Seow HY. Impact of wait times on survival for
women with uterine cancer. J Clin Oncol 2014;32(1):2733.
[32] Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba T, et al. Time interval
between endometrial biopsy and surgical staging for type I endometrial cancer. as-
sociation between tumor characteristics and survival outcome. Obstet Gynecol
2015;125(2):42433.
S103
[33] Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin III F, et al.
Adenocarcinoma of the endometrium: survival comparisons of patients with and
without pelvic node sampling. Gynecol Oncol 1995;56(1):2933.
[34] Larson DM, Broste SK, Krawisz BR. Surgery without radiotherapy for primary treat-
ment of endometrial cancer. Obstet Gynecol 1998;91(3):3559.
[35] Cragun JM, Havrilesky LJ, Calingaert B, Synan I, Secord AA, Soper JT, et al. Retrospec-
tive analysis of selective lymphadenectomy in apparent early-stage endometrial
cancer. J Clin Oncol 2005;23(16):366875.
[36] ASTEC Study Group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efcacy of
systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a
randomised study. Lancet 2009;373(9658):12536.
[37] Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G,
et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage
endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008;100(23):
170716.
[38] Aalders JG, Thomas G. Endometrial cancerrevisiting the importance of pelvic and
para aortic lymph nodes. Gynecol Oncol 2007;104(1):22231.
[39] Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N. Survival effect of
para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospec-
tive cohort analysis. Lancet 2010;375(9721):116572.
[40] Poulsen HK, Jacobsen M, Bertelsen K, Andersen K, Ahrons S, Bock J, et al. Adjuvant
radiation therapy is not necessary in the management of endometrial carcinoma
stage I, low risk cases. Int J Gynecol Cancer 1996;6(1):3843.
[41] Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and
prognostic parameters in stage I endometrial carcinoma: clinical and histopatho-
logic study of 540 patients. Obstet Gynecol 1980;56(4):41927.
[42] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis
CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients
with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study
Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;
355(9213):140411.
[43] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III
trial of surgery with or without adjunctive external pelvic radiation therapy in in-
termediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group
study. Gynecol Oncol 2004;92(3):74451.
[44] Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external
beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC
CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-
analysis. Lancet 2009;373(9658):13746.
[45] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis
CC, et al. Survival after relapse in patients with endometrial cancer: results from a
randomized trial. Gynecol Oncol 2003;89(2):2019.
[46] Nout RA, Smit VT, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, et al. Vag-
inal brachytherapy versus pelvic external beam radiotherapy for patients with en-
dometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-
inferiority, randomised trial. Lancet 2010;375(9717):81623.
[47] Nout RA, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-
Banasik EM, et al. Quality of life after pelvic radiotherapy or vaginal brachytherapy
for endometrial cancer: rst results of the randomized PORTEC-2 trial. J Clin Oncol
2009;27(21):354756.
[48] Ortoft G, Hansen ES, Bertelsen K. Omitting adjuvant radiotherapy in endometrial
cancer increases the rate of locoregional recurrences but has no effect on long-
term survival: the Danish Endometrial Cancer Study. Int J Gynecol Cancer 2013;
23(8):142937.
[49] Kunneman M, Pieterse AH, Stiggelbout AM, Nout RA, Kamps M, Lutgens LC, et al.
Treatment preferences and involvement in treatment decision making of patients
with endometrial cancer and clinicians. Br J Cancer 2014;111(4):6749.
[50] Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, et al. Sequen-
tial adjuvant chemotherapy and radiotherapy in endometrial cancerresults from
two randomised studies. Eur J Cancer 2010;46(13):242231.
[51] Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, et al. Randomized
phase III trial of pelvic radiotherapy versus cisplatin-based combined chemothera-
py in patients with intermediate- and high-risk endometrial cancer. a Japanese
Gynecol Oncol Group study. Gynecol Oncol 2008;108(1):22633.
[52] Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, et al. Adjuvant chemo-
therapy vs radiotherapy in high-risk endometrial carcinoma: results of a
randomised trial. Br J Cancer 2006;95(3):26671.
[53] McMeekin DS, Filiaci VL, Aghajanian C, Cho J, Kim JW, DiSilvestro PA, et al. A ran-
domized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff
brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in pa-
tients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic On-
cology Group trial (Abstract). Presented at: SGO 45th Annual Meeting on Women's
Cancer. March 2014; Tampa, FL, USA; 2014.
[54] Martin-Hirsch PL, Lilford RJ, Jarvis GJ. Adjuvant progestagen therapy for the
treatment of endometrial cance: review and meta-analyses of published
randomised controlled trials. Eur J Obstet Gynecol Reprod Biol 1996;65(2):
2017.
[55] COSA-NZ-UK Endometrial Cancer Study Groups. Adjuvant medroxyprogesterone
acetate in high-risk endometrial cancer. Int J Gynecol Cancer 1998;8(5):38791.
[56] Takano M, Ochi H, Takei Y, Miyamoto M, Hasumi Y, Kaneta Y, et al. Surgery for en-
dometrial cancers with suspected cervical involvement: is radical hysterectomy
needed (a GOTIC study)? Br J Cancer 2013;109(7):17605.
[57] Sartori E, Gadducci A, Landoni F, Lissoni A, Maggino T, Zola P, et al. Clinical be-
havior of 203 stage II endometrial cancer cases: the impact of primary surgical
approach and of adjuvant radiation therapy. Int J Gynecol Cancer 2001;11(6):
4307.
S104 F. Amant et al. / International Journal of Gynecology and Obstetrics 131 (2015) S96S104
[58] Mariani A, Webb MJ, Keeney GL, Calori G, Podratz KC. Role of wide/radical hyster-
ectomy and pelvic lymph node dissection in endometrial cancer with cervical in-
volvement. Gynecol Oncol 2001;83(1):7280.
[59] Wright JD, Fiorelli J, Kansler AL, Burke WM, Schiff PB, Cohen CJ, et al. Optimizing the
management of stage II endometrial cancer: the role of radical hysterectomy and
radiation. Am J Obstet Gynecol 2009;200(4):419.e17.
[60] Disaia PJ. Predicting parametrial involvement in endometrial cancer: is this the end
for radical hysterectomies in stage II endometrial cancers? Obstet Gynecol 2010;
116(5):10167.
[61] Mundt AJ, McBride R, Rotmensch J, Waggoner SE, Yamada SD, Connell PP. Signi-
cant pelvic recurrence in high-risk pathologic stage IIV endometrial carcinoma
patients after adjuvant chemotherapy alone: implications for adjuvant radiation
therapy. Int J Radiat Oncol Biol Phys 2001;50(5):114553.
[62] Klopp AH, Jhingran A, Ramondetta L, Lu K, Gershenson DM, Eifel PJ. Node-positive
adenocarcinoma of the endometrium: outcome and patterns of recurrence with
and without external beam irradiation. Gynecol Oncol 2009;115(1):611.
[63] Galaal K, Al Moundhri M, Bryant A, Lopes AD, Lawrie TA. Adjuvant chemotherapy
for advanced endometrial cancer. Cochrane Database Syst Rev 2014;5:CD010681.
[64] Randall ME, Spirtos NM, Dvoretsky P. Whole abdominal radiotherapy versus com-
bination chemotherapy with doxorubicin and cisplatin in advanced endometrial
carcinoma (phase III): Gynecologic Oncology Group Study No. 122. J Natl Cancer
Inst Monogr 1995;19:135.
[65] Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos NM, et al. A randomized
phase III trial in advanced endometrial carcinoma of surgery and volume directed
radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gyne-
cologic Oncology Group study. Gynecol Oncol 2009;112(3):54352.
[66] Vargo JA, Boisen MM, Comerci JT, Kim H, Houser CJ, Sukumvanich P, et al. Neoad-
juvant radiotherapy with or without chemotherapy followed by extrafascial hys-
terectomy for locally advanced endometrial cancer clinically extending to the
cervix or parametria. Gynecol Oncol 2014;135(2):1905.
[67] Barlin JN, Puri I, Bristow RE. Cytoreductive surgery for advanced or recurrent endo-
metrial cancer: a meta-analysis. Gynecol Oncol 2010;118(1):148.
[68] Vandenput I, Van Calster B, Capoen A, Leunen K, Berteloot P, Neven P, et al. Neoad-
juvant chemotherapy followed by interval debulking surgery in patients with se-
rous endometrial cancer with transperitoneal spread (stage IV): a new preferred
treatment? Br J Cancer 2009;101(2):2449.
[69] Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, et al. Phase III
trial of doxorubicin plus cisplatin with or without paclitaxel plus lgrastim in ad-
vanced endometrial carcinoma: A Gynecologic Oncology Group Study. J Clin
Oncol 2004;22(11):215966.
[70] van Wijk FH, Aapro MS, Bolis G, Chevallier B, van der Burg ME, Poveda A, et al.
Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: denitive
results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.
Ann Oncol 2003;14(3):4418.
[71] Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, et al.
Phase III trial of doxorubicin with or without cisplatin in advanced endometrial
carcinoma. a Gynecol Oncol group study. J Clin Oncol 2004;22(19):39028.
[72] Akram T, Maseelall P, Fanning J. Carboplatin and paclitaxel for the treatment of ad-
vanced or recurrent endometrial cancer. Am J Obstet Gynecol 2005;192(5):
13657.
[73] Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, Acquino-Parsons C, et al. Pacli-
taxel and carboplatin, alone or with irradiation, in advanced or recurrent endome-
trial cancer: a phase II study. J Clin Oncol 2001;19(20):404853.
[74] Miller D, Filiaci V, Fleming G, Mannel R, Cohn D, Matsumoto T, et al. Late-Breaking
Abstract 1: Randomized phase III noninferiority trial of rst line chemotherapy for
metastatic or recurrent endometrial carcinoma: A Gynecologic Oncology Group
study. Gynecol Oncol 2012;125(3):771.
[75] Sorbe B, Andersson H, Boman K, Rosenberg P, Kalling M. Treatment of primary ad-
vanced and recurrent endometrial carcinoma with a combination of carboplatin
and paclitaxel-long-term follow-up. Int J Gynecol Cancer 2008;18(4):8038.
[76] Zagouri F, Bozas G, Kafantari E, Tsiatas M, Nikitas N, Dimopoulos MA, et al. Endome-
trial cancer: what is new in adjuvant and molecularly targeted therapy? Obstet
Gynecol Int 2010;2010:749579.
[77] Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, et al. Anti-
cancer chemosensitization and radiosensitization by the novel poly(ADP-ribose)
polymerase-1 inhibitor AG14361. J Natl Cancer Inst 2004;96(1):5667.
[78] Bansal N, Yendluri V, Wenham RM. The molecular biology of endometrial cancers
and the implications for pathogenesis, classication, and targeted therapies. Cancer
Control 2009;16(1):813.
[79] Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, et al. Phase II study
of temsirolimus in women with recurrent or metastatic endometrial cancer. a trial
of the NCIC Clinical Trials Group. J Clin Oncol 2011;29(24):327885.
[80] Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, et al. A
phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus,
in patients with recurrent endometrial carcinoma. Cancer 2010;116(23):54159.
[81] Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl
Cancer Inst 1990;82(1):46.
[82] Kaku T, Kamura T, Kinukawa N, Kobayashi H, Sakai K, Tsuruchi N, et al. Angiogen-
esis in endometrial carcinoma. Cancer 1997;80(4):7417.
[83] Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial
growth factor is a secreted angiogenic mitogen. Science 1989;246(4935):13069.
[84] Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells se-
crete a vascular permeability factor that promotes accumulation of ascites uid.
Science 1983;219(4587):9835.
[85] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med
2003;9(6):66976.
[86] Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor
(VEGF) and its receptors. FASEB J 1999;13(1):922.
[87] Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular
endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-
2-mediated endothelial cell proliferation, but not migration, through phos-
phatidylinositol 3-kinase-dependent pathways. J Biol Chem 2001;276(29):
2696979.
[88] Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, et al. Phase II
trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic
Oncology Group study. J Clin Oncol 2011;29(16):225965.
[89] Simpkins F, Drake R, Escobar PF, Nutter B, Rasool N, Rose PG. A phase II trial of pac-
litaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carci-
noma (EMCA). Gynecol Oncol 2015;136(2):2405.
[90] Alvarez EA, Brady WE, Walker JL, Rotmensch J, Zhou XC, Kendrick JE, et al. Phase II
trial of combination bevacizumab and temsirolimus in the treatment of recurrent
or persistent endometrial carcinoma: a Gynecologic Oncology Group study.
Gynecol Oncol 2013;129(1):227.
[91] Leslie KK, Sill MW, Fischer E, Darcy KM, Mannel RS, Tewari KS, et al. A phase II eval-
uation of getinib in the treatment of persistent or recurrent endometrial cancer: a
Gynecologic Oncology Group study. Gynecol Oncol 2013;129(3):48694.
[92] Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, et al.
Phase II study of everolimus and letrozole in patients with recurrent endometrial
carcinoma. J Clin Oncol 2015;33(8):9306.
[93] Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, et al. HER-2 is
an independent prognostic factor in endometrial cancer: association with outcome
in a large cohort of surgically staged patients. J Clin Oncol 2006;24(15):237685.
[94] Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al. Phase II
trial of trastuzumab in women with advanced or recurrent, HER2-positive endo-
metrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2010;
116(1):1520.
[95] Podzielinski I, Randall ME, Breheny PJ, Escobar PF, Cohn DE, Quick AM, et al. Prima-
ry radiation therapy for medically inoperable patients with clinical stage I and II en-
dometrial carcinoma. Gynecol Oncol 2012;124(1):3641.
[96] Koskas M, Uzan J, Luton D, Rouzier R, Darai E. Prognostic factors of oncologic and
reproductive outcomes in fertility-sparing management of endometrial atypical
hyperplasia and adenocarcinoma: systematic review and meta-analysis. Fertil
Steril 2014;101(3):78594.
[97] Koskas M, Bendifallah S, Luton D, Darai E, Rouzier R. Safety of uterine and/or ovar-
ian preservation in young women with grade 1 intramucous endometrial adeno-
carcinoma: a comparison of survival according to the extent of surgery. Fertil
Steril 2012;98(5):122935.
[98] Allsop JR, Preston J, Crocker S. Is there any value in the long-term follow up of
women treated for endometrial cancer? BJOG 1997;104(1):122.
[99] Salvesen HB, Akslen LA, Iversen T, Iversen OE. Recurrence of endometrial carcino-
ma and the value of routine follow up. BJOG 1997;104(11):13027.
[100] Agboola OO, Grunfeld E, Coyle D, Perry GA. Costs and benets of routine follow-up
after curative treatment for endometrial cancer. CMAJ 1997;157(7):87986.
[101] Shumsky AG, Stuart GC, Brasher PM, Nation JG, Robertson DI, Sangkarat S. An eval-
uation of routine follow-up of patients treated for endometrial carcinoma. Gynecol
Oncol 1994;55(2):22933.
[102] Ackerman I, Malone S, Thomas G, Franssen E, Balogh J, Dembo A. Endometrial
carcinomarelative effectiveness of adjuvant irradiation vs therapy reserved for re-
lapse. Gynecol Oncol 1996;60(2):17783.
[103] Fung-Kee-Fung M, Dodge J, Elit L, Lukka H, Chambers A, Oliver T. Follow-up after
primary therapy for endometrial cancer. a systematic review. Gynecol Oncol
2006;101(3):5209.
[104] Kew FM, Roberts AP, Cruickshank DJ. The role of routine follow-up after gynecolog-
ical malignancy. Int J Gynecol Cancer 2005;15(3):4139.
[105] Salani R, Nagel CI, Drennen E, Bristow RE. Recurrence patterns and surveillance for
patients with early stage endometrial cancer. Gynecol Oncol 2011;123(2):2057.
[106] Sartori E, Pasinetti B, Carrara L, Gambino A, Odicino F, Pecorelli S. Pattern of failure
and value of follow-up procedures in endometrial and cervical cancer patients.
Gynecol Oncol 2007;107(1 Suppl 1):S2417.
[107] Berchuck A, Anspach C, Evans AC, Soper JT, Rodriguez GC, Dodge R, et al. Postsurgi-
cal surveillance of patients with FIGO stage I/II endometrial adenocarcinoma.
Gynecol Oncol 1995;59(1):204.
[108] Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al. Screening for
Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial
cancer patients. Cancer Res 2006;66(15):78107.
[109] Moline J, Eng C. Equality in lynch syndrome screening: why should we hold pa-
tients with endometrial cancer to a different standard? J Clin Oncol 2014;
32(21):2277.
[110] Wiltink LM, Nout RA, Fiocco M, Meershoek-Klein Kranenbarg E, Jurgenliemk-
Schulz IM, Jobsen JJ, et al. No increased risk of second cancer after radiotherapy
in patients treated for rectal or endometrial cancer in the randomized TME,
PORTEC-1, and PORTEC-2 Trials. J Clin Oncol 2015;33(15):16406.