Seminar
Endometrial cancer
Lancet 2016; 387: 1094–108
Published Online
September 7, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)00130-0
Department of Gynecologic
Surgery (Prof P Morice MD),
Department of Medical
Oncology (A Leary MD),
Translational Research Lab
U981 (A Leary), Gustave
Roussy, Villejuif, France; Unit
INSERM U 1030, Gustave
Roussy, Villejuif, France
(Prof P Morice); Université
Paris-Sud (Paris XI), Le Kremlin
Bicêtre, France (Prof P Morice);
Department of Radiation
Oncology, Leiden University
Medical Center, Leiden,
Netherlands
(Prof C Creutzberg MD);
Memorial Sloan-Kettering
Cancer Center, New York, NY,
USA (Prof N Abu-Rustum MD);
Department of Obstetrics and
Gynaecology, Hôpital Tenon,
Paris, France (Prof E Darai MD);
INSERM UMRS 938, Paris,
France (Prof E Darai); and
Université Pierre et Marie Curie
(Paris VI), Paris, France
(Prof E Darai)
Correspondence to:
Dr Philippe Morice, Department
of Gynecologic Surgery, Gustave
Roussy, 114 rue Edouard Vaillant,
94805 Villejuif Cedex, France
philippe.morice@
gustaveroussy.fr
1094
Philippe Morice, Alexandra Leary, Carien Creutzberg, Nadeem Abu-Rustum, Emile Darai
Endometrial cancer is the most common gynaecological tumour in developed countries, and its incidence is
increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often
diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and
bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node
surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space),
disease stage (including myometrial invasion), patients’ characteristics (age and comorbidities), and national and
international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are
used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival
ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence
(including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that
best balance optimisation of survival with the lowest adverse effects on quality of life.
Introduction Epidemiology and risk factors
Endometrial cancer—a tumour originating in the In 2012, around 320 000 new cases of endometrial cancer
endometrium—is the most common gynaecological were diagnosed worldwide. Endometrial cancer is the
tumour in developed countries, and its prevalence is fifth most common cancer in women (4·8% of cancers in
increasing.1 As the disease is frequently symptomatic at women), who have a cumulative risk of 1% of developing
an early stage, endometrial cancer is often diagnosed the disease by age 75 years.1 It is the 14th cancer in terms
at stage I. Historically, standard treatment consisted of of mortality (76 000 deaths); cumulative risk of death by
hysterectomy, bilateral salpingo-oophorectomy, and pelvic age 75 years is 0·2%.1 The highest incidences in 2012
lymph node dissection followed by adjuvant therapy are estimated in the USA and Canada (19·1/100 000)
tailored on the basis of final histology. and northern (12·9/100 000) and western Europe
Management of endometrial cancer has become more (15·6/100 000).1,5 Although endometrial cancer is
complex during the past 5–10 years for several reasons: conventionally thought to be a cancer of the
changes in histological classification that affect surgical postmenopausal period (ie, the sixth and seventh decades
management, adjuvant therapies, and prognosis; changes of life), 14% of cases are diagnosed in premenopausal
in the indications and modalities of lymphadenectomy; women, 5% of whom are younger than 40 years.6–8 The
de-escalation of adjuvant therapy based on data from increased incidence of endometrial cancer in Europe and
randomised trials; and discrepancies between the various North America could be related to a greater overall
classifications used to characterise recurrence risk factors. prevalence of obesity and metabolic syndromes in these
These modifications have led national scientific regions, in addition to the ageing of the population.8–11
societies to review the emerging data and unanswered Projections show that the number of cases will increase
questions, and to publish specific recommendations for to 42·13 per 100 000 in 2030 in the USA.10
endometrial cancer.2–4 The main risk factor is exposure to endogenous and
This Seminar focuses on the epidemiology and the exogenous oestrogens associated with obesity, diabetes,
histological and molecular classification of endometrial early age at menarche, nulliparity, late-onset menopause,
cancer. We also describe current practice and trials of older age (≥55 years), and use of tamoxifen.12–17 The
surgery, adjuvant treatment, and novel targeted therapies. relation between diabetes and endometrial cancer is
controversial.18 Of the four cohort studies in which
adjustments were made for body-mass index (BMI), an
Search strategy and selection criteria independent association between endometrial cancer and
We searched MEDLINE, Current Contents, and PubMed with the diabetes was noted in only one.18–21 The levonorgestrel-
terms “endometrial cancer”, “hysterectomy”, releasing intrauterine system might have a protective
“lymphadenectomy”, “sentinel node”, “chemotherapy”, effect against endometrial malignant transformation.22
“radiation therapy”, “targeted therapy”, “fertility sparing
management”, “ovarian preservation”, and “molecular Pathogenesis and histological or molecular
classification” for articles published in English between classifications
Jan 1, 1990, and Jan 1, 2015. We also reviewed the reference In the past 30 years, endometrial cancer has been broadly
lists of articles identified by this search. We focused our search classified into two subtypes on the basis of histological
strategy on systematic reviews, meta-analyses, and clinical characteristics, hormone receptor expression, and grade
trials registered on http://clinicaltrials.gov, and selected articles (table 1).23 The most common subtype is low-grade,
on the basis of their representativeness and relevance. endometrioid, diploid, hormone-receptor-positive endo-
metrial cancer, which has a good prognosis. Type II
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endometrial cancers are described as non-endometrioid,
high grade, aneuploid, TP53-mutated, hormone-receptor-
negative tumours that are associated with a higher risk of
metastasis and a poor prognosis (table 1).23 Although this
dualistic classification has started to become incorporated
into clinical decision-making algorithms defining
high-risk patients, its prognostic value remains limited
because 20% of endometrioid (ie, type I) endometrial
cancers relapse, whereas 50% of non-endometrioid
(ie, type II) endometrial cancers do not.23 Additionally,
15–20% of endometrioid tumours are high-grade lesions,
and where they fit into the dualistic model is unclear.24,25
That endometrial cancer comprises a range of diseases
with distinct genetic and molecular features is becoming
increasingly clear.26
Within type I endometrial cancer, the PIK3CA pathway
is the most frequently altered: mutations are noted in
more than 90% of lesions.26 KRAS mutations are also
common (reported in about 20% of tumours), and 12%
of tumours harbour an FGFR2 mutation.27 Type II
endometrial cancers include a range of histological
subtypes, each showing distinct molecular and genomic
features (table 2).26–28 Serous disease shares genomic
features with triple-negative basal-like breast cancer and
high-grade serous ovarian cancer, suggesting possible
overlap in therapeutic opportunities.25 Clear-cell
endometrial cancer resembles its ovarian clear-cell
counterpart, with inactivating mutations in the
chromatin remodelling gene ARID1A in 20–40% of
cases and universal expression of hepatocyte nuclear
factor-1β.29–31
Analyses of the Cancer Genome Atlas focusing on
endometrioid and serous endometrial cancer further
emphasise the disease’s heterogeneity by identifying four
distinct molecular subgroups: POLE ultramutated,
microsatellite instability hypermutated, copy-number-low
microsatellite stable, and copy-number-high serous-like
(figure 1),26 showing increasing grade, TP53, and somatic
copy number alterations, but decreasing mutation rates
(figure 1A). The newly identified POLE ultramutated
category is the smallest subgroup, but defines a unique
subset that is characterised by mutations in the
exonuclease domain of POLE, high mutation load, and
an excellent prognosis (figure 1B).32 60% of POLE
ultramutated endometrial cancers are high-grade
endometrioid lesions, and 35% harbour TP53 mutations.
Roughly 30–40% of endometrioid endometrial cancers
show loss of DNA mismatch repair proteins (MLH1,
MSH2, MSH6, and PMS2); in sporadic cases this is
secondary to MLH1 promoter hypermethylation, and in
hereditary Lynch syndrome it can be caused by mutations
in any of the DNA mismatch repair genes.33 The
microsatellite stable subgroup is characterised by low
mutation load, a low rate of somatic copy number
alterations, and intermediate prognosis. The copy-number-
high subgroup includes most serous endometrial cancers
and 25% of the high-grade endometrioid cancers that
www.thelancet.com Vol 387 March 12, 2016
Seminar
display genomic instability, with frequent somatic copy
number alterations and poor prognosis.
High-grade endometrioid endometrial cancers are
heterogeneous: a quarter are copy-number-high serous
endometrial cancers with poor prognosis; another
quarter are ultramutated POLE cancers, which have good
prognosis. This heterogeneity could lend support to the
incorporation of POLE mutations and copy-number
assessments in establishment of the prognosis of
high-grade endometrioid tumours.
Assessment
Clinical presentation and diagnostic assessment
Abnormal uterine bleeding—sometimes associated with
vaginal discharge and pyometra—is the most frequent
symptom of endometrial cancer and is noted in about
90% of patients (usually during menopause). Patients
with advanced disease might have symptoms similar to
those of advanced ovarian cancer, such as abdominal or
pelvic pain and abdominal distension. Disease can easily
be diagnosed on the basis of office-based pipelle sampling
or other techniques.34,35 The histological information
provided by endometrial biopsy is sufficient for
preoperative assessment and planning. However, pipelle
sampling can be infeasible in some postmenopausal
women because of cervical stenosis.
When histological findings from an endometrial biopsy
are insufficient to confirm diagnosis, cervical dilation and
curettage is recommended, although this investigation
necessitates anaesthesia and has been associated with
disease underestimation.36,37 A biopsy under hysteroscopy
remains the gold standard for diagnosis of endometrial
cancer and yields higher accuracy than does blind dilation
and curettage.37,38 Results of some studies suggested a
higher incidence of malignant peritoneal cytology at the
time of hysterectomy in patients who underwent previous
hysteroscopy than in those who did not, but no evidence
supports an association between diagnostic hysteroscopy
and worse prognosis.39
Thus, the standard strategy for investigation of
abnormal uterine bleeding is pelvic ultrasonography
Type I Type II
Associated clinical features Metabolic syndrome: obesity, None
hyperlipidaemia, hyperglycaemia, and
increased oestrogen concentrations
Grade Low High
Hormone receptor expression Positive Negative
Histology Endometrioid Non-endometrioid (serous,
clear-cell carcinoma)
Genomic stability Diploid, frequent microsatellite instability Aneuploid
(40%)
TP53 mutation No Yes
Prognosis Good (overall survival 85% at 5 years) Poor (overall survival 55% at
5 years)
Table 1: Dualistic classification of endometrial cancers, by Bokhman subtype
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Endometrioid Serous Carcinosarcoma Clear cell

Bokhman subtype I II II II
TP53 mutation Rare >90% 60–90% 35%
PI3K alterations PTEN mutation (75–85%) PTEN mutation (11%) PTEN mutation (19%) PTEN loss (80%)
PIK3CA mutation (50–60%) PIK3CA amplification (45%) PIK3CA mutation (35%) PIK3CA mutation (18%)
PIK3R1 mutation (40–50%) PIK3CA mutation (35%) PIK3CA amplification (14%)
PIK3R1 mutation (12%)
KRAS mutation 20–30% 3% 17% 0%
ERBB alterations None ERBB2 amplification (25–30%) ERBB2 amplification (13–20%) ERBB2 mutation (12%)
ERBB3 amplification or mutation (13%) ERBB2 amplification (16%)
FGFR amplification FGFR2 mutation (12%) FGFR2 mutation (5%) FGFR3 amplification (20%) ··
or mutation Frequent FGFR1 and FGFR3
amplification
Wnt/β-catenin CTNNB1 mutation (25%) CTNNB1 mutation (3%) ·· ··
Other ARID1A mutation (35–40%) PPP2R1A mutation (20%) PPP2R1A mutation (28%) ARID1A (25%)
FBXW7 mutation (20% of FBXW7 mutation (35–40%) TERT promoter mutations
undifferentiated endometrial ARID1A mutation (25%)
carcinoma) CCNE1 amplification (42%)
LRPB1 deletion SOX17 amplification (25%)
Frequent amplifications in MYC,
CCNE1, and SOX17

Table 2: Molecular classification of endometrial cancers, by histology

with an endometrial biopsy in cases of increased
endometrial thickness and a hysteroscopy when
diagnosis is uncertain.3 A review40 of 13 studies showed
that, in menopausal women, an endometrial thickness
cutoff of 5 mm on ultrasonography had sensitivity of
90% and specificity of 54% compared with 98% and 35%,
respectively, when the cutoff was reduced to 3 mm.40
Preoperative staging
The role of preoperative staging is to establish
recurrence risk group, mainly on the basis of assessment
of myometrial and cervical invasion and lymph node
metastasis, to define the surgical management. MRI is
judged the best imaging technique for preoperative
staging and has a high interobserver concordance
(figure 2).41 Some studies42,43 suggest that transvaginal
ultrasonography by an experienced radiologist has
similar accuracy to that of MRI for assessment of
myometrial and cervical invasion. Transvaginal
ultrasonography is less costly than MRI but cannot be
used to assess lymph node status. If MRI is not available,
CT can be used to determine extrauterine disease (nodal
and peritoneal).
For myometrial invasion, in a review of 11 studies44,45 of
T2-weighted imaging and contrast-enhanced MRI,
pooled specificity of contrast-enhanced MRI was higher
than that of T2-weighted imaging (0·72 vs 0·58;
p=0·001).44,45 Despite heterogeneous results on
diffusion-weighted imaging, these sequences seem to
improve the accuracy of preoperative staging of
endometrial cancer and 3·0 T MRI.46 Overall, the major
limitation of imaging techniques is poor detection of
lymph node metastases. In a meta-analysis by Selman
and colleagues47 comprising 18 studies, MRI had a
pooled positive likelihood ratio of 26·7 (95% CI
10·6–67·6) and a negative likelihood ratio of 0·29
(0·17–0·49) for assessment of lymph node status.
Various series have underlined the high accuracy of
¹⁸F-fluorodeoxyglucose PET-CT in detection of
myometrial and cervical invasion and lymph node
metastatic disease. However, although its prognostic
value has been shown for advanced stage endometrial
cancer, use in preoperative staging in early stage disease
remains questionable.48,49 Emerging molecular imaging
techniques, such as hybrid PET/MRI, could improve
diagnostic accuracy through superior soft tissue contrast,
multiplanar image acquisition, and functional imaging.50
Staging classifications, clinical and biological prognostic
factors
The main goal of staging classifications is to define
groups of patients with similar outlooks to standardise
management and allow comparisons of therapeutic
strategies. The 2009 International Federation of
Gynecology and Obstetrics (FIGO) and the TNM
classifications are the most-adopted classifications

Figure 1: Molecular and genomic heterogeneity of endometrial cancer

Four novel genomic classes (A); outlook according to genomic class (B); genomic profile of copy-number-high, serous-like endometrial cancer, high-grade serous
ovarian cancer, and triple-negative breast cancer (C); and frequently mutated pathways in endometrial cancer (D). In (A), light blue represents grade 1, medium blue
represents grade 2, and dark blue represents grade 3. (B–D) are reproduced from the Cancer Genome Atlas’s integrated genomic characterisation of endometrial
carcinoma,26 by permission of Nature Publishing Group. The genomic profile of copy-number-high, serous-like endometrial cancer closely resembles those of high-
grade serous ovarian cancer and triple-negative, basal-like breast cancer. The most frequently altered pathways in endometrial cancer are the RTK/RAS/β-cathenin
pathway, which is altered in 70% of samples, and the PI3K pathway, which is altered in 84% of samples. MSI=microsatellite instability. MSS=microsatellite stable.

1096 www.thelancet.com Vol 387 March 12, 2016

 Seminar

A B
POLE MSI Copy-number Copy-number
100
ultramutated hypermutated low, MSS high, serous-like
Mutation load

80
Somatic copy number

Progression-free survival (%)

alterations load

Histology Endometrioid Endometrioid Endometrioid Serous and 60

endometrioid

Grade
40 Log-rank p=0·02
PI3K alterations

20 POLE (ultramutated)
KRAS mutation MSI (hypermutated)
Copy-number low (endometrioid)
TP53 mutation 35% 5% 1% >90% Copy-number high (serous-like)
0
Prognosis Excellent Intermediate Intermediate Poor 0 20 40 60 80 100 120
Months

C
Chr Endometrial Ovarian Breast
1

3
4

6 Gain
7
8
9
10
11
12
13
14
15
16
17
18 19
20 21
22
X Loss

D
70% of samples altered
RTK/RAS/β-catenin
MSI (hypermutations) (71%) Copy-number low (endometrioid) (82%) Copy-number high (serous) (50%)
FGFR2 ERBB2
16% 11% 5% 9% 1% 25% FGFR2 Amplification
Somatic
ERBB2
mutation
KRAS
CTNNB1
36% 15% 3%
SOX17 FBXW7 KRAS
0% 8% 0% GSK3B 12% 5% 22%
SOX17
FBXW7
CTNNB1
19% 53% 3% SOX17 mutations S403I
Missense A96G
Proliferation
Gene
1 414
High mobility group domain C-terminal transactivation
MSI CN low CN high Inactivating Activating binds TCF/LEF domain

PI(3)K pathway 84% of samples altered

PTEN MSI (hypermutation) (95%) Copy-number low (endometrioid) (92%) Copy-number high (serous) (60%)
88%77% 15%
PIK3CA PTEN Homozygous
55% 53%47% PIK3R1 deletion
PIK3R1
40%34% 13% Somatic
Proliferation, PIK3CA mutation
cell survival, translation

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A B C

Figure 2: Endometrial thickening in endometrioid adenocarcinoma stage IB as shown in an oblique T2-weighted image (A), a diffusion-weighted image (B),
and a fused sequence between the oblique thin T2-weighted and diffusion-weighted sequences acquired in a plane perpendicular to the uterus (C)
In (A) signal intensity is intermediate and margins are irregular. Contrast between the tumour and adjacent normal myometrium is better in the diffusion-weighted
than in the T2-weighted image.

very similar, the combination of defining variables varies.

FIGO stage*
Primary tumour cannot be assessed ··
No evidence of primary tumour ··
Carcinoma in situ ··
Tumour confined to the corpus uteri Stage I
Tumour limited to endometrium or invades less than 50% of the Stage IA
myometrium
Tumour invades 50% or more of the myometrium Stage IB
Tumour invades cervical stroma but does not extend beyond uterus Stage II
Tumour with local or regional extension Stage III
Tumour involves serosa or adnexa, or both Stage IIIA
Vaginal involvement or parametrial involvement Stage IIIB
Regional lymph node metastasis Stage IIIC
Regional pelvic lymph node metastasis Stage IIIC1
Regional para-aortic lymph node metastasis with or without pelvic Stage IIIC2
lymph node metastasis
Tumour invades bladder or bowel mucosa, or distant metastatic Stage IV
disease present (or any combination thereof)
Tumour invades bladder or bowel, or both Stage IVA
Distant metastatic disease (includes inguinal lymph node, Stage IVB
intraperitoneal disease, lung, bone, or liver)
TNM classification: NX (regional lymph nodes cannot be assessed), N0 (no regional lymph node metastasis), and M0
(no distant metastasis). FIGO=International Federation of Gynecology and Obstetrics. *Either G1, G2, or G3. †FIGO does
not include stage 0 (Tis) in its classification.
Table 3: FIGO and TNM classification of endometrial cancer, by surgical and histological characteristics
(table 3).51,52 They are based on surgical staging and
include assessment of the extent of myometrial invasion
and local and distant metastatic disease—overriding
prognostic factors in endometrial cancer.51,53,54
Other prognostic factors not included in the FIGO or
TNM classifications have also been identified: histological
type and grade, the patient’s age, tumour size, and
lymphovascular space involvement. Thus, risk
stratification systems that aggregate these prognostic
factors to define recurrence risk groups54–58 have been
developed and are now used worldwide to guide decision
making and design clinical trials (table 4).55–58 Although
the core variables of these risk stratification systems are
TNM category
Results of a 2014 study—a simultaneous comparison of
TX five risk stratification systems in the same cohort—
T0 suggested that the European Society for Medical
Tis† Oncology modified system was the most accurate in the
T1 prediction of lymph node status and survival.58
T1a Because of the limits of the conventional methods
used for histological classification of endometrial
T1b
cancer subtypes, Murali and colleagues54 suggested
T2
incorporation of molecular and genetic characteristics
T3 or N1–2, or both into classifications for better appraisal of prognostic
T3a and predictive factors. Novel candidate prognostic
T3b markers, such as stathmin or L1 cell adhesion molecule
(L1CAM), and POLE mutations have been identified.
N1 Stathmin, a regulator of microtubule dynamics, is
N2 thought to be a potential predictive biomarker for
resistance to taxanes.59 L1CAM was found to be a
negative prognostic marker for type I, stage I
endometrial cancer in a large study (of 1021 patients)
T4
and outperformed risk stratification systems.60 These
M1
results were validated in a combined analysis of the
Post Operative Radiation Therapy in Endometrial
Carcinoma (PORTEC) 1 and PORTEC 2 trials; the
analysis also showed L1CAM to be a strong predictor of
distant relapse.61
POLE mutant endometrial cancers have an excellent
prognosis, and patients could be spared unnecessary
adjuvant treatment.26 Accurate prognosis will probably
necessitate use of a panel of markers—eg, TP53 mutation
combined with a high copy number and no POLE
mutation could suggest high-grade endometrioid
endometrial cancer at increased risk of metastatic relapse.
Survival
Estimated cumulative risk of endometrial cancer is 0·96%;
the corresponding mortality risk is 0·23% and mortality-
to-incidence ratio is 0·24—lower than that of breast cancer
(0·32), ovarian cancer (0·63), and uterine cervical cancer
(0·55).1,62 Most endometrial cancers (75%) are diagnosed at
an early stage (FIGO stages I or II): 5 year overall survival

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Low risk Intermediate risk High intermediate risk High risk

PORTEC 1 Grade 1 endometrial Endometrial adenocarcinoma Age >60 years with grade 1 or 2 histology Stage III–IV disease
adenocarcinoma Stage I based on uterine factors and myometrial invasion >50% Uterine serous carcinoma or clear-cell
Stage IA Grade 1 histology and myometrial invasion of ≥50% Age >60 years with grade 3 histology and carcinoma of any stage
Grade 2 histology with any myometrial invasion myometrial invasion <50%
Grade 3 histology with myometrial invasion <50%
GOG-99 Grade 1 or 2 endometrioid Age ≤50 years and ≤2 pathological risk factors* Any age and 3 pathological risk factors Stage III–IV disease, irrespective of
cancers confined to the Age 50–69 years and ≤1 pathological risk factors* Age 50–69 years and ≥2 pathological risk histology or grade
endometrium Age ≥70 years and no pathological risk factors* factors Uterine serous carcinoma or clear-cell
Stage IA Age ≥70 years and ≥1 pathological risk carcinoma of any stage
factors*
SEPAL Stage IA or IB endometrioid Stage IA grade 3 endometrioid adenocarcinoma with any ·· Stage III or IV, any grade, any LVSI
type cancers with no LVSI grade of non-endometrioid carcinoma† or any LVSI
Stage IB, grade 1–2 endometrioid adenocarcinoma with LVSI
Stage IB, grade 3 endometrioid adenocarcinoma with any
grade of non-endometrioid carcinoma or any LVSI
Stage IC, stage II, any grade, any LVSI
ESMO Stage IA grade 1 and grade 2 Stage IA grade 3 endometrioid type ·· Stage IB grade 3 endometrioid type
endometrioid type Stage IB grade 1 and grade 2 endometrioid type Non-endometrioid disease of all stages
ESMO modified Stage IA grade 1 and grade 2 Stage IA grade 1 and grade 2 endometrioid type with LVSI Stage IA grade 3 endometrioid type with Stage IB grade 3 endometrioid type
endometrioid type with no Stage IA grade 3 endometrioid type with no LVSI LVSI with positive LVSI
LVSI Stage IB grade 1 and grade 2 endometrioid type with no Stage IB grade 1 and grade 2 endometrioid Non-endometrioid disease of all stages
LVSI type with LVSI
Stage IB grade 3 endometrioid type
with no LVSI

PORTEC 1=Post-Operative Radiation Therapy in Endometrial Carcinoma. GOG=Gynaecologic Oncology Group adjuvant radiation for intermediate-risk endometrial cancers. LVSI=lymphovascular space invasion.
SEPAL=Survival Effect of Para-Aortic Lymphadenectomy in endometrial cancer. ESMO=European Society for Medical Oncology. *Risk factors: grade 2 or 3 histology, positive LVSI, myometrial invasion to outer
third. †Serous adenocarcinoma, clear cell adenocarcinoma, or other type of carcinoma.

Table 4: Variation in classifications of risk factors according to trials or society guidelines

ranges from 74% to 91%;5,63 for FIGO stage III, 5 year
overall survival is 57–66%, and for FIGO stage IV disease
is 20–26%.5,63 5 year disease-free survival is estimated at
90% in patients without lymph node metastasis, 60–70%
in those with pelvic lymph node metastasis, and 30–40%
in those with para-aortic lymph node metastasis. However,
a substantial proportion of patients with endometrial
cancer die from other health conditions as these patients
often have several comorbidities.
Survival is dependent on other predictive factors, such
as the tumour grade, age, comorbidities, tumour
diameter, American Society of Anesthesiologists score,
lymphovascular space involvement, and postoperative
complications at 30 days.55,64–69 Among the various
nomograms predicting survival, two have been validated
externally.64,70 The first to be published consists of
five simple criteria (age at diagnosis, negative lymph
nodes, FIGO stage, final histological grade, and
histological subtype). The second was validated in
randomly assigned patients from the PORTEC 1 and
PORTEC 2 trials,70 and showed that age, tumour grade,
and lymphovascular space involvement were highly
predictive for all outcomes.70 Bendifallah and colleagues67
devised a nomogram providing an estimation of lymph
node metastasis with a discrimination accuracy of 0·79
(95% CI 0·78–0·80) and an estimated concordance
probability of 0·80 (0·78–0·82). These encouraging
results underline the future contribution of predictive
models for management of endometrial cancer.
Surgery
Principles of surgical treatment
Total hysterectomy and removal of both tubes and
ovaries is the standard treatment for apparent stage I
endometrial cancer and is effective in most cases.
Alternatives to primary hysterectomy in women who
want to preserve their fertility have been
comprehensively reviewed.71 Hysterectomy and
adnexectomy can be done with minimally invasive
techniques (laparoscopy or robot-assisted surgery),
vaginally, or laparotomically. The safety of laparoscopy
has been shown in randomised clinical trials72,73 and is
associated with shorter hospital stays and fewer
postoperative complications than laparotomy. Survival
rates seem similar, which should be confirmed by
completed trials (eg, NCT00096408).
Laparoscopic or robotic approaches should be avoided
in cases of bulky uterine malignant disease that might
necessite morcellation, because morcellation can lead
to tumour spillage, increasing local or peritoneal
recurrence and thereby affecting survival. Although
simple total hysterectomy is sufficient for most women,
radical hysterectomy is sometimes done in cases of
gross cervical invasion or when uncertainty exists about
whether the primary tumour is endocervical or
endometrial in origin. Surgical staging for endometrial
cancer includes careful assessment of the peritoneal
surfaces. Omental and peritoneal biopsies are commonly
done in high-risk disease.

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Lymphadenectomy and sentinel node biopsy
Surgical assessment of lymph nodes for staging at
primary surgery remains one of the most varied practices
worldwide, ranging from no nodal assessment, to
sentinel node mapping, to complete pelvic and aortic
lymphadenectomy up to the renal vessels. Most
clinicians agree that excision or biopsy of suspicious or
enlarged lymph nodes in the pelvic or para-aortic regions
is important to exclude nodal metastatic disease. Pelvic
nodal dissection and pathological assessment continue
to be important aspects of surgical staging for apparent
stage I endometrial cancer in many practices, and might
be based on preoperative criteria such as histology,
grade, or MRI findings, or on intraoperative histology.
Para-aortic nodal assessment from the intramesenteric
and infrarenal regions is also done for staging selected
See Online for appendix high-risk tumours, such as deeply invasive lesions,
high-grade endometrioid endometrial cancers, and
type II disease.74
The extent of lymphadenectomy varies tremendously
between practices and practitioners. However, no survival
advantage has yet been associated with staging
lymphadenectomy in prospective, randomised, clinical
trials. Furthermore, between 8% and 50% of patients
develop limb lymphoedema, depending on the number
of nodes removed, extent of lymphadenectomy, and use
of adjuvant treatment.75 Most available retrospective
evidence suggesting a survival advantage with
lymphadenectomy is from historical series of selected
patients and contrasts sharply with findings from
prospective randomised trials.57,76–78
Type II endometrial cancers account for 10–15% of
endometrial cancers but cause 40% of deaths because of
the high incidence of associated extrauterine disease,
especially lymph node metastasis.79–81 Surgical manage-
ment includes hysterectomy with bilateral salpingo-
oophorectomy, pelvic and para-aortic lymphadenectomy,
omentectomy, and peritoneal biopsies.82
Uterine corpus histology
Eltabbakh and colleagues83 underscored the risk of
underestimation of endometrial cancer grade based on
biopsy specimens: a third of endometrial cancers
diagnosed as stage I on the basis of biopsy were upstaged
on final histology.83 Frumovitz and colleagues84 also
reported discrepancies between preoperative and
intraoperative versus postoperative histological grading
in 27% of cases. Similarly, Ballester and colleagues85,86
noted that only 70% of early stage endometrial cancers
were correctly staged by MRI and that 21·4% of patients
with presumed low-risk disease according to European
Society for Medical Oncology classification (table 4) had
intermediate-risk or high-risk lesions on final histology.
In a 2012 meta-analysis87 of 16 studies in which the
contribution of intraoperative histology was assessed,
pooled sensitivity was 75%, specificity was 92%, and
overall accuracy was 87%, suggesting that this approach
1100
could be useful to avoid further surgery.87 Nonetheless,
discrepancies between intraoperative and final
histological analysis, estimated to be 10–20%, remain a
major concern. Thus, some practices no longer do
intraoperative histology, which has been replaced by
either preoperative criteria (histology and MRI findings)
or systematic sentinel lymph node biopsy irrespective of
preoperative findings, on the understanding that low-risk
endometrial cancer can be diagnosed only after final
histological analysis.
During the past 5–7 years, sentinel lymph node
mapping has emerged as an approach for surgical
staging.88–90 Coloured dye and radiolabelled colloid
technetium 99 (⁹⁹mTc) are most commonly injected
directly into the cervix, which is increasingly the most
validated and popular injection site for uterine cancer
mapping (appendix).88–90 Several coloured dyes are
available (isosulfan blue 1% and methylene blue 1%,
patent blue 2·5% sodium). Indocyanine green is
currently being assessed as an alternative that
necessitates use of a near-infrared camera to localise
nodes and achieve a high detection rate. Another
advantage of sentinel lymph node mapping in
endometrial cancer is that low-volume metastatic disease
can be detected in the sentinel lymph node by enhanced
pathological ultrastaging.91–97 The clinical significance of
low-volume metastatic disease in sentinel lymph node
mapping is under investigation.
Restaging surgery
Low-risk endometrial cancer can be diagnosed only after
permanent section pathology. When this information is
available, several criteria can be used to predict the risk of
pelvic nodal metastasis and guide the clinician as to
whether restaging surgery is necessary. Decisions to return
to the operating room for secondary surgery are usually
based on uterine factors, postoperative imaging findings,
and the comorbidities and age of the patient.
Adjuvant treatment
Radiotherapy
Around 55% of patients with endometrial cancer have
uterine-confined disease with low-risk features, and are
treated with surgery only, which is associated with a 95%
probability of relapse-free survival at 5 years
(appendix).72,76,77 Four randomised trials and a Cochrane
meta-analysis have assessed the role of external-beam
pelvic radiation therapy (EBRT) in stage I endometrial
cancer (appendix).55,56,98–104 In a Norwegian trial,
540 patients with clinical stage I endometrial cancer who
received vaginal brachytherapy after surgery were then
randomly allocated to additional EBRT or observation.
Although vaginal and pelvic relapse rates were
significantly lower in the EBRT than in the observation
group, survival rates were similar.98 However, patients
with grade 3 tumours with deep (>50%) myometrial
invasion tended to achieve better local control and
www.thelancet.com Vol 387 March 12, 2016

survival with EBRT than with observation only.98 EBRT
after surgery versus observation after surgery were
compared in the PORTEC 1 (n=714),55 ASTEC/EN5
(n=905),56 and Gynecologic Oncology Group (GOG) 99
(n=392) trials.101 These trials and the Cochrane meta-
analysis showed a significant reduction in the risk of
vaginal and pelvic relapse with EBRT compared with
observation (14% vs 4% in PORTEC 1, p<0·001), but
overall survival did not differ significantly between
groups (appendix).55,100,104 The Cochrane meta-analysis did
not show a survival advantage from adjuvant EBRT for
high-risk stage I endometrial cancer, but the meta-
analyses of this subgroup were underpowered and also
included high-intermediate-risk women.104
On the basis of these trials, use of radiation therapy was
restricted to patients with high-intermediate risk features
as defined in the PORTEC 1 and GOG-99 trials (table 4).
In the PORTEC 2 trial102 vaginal brachytherapy and EBRT
were compared in 427 patients with high-intermediate-
risk endometrial cancer. 5 year vaginal recurrence rate was
less than 2% in both groups.102 Most of the pelvic relapses
(5% in the vaginal brachytherapy group vs 2% in the EBRT
group; p=0·17) were associated with distant metastatic
disease. The rate of distant metastatic disease or survival
did not differ significantly between groups. In a Swedish
trial,103 EBRT followed by a vaginal brachytherapy boost
was compared with vaginal brachytherapy alone in
patients with intermediate-risk endometrial cancer.
Locoregional control was significantly better in the EBRT
group than in the control group, but was not better than
that obtained with EBRT alone in other trials. Survival did
not differ between groups, but more toxic effects were
noted in the EBRT and vaginal brachytherapy group than
in the group having vaginal brachytherapy alone.103
In view of the good rates of vaginal control without major
toxic effects, vaginal brachytherapy is the standard adjuvant
treatment for patients with FIGO 2009 stage I endometrial
cancer at high-intermediate risk.102 Nonetheless, a trade-off
exists between watchful waiting (with a 20% risk of
recurrence) and a simple and effective preventive treatment
with the same long-term quality of life. Most patients
preferred treatment, even at a 5% benefit level.105 In the
randomised PORTEC 4 trial, which is underway, the
effects and outcome of watchful waiting compared with
vaginal brachytherapy are being investigated.
Chemotherapy
Adjuvant chemotherapy versus pelvic EBRT alone
has been compared in three randomised trials
(appendix).106–108 CAP (cyclophosphamide, doxorubicin,
and cisplatin) was used in both the Japanese106
(three cycles) and Italian107 (five cycles) trials. In the
Japanese trial (n=385)106 of patients with favourable
disease characteristics, no significant differences were
noted in overall survival, relapse, or progression-free
survival. Nevertheless, an unplanned subgroup analysis
of patients (with stage IC endometrial cancer and older
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Seminar
than 70 years, or with G3 endometrioid adenocarcinoma,
or stage II endometrial cancer, or positive cytology),
might have benefited from chemotherapy instead of
radiation.106 The Italian trial (n=345) comprised patients
with advanced stage disease (65% had stage III
endometrial cancer); no significant differences were
reported in 5 year overall survival, progression-free
survival, or relapse, but more grade 3 toxic effects
occurred in the CAP group than in the EBRT group.107
Combined radiation therapy and chemotherapy
The trials in which adjuvant chemotherapy alone and
EBRT alone were compared showed that, although
chemotherapy delayed distant relapse, pelvic EBRT
delayed pelvic relapse, and overall and relapse-free
survival were similar between groups.107–111 In the NSGO
9501/EORTC 55991 trial of 382 patients, in which EBRT
only was compared with EBRT and four cycles of
chemotherapy, progression-free survival was 7% higher
in the chemotherapy group (p=0·009), but overall
survival did not differ significantly (appendix). Similar
results were reported in pooled data analysis with the
Italian MaNGO ILIADE-III trial.111
The GOG analysed differences in response and
progression-free survival between serous or clear-cell and
endometrioid cancer in patients with advanced or
metastatic endometrial cancer.112 They noted that serous
and clear-cell carcinomas did not respond differently to
chemotherapy from endometrioid cancers. In other
reports, improved survival has been suggested in patients
with early stage serous endometrial cancer who are given
chemotherapy, underlining the need to investigate
optimum chemotherapy or other systemic treatments.113
In the GOG-249 trial, in which vaginal brachytherapy
followed by three cycles of carboplatin-paclitaxel was
compared with pelvic EBRT in 601 patients with stage I
or II endometrial cancer with high-intermediate or
high-risk factors, no significant differences were noted in
relapse-free or overall survival at a median follow-up of
24 months.114 Ongoing and recently completed trials have
focused on the role of adjuvant chemotherapy, EBRT, or a
combination of both in high-risk disease (appendix).
Management of metastatic or recurrent disease
Surgery or other local treatment (radiation therapy in a
non-irradiated area) are options in patients with
metastatic or recurrent disease—mainly in patients with
an isolated centropelvic recurrence or a single metastatic
site.115 5 year overall survival after exenteration for pelvic
recurrence ranges from 20% to 40%.115,116 Results of
studies suggest that management of endometrial cancer
with peritoneal spread could be similar to that of ovarian
cancer, which emphasises the importance of surgery.117–119
In patients with so-called unresectable peritoneal disease
(those who are ineligible for primary complete
cytoreductive surgery), primary chemotherapy followed
by surgery is associated with improved survival.120,121
1101
 Seminar

Phase Selection of patients Activity and toxic effects Candidate biomarkers identified
mTOR inhibitors
Ridaforolimus125 2 No RR <10% None
Ridaforolimus126 2 No RR <10% None
Ridaforolimus vs progestin or 2 No RR <10% None
chemotherapy127
Everolimus128 2 No RR <10% None
Temsirolimus129 2 No RR <10% None
Everolimus plus letrozole130 2 No RR=32% Yes (endometrioid histology and
(11/35, including nine complete CTNNB1 mutations)
responses)
PI3K inhibitors
BKM120 (NCT01289041) 2 No Halted for toxic effects None
Pilaralisib131 2 No RR=6% None
Grade 3 or 4 adverse events: rash (9%),
diarrhoea (5%), increased ALT (5%)
Dual PI3K/mTOR inhibitors
GDC0980132 2 No RR=9% None
45% grade 3–4 hyperglycaemia
AKT inhibitors
MK2206 (NCT01307631) 2 No Pending None
MEK inhibitors
AZD6244133 2 No RR=6% None
ErbB family inhibitors134
Trastuzumab (antibody against HER2) 2 HER2 2+/3+ or FISH+ RR=0% None
Lapatinib (kinase inhibitor against EGFR and 2 No RR=3% (1/30) Only response in EGFR (mutation-
HER2) positive endometrial cancer)
Erlotinib (kinase inhibitor against EGFR) 2 No RR=12% (4/32) None
Cetuximab (antobogy against EGFR) 2 No RR=5% None
Targeting insulin/IGF1R135
Metformin in four window-of-opportunity 2 No Reduction in Ki67 in paired biopsies None
trials
FGFR/VEGFR inhibitors
VEGF antibody, bevacizumab136 2 No RR=15% None
Sunitinib (targets VEGFR/RET/PDGFR/flt3)137 2 No RR=18% None
90% grade 3 toxic effects (fatigue,
hypertension, diarrhoea, PPE,
haematological)
Multi-targeted VEGFR/FGFR inhibitors
Brivanib (targets FGFR/VEGFR)138 2 No RR=19% VEGF, angiopoietin-2, and oestrogen
Toxic effects: grade 1 fistulae (1/43), receptor expression
grade 3–4 hypertension (9/43)
Lenvatinib (targets FGFR/VEGFR/RET/ 2 No RR=14% Angiopoietin-2
PDGFR)139 Grade 3–4 toxic effects: hypertension
(33%), fatigue (13%), diarrhoea (5%),
anorexia/nausea (5%), fistulae/
perforation (5%)
Bevacizumab plus temsirolimus140 2 No RR=24% None
Toxic effects: grade 1 fistulae or
perforations (4/49), grade 3 epistaxis
(1/49), TEE (2/49)

mTOR=mammalian target of rapamycin. RR=response rate. ALT=alanine transaminase. FISH=fluorescence in-situ hybridisation. PPE=palmar-plantar erythrodysesthaesia.
TEE=thromboembolic event.

Table 5: Completed clinical trials of targeted drugs in endometrial cancer

For patients with a relapse not amenable to local alternative to the three-drug combination for metastatic
therapy, a carboplatin–paclitaxel combination is as or relapsed endometrial cancer.116 No data support use
effective and less toxic than paclitaxel, adriamycin, and of hormonal therapy in early stage endometrial cancer.
cisplatin, and is increasingly used as a first-line For advanced stage disease, a 33% response rate

1102 www.thelancet.com Vol 387 March 12, 2016


was noted after sequential alternate tamoxifen and
medroxyprogesterone.122 In recurrent or metastatic
endometrial cancer, progestogens (response rate 11–56%
depending on grade), tamoxifen alternated with
megestrol, gonadotropin-releasing hormone analogues
(11%),123 selective oestrogen receptor modulators
(25–31%), and aromatase inhibitors have been used.124
There are no standard second-line therapies.
Targeted therapies
No approved targeted therapies are available for endometrial
cancer. The PI3K/AKT/mammalian target of the rapamycin
(mTOR) pathway is the most commonly deregulated
pathway in endometrial cancer but results of trials with
mTOR inhibitors showed response rates of less than 10%
(table 5).125–132 Several hypotheses have been put forward to
explain the ineffectiveness of mTOR inhibitors in
endometrial cancer: first, a preponderant cytostatic effect;
second, limited activity in an unselected population; and,
finally, that mTOR inhibitors might be poor inhibitors of
the pathway.126 Novel AKT, PI3K, and dual PI3K–mTOR
inhibitors, and combinations thereof, are being tested
(table 5).131 However, patients with endometrial cancer are
often older than 65 years and have comorbidities, and
tolerability is an issue especially with targeted therapy
combinations. Oestrogen-receptor-positive endometrioid
endometrial cancer with PTEN or PIK3CA mutations
might be responsive to combined inhibition of PI3K and
the oestrogen receptor. The combination of everolimus
plus letrozole resulted in an objective response rate of 32%
(appendix).
Trials of EGFR and HER2 inhibitors as single agents in
endometrial cancer have had disappointing results
(table 5).134 However, in view of the known prevalence of
HER2 amplification in serous endometrial cancer
(12–15%), a randomised study of carboplatin and paclitaxel
with or without trastuzumab in HER2-positive (+++ by
immunohistochemistry or amplification by fluorescence
in-situ hybridisation) serous endometrial cancer is
ongoing (NCT01367002).
The results of two retrospective studies have suggested
that metformin is associated with improved overall
survival in patients with diabetes who have endometrial
cancer.135 However, the primary endpoint was all-cause
mortality, so drawing conclusions about the effect of
metformin on endometrial-cancer-related death is
difficult. Trials of metformin combined with
chemotherapy or other targeted therapies are ongoing
(appendix).
Use of anti-angiogenic drugs, such as bevacizumab and
sunitinib, as single agents in endometrial cancer has
resulted in objective response rates of 12–15%.136,137 In
one study,140 a combination of bevacizumab and the
mTOR inhibitor temsirolimus was efficacious, but caused
intestinal fistulas and perforations (table 5). Use of
multitargeted VEGF/FGFR inhibitors (brivanib,
lenvatinib) has yielded encouraging results (response
www.thelancet.com Vol 387 March 12, 2016
Seminar
rates 14–19%).138,139 In view of the recent identification of
FGFR1 or FGFR3 amplifications in 10–20% of serous
endometrial cancers or carcinosarcomas and FGFR2
mutations in endometrioid endometrial cancers, clinical
trials of FGFR inhibitors are ongoing. The rationale for
other targeted strategies and ongoing trials in endometrial
cancer are summarised in the appendix.
Luteinising-hormone-releasing hormone (LHRH)
receptors are expressed in 80% of endometrial cancers. In
a phase 2 trial, AEZS-108—an LHRH agonist conjugated
to doxorubicin via a protease-cleavable linker—showed
activity in LHRH-receptor-positive recurrent endometrial
cancer and was well tolerated.141 A randomised phase 3
trial comparing doxorubicin to AESZ-108 is ongoing.
Objective responses have been reported with PARP
inhibitors in homologous-recombination-deficient BRCA
wild-type high-grade serous ovarian cancer.142 The
substantial genomic homology between triple-negative
breast cancer, high-grade serous ovarian cancer, and
serous endometrial cancer suggests that genomically
unstable, copy-number-high endometrial cancer might
also have homologous-recombination defects predictive
of PARP inhibitor sensitivity. PARP inhibitors are also
synthetically lethal in microsatellite unstable tumour
models and in PTEN-null endometrial cancer cell lines,
suggesting that a further biomarker-defined subset of
endometrial cancers could benefit from these drugs.143 A
phase 2 trial of the PARP inhibitor BMN673 is underway
in patients with relapsed endometrial cancer.
Restoring host anti-tumour immunity might also
provide a novel therapeutic strategy in endometrial
cancer. Immune checkpoint regulators such as
programmed cell death 1 (PD1) promote escape from
tumour immune surveillance, and 80% of endometrial
cancers express high levels of PD1, or its ligand, PDL1,
which are possible predictive biomarkers for anti-PD1/
PDL1 antibodies.144 Additionally, high mutation load
correlates with increased PD1 expression, and data
suggest that POLE-mutated or microsatellite instability
endometrial tumours might be excellent candidates for
PD1-directed immune therapies.145 Ongoing phase 1 trials
of PD1/PDL1 inhibitors are selecting patients with
microsatellite instability endometrial cancers before
enrolment.
Genetic counselling
5–25% of endometrial cancers are related to high-risk
germline mutations, which are characterised by early
onset of disease—ie, before age 40 years.146 Genetic
testing and counselling should be considered for women
with endometrial cancer who are younger than 50 years,
and those with a clinically significant family history of
endometrial or colorectal cancer.147
Women with Lynch syndrome or hereditary non-
polyposis colon cancer are at increased risk of endometrial,
colon, and ovarian cancer linked to germline mutations in
one of the mismatch repair genes (MLH1, MSH2, MSH6,
1103
 Seminar
and PMS2).148 Bonadona and colleagues149 estimated the
cumulative risk of endometrial cancer by age 70 years at
54% for MLH1 mutations, 21% for MSH2 mutations, and
16% for MSH6 mutations. Data for prophylactic surgery
are scarce. Schmeler and colleagues150 concluded that
prophylactic hysterectomy with an oophorectomy should
be considered in patients older than 35 years, after
completion of childbearing. The positive results of this
strategy have been shown in a modelling study.151
Screening
In the general population, evidence to support screening
for endometrial cancer is insufficient. However,
women—particularly those who are overweight—should
be informed by their family doctor about the risks of
endometrial cancer, and encouraged to consult their
physician immediately in cases of uterine bleeding or
spotting during the perimenopausal period.
No screening strategy has proven efficacy for women
with hereditary non-polyposis colon cancer or Lynch
syndrome. In view of the frequency of interval cancers, a
yearly clinical examination and transvaginal ultrasound
would probably be ineffective. An additional endometrial
biopsy could improve screening performance but the
acceptability to women of this screening strategy and
potential compliance with such a strategy are unknown.152
Furthermore, the relevance of outpatient hysteroscopy
in detection of endometrial cancer is still under
investigation.150,153
Management of comorbidities
Patients with comorbidities are more likely to be
suboptimally managed, particularly in terms of lymph
node dissection and adjuvant therapy. In a review of
12 studies,154 obesity did not seem to affect either
progression-free or disease-specific survival. However,
Arem and colleagues155 reported that patients with poorly
differentiated endometrial cancer had a specific mortality
hazard ratio of 1·39 (95% CI 1·04–1·85) per five-unit
increase in BMI, whereas no differences were detected
for well differentiated or moderately differentiated
endometrial cancer.
In a meta-analysis,156 the relative risk of disease-
specific mortality in women with diabetes versus those
without diabetes was 1·32 (95% CI 1·10–1·60, p=0·003),
but standardised mortality ratios were not significant.
However, for severely obese women in the low-risk and
intermediate-risk groups, elderly patients, or those with
comorbidities, the risks of laparoscopy or laparotomy
could outweigh the benefits. In these circumstances,
vaginal hysterectomy is a legitimate option, resulting in
similar survival to that obtained with the conventional
approach.157
Age does not justify modification of the classic
management of endometrial cancer. Various randomised
trials have shown that age is an independent prognostic
factor, with the oldest individuals having the poorest
1104
outlooks.55,106 The Charlson comorbidity index, a
prognostic classification that takes into account the
effects of patients’ adverse medical states, has been used
in patients with early stage endometrial cancer.158 In
patients with inoperable disease, primary curative
radiation therapy is an option. However, improvement in
the patient’s general wellbeing has an important role in
this setting, because a substantial proportion of deaths
are related to the patient’s comorbidities rather than to
the cancer itself.
Controversies and outstanding research
questions
Recently completed and ongoing trials are focusing on the
role of chemotherapy, radiation therapy, or a combination
of both in patients with high-risk and advanced
endometrial cancer (appendix). In the international
PORTEC 3 trial, patients with high-risk endometrial
cancer have been randomly assigned to EBRT alone or to
a combination of EBRT and chemotherapy. In the GOG-
258 trial, adjuvant chemotherapy alone is being compared
with chemotherapy combined with radiotherapy (schedule
as used in PORTEC 3). Results are expected from
both trials in 2016. Finally, in the recently begun
ENGOT-EN2-DGCG trial, patients with node-negative
endometrial cancer and high-risk features have been
randomly assigned to adjuvant chemotherapy or
observation. Vaginal brachytherapy is optional in both
groups.
Trials are needed to establish the role of lymphad-
enectomy and targeted drugs in high-risk endometrial
cancer. The international STATEC trial of
lymphadenectomy-directed adjuvant therapy is about to
start recruitment. Unfortunately, the emergence of
predictive tests for targeted drugs often lags behind the
introduction of new drugs. The signal pathways that have
been targeted in clinical trials in endometrial cancer are
those that inhibit EGFR, VEGFR, and PI3K/PTEN/AKT/
mTOR. Multitarget VEGF inhibitors are thought to be the
most promising (appendix). An international multicentre
trial (TOTEM) is testing two follow-up regimens
(intensive vs minimalist) in patients with recurrence to
assess the effect of these modalities on outcome according
to patients’ characteristics. This study includes a cost-
effectiveness analysis.
In conclusion, endometrial cancer is a major issue for
the health-care system because of its increasing incidence
in high-income countries. More effort needs to be put
into promoting trials that will improve patient selection
for adjuvant treatment including targeted therapies.
Contributors
All authors contributed equally to the writing of this Seminar.
Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Lorna Saint Ange for editing and Isabelle Thomassin-Naggara
and Marc Bazot for radiological imaging.
www.thelancet.com Vol 387 March 12, 2016

References
1 Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and
mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86.
2 Querleu D, Planchamp F, Narducci F, et al, and the Institut
National du Cancer, and the Societe Francaise d’Oncologie
Gynecologique. Clinical practice guidelines for the management of
patients with endometrial cancer in France: recommendations of
the Institut National du Cancer and the Société Française
d’Oncologie Gynécologique. Int J Gynecol Cancer 2011; 21: 945–50.
3 Burke WM, Orr J, Leitao M, et al, and the SGO Clinical Practice
Endometrial Cancer Working Group, and the Society of Gynecologic
Oncology Clinical Practice Committee. Endometrial cancer:
a review and current management strategies: part I. Gynecol Oncol
2014; 134: 385–92.
4 Burke WM, Orr J, Leitao M, et al, and the SGO Clinical Practice
Endometrial Cancer Working Group, and the Society of Gynecologic
Oncology Clinical Practice Committee. Endometrial cancer:
a review and current management strategies: part II. Gynecol Oncol
2014; 134: 393–402.
5 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015.
CA Cancer J Clin 2015; 65: 5–29.
6 Evans-Metcalf ER, Brooks SE, Reale FR, Baker SP. Profile of women
45 years of age and younger with endometrial cancer. Obstet Gynecol
1998; 91: 349–54.
7 Lee TS, Jung JY, Kim JW, et al. Feasibility of ovarian preservation in
patients with early stage endometrial carcinoma. Gynecol Oncol
2007; 104: 52–57.
8 Duska LR, Garrett A, Rueda BR, Haas J, Chang Y, Fuller AF.
Endometrial cancer in women 40 years old or younger.
Gynecol Oncol 2001; 83: 388–93.
9 Lacey JV Jr, Chia VM, Rush BB, et al. Incidence rates of endometrial
hyperplasia, endometrial cancer and hysterectomy from
1980 to 2003 within a large prepaid health plan. Int J Cancer 2012;
131: 1921–29.
10 Sheikh MA, Althouse AD, Freese KE, et al. USA endometrial cancer
projections to 2030: should we be concerned? Future Oncol 2014;
10: 2561–68.
11 Trabert B, Wentzensen N, Felix AS, Yang HP, Sherman ME,
Brinton LA. Metabolic syndrome and risk of endometrial cancer in
the United States: a study in the SEER-medicare linked database.
Cancer Epidemiol Biomarkers Prev 2015; 24: 261–67.
12 Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’
oestrogens and endometrial mitotic rate: its central role in explaining
and predicting endometrial cancer risk. Br J Cancer 1988; 57: 205–12.
13 Pike MC, Peters RK, Cozen W, et al. Estrogen–progestin replacement
therapy and endometrial cancer. J Natl Cancer Inst 1997; 89: 1110–16.
14 Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones,
and endometrial cancer risk: a synthetic review.
Cancer Epidemiol Biomarkers Prev 2002; 11: 1531–43.
15 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M.
Body-mass index and incidence of cancer: a systematic review and
meta-analysis of prospective observational studies. Lancet 2008;
371: 569–78.
16 Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D.
Hormone replacement therapy and endometrial cancer risk:
a meta-analysis. Obstet Gynecol 1995; 85: 304–13.
17 Purdie DM, Green AC. Epidemiology of endometrial cancer.
Best Pract Res Clin Obstet Gynaecol 2001; 15: 341–54.
18 Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and
risk of endometrial cancer: a meta-analysis. Diabetologia 2007;
50: 1365–74.
19 Terry P, Baron JA, Weiderpass E, Yuen J, Lichtenstein P, Nyrén O.
Lifestyle and endometrial cancer risk: a cohort study from the
Swedish Twin Registry. Int J Cancer 1999; 82: 38–42.
20 Anderson KE, Anderson E, Mink PJ, et al. Diabetes and endometrial
cancer in the Iowa women’s health study.
Cancer Epidemiol Biomarkers Prev 2001; 10: 611–16.
21 Luo J, Beresford S, Chen C, et al. Association between diabetes,
diabetes treatment and risk of developing endometrial cancer.
Br J Cancer 2014; 111: 1432–39.
22 Soini T, Hurskainen R, Grénman S, Mäenpää J, Paavonen J,
Pukkala E. Cancer risk in women using the levonorgestrel-releasing
intrauterine system in Finland. Obstet Gynecol 2014; 124: 292–99.
www.thelancet.com Vol 387 March 12, 2016
Seminar
23 Bokhman JV. Two pathogenetic types of endometrial carcinoma.
Gynecol Oncol 1983; 15: 10–17.
24 Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity
in endometrial cancer: evidence from a Gynecologic Oncology
Group trial. Gynecol Oncol 2013; 129: 277–84.
25 Zannoni GF, Vellone VG, Arena V, et al. Does high-grade
endometrioid carcinoma (grade 3 FIGO) belong to type I or type II
endometrial cancer? A clinical-pathological and
immunohistochemical study. Virchows Arch 2010; 457: 27–34.
26 Kandoth C, Schultz N, Cherniack AD, et al, and the Cancer
Genome Atlas Research Network. Integrated genomic
characterization of endometrial carcinoma. Nature 2013; 497: 67–73.
27 Byron SA, Pollock PM. FGFR2 as a molecular target in endometrial
cancer. Future Oncol 2009; 5: 27–32.
28 Kuhn E, Ayhan A, Bahadirli-Talbott A, Zhao C, Shih IM. Molecular
characterization of undifferentiated carcinoma associated with
endometrioid carcinoma. Am J Surg Pathol 2014; 38: 660–65.
29 Zhang ZM, Xiao S, Sun GY, et al. The clinicopathologic significance
of the loss of BAF250a (ARID1A) expression in endometrial
carcinoma. Int J Gynecol Cancer 2014; 24: 534–40.
30 Fadare O, Gwin K, Desouki MM, et al. The clinicopathologic
significance of p53 and BAF-250a (ARID1A) expression in clear cell
carcinoma of the endometrium. Mod Pathol 2013; 26: 1101–10.
31 Hoang LN, Han G, McConechy M, et al. Immunohistochemical
characterization of prototypical endometrial clear cell carcinoma—
diagnostic utility of HNF-1β and oestrogen receptor. Histopathology
2014; 64: 585–96.
32 Hussein YR, Weigelt B, Levine DA, et al. Clinicopathological
analysis of endometrial carcinomas harboring somatic POLE
exonuclease domain mutations. Mod Pathol 2015; 28: 505–14.
33 Modica I, Soslow RA, Black D, Tornos C, Kauff N, Shia J. Utility of
immunohistochemistry in predicting microsatellite instability in
endometrial carcinoma. Am J Surg Pathol 2007; 31: 744–51.
34 McCluggage WG. My approach to the interpretation of endometrial
biopsies and curettings. J Clin Pathol 2006; 59: 801–12.
35 Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of
endometrial sampling in the diagnosis of patients with endometrial
carcinoma and hyperplasia: a meta-analysis. Cancer 2000;
89: 1765–72.
36 Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial
carcinoma in women with a biopsy diagnosis of atypical
endometrial hyperplasia: a Gynecologic Oncology Group study.
Cancer 2006; 106: 812–19.
37 Touboul C, Piel B, Koskas M, et al. Factors predictive of endometrial
carcinoma in patients with atypical endometrial hyperplasia on
preoperative histology. Anticancer Res 2014; 34: 5671–76.
38 Lee DO, Jung MH, Kim HY. Prospective comparison of biopsy
results from curettage and hysteroscopy in postmenopausal uterine
bleeding. J Obstet Gynaecol Res 2011; 37: 1423–26.
39 Chang YN, Zhang Y, Wang YJ, Wang LP, Duan H. Effect of
hysteroscopy on the peritoneal dissemination of endometrial cancer
cells: a meta-analysis. Fertil Steril 2011; 96: 957–61.
40 Timmermans A, Opmeer BC, Khan KS, et al. Endometrial
thickness measurement for detecting endometrial cancer in women
with postmenopausal bleeding: a systematic review and
meta-analysis. Obstet Gynecol 2010; 116: 160–67.
41 Savelli L, Ceccarini M, Ludovisi M, et al. Preoperative local staging
of endometrial cancer: transvaginal sonography vs magnetic
resonance imaging. Ultrasound Obstet Gynecol 2008; 31: 560–66.
42 Akbayir O, Corbacioglu A, Numanoglu C, et al. Preoperative
assessment of myometrial and cervical invasion in endometrial
carcinoma by transvaginal ultrasound. Gynecol Oncol 2011; 122: 600–03.
43 Jantarasaengaram S, Praditphol N, Tansathit T, Vipupinyo C,
Vairojanavong K. Three-dimensional ultrasound with volume
contrast imaging for preoperative assessment of myometrial
invasion and cervical involvement in women with endometrial
cancer. Ultrasound Obstet Gynecol 2014; 43: 569–74.
44 Andreano A, Rechichi G, Rebora P, Sironi S, Valsecchi MG,
Galimberti S. MR diffusion imaging for preoperative staging of
myometrial invasion in patients with endometrial cancer:
a systematic review and meta-analysis. Eur Radiol 2014; 24: 1327–38.
45 Lin G, Ng KK, Chang CJ, et al. Myometrial invasion in endometrial
cancer: diagnostic accuracy of diffusion-weighted 3·0-T MR
imaging—initial experience. Radiology 2009; 250: 784–92.
1105
 Seminar
46 Hori M, Kim T, Onishi H, et al. Endometrial cancer: preoperative
staging using three-dimensional T2-weighted turbo spin-echo and
diffusion-weighted MR imaging at 3·0 T: a prospective comparative
study. Eur Radiol 2013; 23: 2296–305.
47 Selman TJ, Mann CH, Zamora J, Khan KS. A systematic review of
tests for lymph node status in primary endometrial cancer.
BMC Womens Health 2008; 8: 8.
48 Liu FY, Chao A, Lai CH, Chou HH, Yen TC. Metabolic tumor
volume by ¹⁸F-FDG PET/CT is prognostic for stage IVB endometrial
carcinoma. Gynecol Oncol 2012; 125: 566–71.
49 Lai CH, Lin G, Yen TC, Liu FY. Molecular imaging in the
management of gynecologic malignancies. Gynecol Oncol 2014;
135: 156–62.
50 Chicklore S, Gnanasegaran G, Vijayanathan S, Fogelman I.
Potential role of multislice SPECT/CT in impingement syndrome
and soft-tissue pathology of the ankle and foot. Nucl Med Commun
2013; 34: 130–39.
51 Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix,
and endometrium. Int J Gynaecol Obstet 2009; 105: 103–04.
52 Union internationale contre le cancer (UICC). TNM: Classification
des tumeurs malignes, 7th edn. New York, NY: Wiley-Blackwell,
2009.
53 Barlin JN, Zhou Q, St Clair CM, et al. Classification and regression
tree (CART) analysis of endometrial carcinoma: seeing the forest
for the trees. Gynecol Oncol 2013; 130: 452–56.
54 Murali R, Soslow RA, Weigelt B. Classification of endometrial
carcinoma: more than two types. Lancet Oncol 2014; 15: e268–78.
55 Creutzberg CL, van Putten WL, Koper PC, 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: 1404–11.
56 Keys HM, Roberts JA, Brunetto VL, et al, and the Gynecologic
Oncology Group. A phase III trial of surgery with or without
adjunctive external pelvic radiation therapy in intermediate risk
endometrial adenocarcinoma: a Gynecologic Oncology Group study.
Gynecol Oncol 2004; 92: 744–51.
57 Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N.
Survival effect of para-aortic lymphadenectomy in endometrial
cancer (SEPAL study): a retrospective cohort analysis. Lancet 2010;
375: 1165–72.
58 Bendifallah S, Canlorbe G, Raimond E, et al. A clue towards
improving the European Society of Medical Oncology risk group
classification in apparent early stage endometrial cancer? Impact of
lymphovascular space invasion. Br J Cancer 2014; 110: 2640–46.
59 Werner HM, Trovik J, Halle MK, et al. Stathmin protein level,
a potential predictive marker for taxane treatment response in
endometrial cancer. PLoS One 2014; 9: e90141.
60 Zeimet AG, Reimer D, Huszar M, et al. L1CAM in early-stage type I
endometrial cancer: results of a large multicenter evaluation.
J Natl Cancer Inst 2013; 105: 1142–50.
61 Bosse T, Nout RA, Stelloo E, et al. L1 cell adhesion molecule is a
strong predictor for distant recurrence and overall survival in early
stage endometrial cancer: pooled PORTEC trial results. Eur J Cancer
2014; 50: 2602–10.
62 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: 1675–84.
63 Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the
corpus uteri. FIGO 26th annual report on the results of treatment
in gynecological cancer. Int J Gynaecol Obstet 2006;
95 (suppl 1): S105–43.
64 Abu-Rustum NR, Zhou Q, Gomez JD, et al. A nomogram for
predicting overall survival of women with endometrial cancer
following primary therapy: toward improving individualized cancer
care. Gynecol Oncol 2010; 116: 399–403.
65 AlHilli MM, Podratz KC, Dowdy SC, et al. Risk-scoring system for
the individualized prediction of lymphatic dissemination in patients
with endometrioid endometrial cancer. Gynecol Oncol 2013;
131: 103–08.
66 AlHilli MM, Mariani A, Bakkum-Gamez JN, et al. Risk-scoring
models for individualized prediction of overall survival in low-
grade and high-grade endometrial cancer. Gynecol Oncol 2014;
133: 485–93.
1106
67 Bendifallah S, Canlorbe G, Raimond E, et al. An external validation
study of nomograms designed to predict isolated loco-regional and
distant endometrial cancer recurrences: how applicable are they?
Br J Cancer 2013; 109: 1498–503.
68 Koskas M, Fournier M, Luton D, Darai E, Rouzier R. Survival
impact of lymphadenectomy stratified by nodal metastatic
probability in endometrial cancer. Ann Surg Oncol 2014; 21: 2376–82.
69 Bendifallah S, Canlorbe G, Raimond E, et al. External validation of
nomograms designed to predict lymphatic dissemination in
patients with early-stage endometrioid endometrial cancer:
a multicenter study. Am J Obstet Gynecol 2015; 212: e1–7.
70 Creutzberg CL, van Stiphout RG, Nout RA, et al. Nomograms for
prediction of outcome with or without adjuvant radiation therapy
for patients with endometrial cancer: a pooled analysis of
PORTEC-1 and PORTEC-2 trials. Int J Radiat Oncol Biol Phys 2015;
91: 530–39.
71 Rodolakis A, Biliatis I, Morice P, et al. ESGO Task Force for Fertility
Preservation: clinical recommendations for fertility-sparing
management in young endometrial cancer patients.
Int J Gynecol Cancer 2015; 25: 1258–65.
72 Janda M, Gebski V, Brand A, et al. Quality of life after total
laparoscopic hysterectomy versus total abdominal hysterectomy for
stage I endometrial cancer (LACE): a randomised trial. Lancet Oncol
2010; 11: 772–80.
73 Lu Q, Liu H, Liu C, et al. Comparison of laparoscopy and
laparotomy for management of endometrial carcinoma:
a prospective randomized study with 11-year experience.
J Cancer Res Clin Oncol 2013; 139: 1853–59.
74 Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of
lymphatic dissemination in endometrial cancer: a paradigm shift in
surgical staging. Gynecol Oncol 2008; 109: 11–18.
75 Beesley VL, Rowlands IJ, Hayes SC, et al, and the Australian
National Endometrial Cancer Study Group. Incidence, risk factors
and estimates of a woman’s risk of developing secondary lower limb
lymphedema and lymphedema-specific supportive care needs in
women treated for endometrial cancer. Gynecol Oncol 2015;
136: 87–93.
76 Kilgore LC, Partridge EE, Alvarez RD, et al. Adenocarcinoma of the
endometrium: survival comparisons of patients with and without
pelvic node sampling. Gynecol Oncol 1995; 56: 29–33.
77 Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK, and the
ASTEC study group. Efficacy of systematic pelvic lymphadenectomy
in endometrial cancer (MRC ASTEC trial): a randomised study.
Lancet 2009; 373: 125–36.
78 Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic
lymphadenectomy vs no lymphadenectomy in early-stage
endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst
2008; 100: 1707–16.
79 Boruta DM 2nd, Gehrig PA, Fader AN, Olawaiye AB. Management of
women with uterine papillary serous cancer: a Society of Gynecologic
Oncology (SGO) review. Gynecol Oncol 2009; 115: 142–53.
80 Mendivil A, Schuler KM, Gehrig PA. Non-endometrioid
adenocarcinoma of the uterine corpus: a review of selected
histological subtypes. Cancer Control 2009; 16: 46–52.
81 Olawaiye AB, Boruta DM 2nd. Management of women with clear
cell endometrial cancer: a Society of Gynecologic Oncology (SGO)
review. Gynecol Oncol 2009; 113: 277–83.
82 Setiawan VW, Yang HP, Pike MC, et al, and the Australian National
Endometrial Cancer Study Group. Type I and II endometrial
cancers: have they different risk factors? J Clin Oncol 2013;
31: 2607–18.
83 Eltabbakh GH, Shamonki J, Mount SL. Surgical stage, final grade,
and survival of women with endometrial carcinoma whose
preoperative endometrial biopsy shows well-differentiated tumors.
Gynecol Oncol 2005; 99: 309–12.
84 Frumovitz M, Singh DK, Meyer L, et al. Predictors of final histology
in patients with endometrial cancer. Gynecol Oncol 2004; 95: 463–68.
85 Ballester M, Koskas M, Coutant C, et al. Does the use of the 2009
FIGO classification of endometrial cancer impact on indications of
the sentinel node biopsy? BMC Cancer 2010; 10: 465–71.
86 Ballester M, Naoura I, Chéreau E, et al. Sentinel node biopsy
upstages patients with presumed low- and intermediate-risk
endometrial cancer: results of a multicenter study. Ann Surg Oncol
2013; 20: 407–12.
www.thelancet.com Vol 387 March 12, 2016

87 Mavromatis ID, Antonopoulos CN, Matsoukis IL, et al. Validity of
intraoperative gross examination of myometrial invasion in patients
with endometrial cancer: a meta-analysis. Acta Obstet Gynecol Scand
2012; 91: 779–93.
88 Khoury-Collado F, Glaser GE, Zivanovic O, et al. Improving sentinel
lymph node detection rates in endometrial cancer: how many cases
are needed? Gynecol Oncol 2009; 115: 453–55.
89 Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph
node mapping for endometrial cancer improves the detection of
metastatic disease to regional lymph nodes. Gynecol Oncol 2011;
122: 251–54.
90 Frimer M, Khoury-Collado F, Murray MP, Barakat RR,
Abu-Rustum NR. Micrometastasis of endometrial cancer to sentinel
lymph nodes: is it an artifact of uterine manipulation?
Gynecol Oncol 2010; 119: 496–99.
91 Leitao MM Jr, Khoury-Collado F, Gardner G, et al. Impact of
incorporating an algorithm that utilizes sentinel lymph node
mapping during minimally invasive procedures on the detection of
stage IIIC endometrial cancer. Gynecol Oncol 2013; 129: 38–41.
92 Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging
improves micrometastasis detection in sentinel lymph nodes
during endometrial cancer staging. Int J Gynecol Cancer 2013;
23: 964–70.
93 Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of
applying a sentinel lymph node mapping algorithm in endometrial
cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;
125: 531–35.
94 Vidal F, Leguevaque P, Motton S, et al. Evaluation of the sentinel
lymph node algorithm with blue dye labeling for early-stage
endometrial cancer in a multicentric setting. Int J Gynecol Cancer
2013; 23: 1237–43.
95 Abu-Rustum NR. The increasing credibility of sentinel lymph node
mapping in endometrial cancer. Ann Surg Oncol 2013; 20: 353–54.
96 Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, et al. Sentinel
lymph node mapping for grade 1 endometrial cancer: is it the
answer to the surgical staging dilemma? Gynecol Oncol 2009;
113: 163–69.
97 Ballester M, Dubernard G, Lécuru F, et al. Detection rate and
diagnostic accuracy of sentinel-node biopsy in early stage endometrial
cancer: a prospective multicentre study (SENTI-ENDO). Lancet Oncol
2011; 12: 469–76.
98 Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external
irradiation and prognostic parameters in stage I endometrial
carcinoma: clinical and histopathologic study of 540 patients.
Obstet Gynecol 1980; 56: 419–27.
99 Onsrud M, Cvancarova M, Hellebust TP, Tropé CG, Kristensen GB,
Lindemann K. Long-term outcomes after pelvic radiation for
early-stage endometrial cancer. J Clin Oncol 2013; 31: 3951–56.
100 Creutzberg CL, Nout RA, Lybeert ML, et al, and the PORTEC Study
Group. Fifteen-year radiotherapy outcomes of the randomized
PORTEC-1 trial for endometrial carcinoma.
Int J Radiat Oncol Biol Phys 2011; 81: e631–38.
101 Blake P, Swart AM, Orton J, et al, and the ASTEC/EN.5 Study
Group. 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: 137–46.
102 Nout RA, Smit VTHB, Putter H, et al, and the PORTEC Study
Group. Vaginal brachytherapy versus pelvic external beam
radiotherapy for patients with endometrial cancer of
high-intermediate risk (PORTEC-2): an open-label, non-inferiority,
randomised trial. Lancet 2010; 375: 816–23.
103 Sorbe B, Horvath G, Andersson H, Boman K, Lundgren C,
Pettersson B. External pelvic and vaginal irradiation versus vaginal
irradiation alone as postoperative therapy in medium-risk
endometrial carcinoma—a prospective randomized study.
Int J Radiat Oncol Biol Phys 2012; 82: 1249–55.
104 Kong A, Johnson N, Kitchener HC, Lawrie TA. Adjuvant radiotherapy
for stage I endometrial cancer: an updated Cochrane systematic
review and meta-analysis. J Natl Cancer Inst 2012; 104: 1625–34.
105 Kunneman M, Pieterse AH, Stiggelbout AM, et al. Treatment
preferences and involvement in treatment decision making of
patients with endometrial cancer and clinicians. Br J Cancer 2014;
111: 674–79.
www.thelancet.com Vol 387 March 12, 2016
Seminar
106 Susumu N, Sagae S, Udagawa Y, et al, and the Japanese Gynecologic
Oncology Group. Randomized phase III trial of pelvic radiotherapy
versus cisplatin-based combined chemotherapy in patients with
intermediate- and high-risk endometrial cancer: a Japanese
Gynecologic Oncology Group study. Gynecol Oncol 2008; 108: 226–33.
107 Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs
radiotherapy in high-risk endometrial carcinoma: results of a
randomised trial. Br J Cancer 2006; 95: 266–71.
108 Randall ME, Filiaci VL, Muss H, et al, and the Gynecologic
Oncology Group study. Randomized phase III trial of
whole-abdominal irradiation versus doxorubicin and cisplatin
chemotherapy in advanced endometrial carcinoma: a Gynecologic
Oncology Group study. J Clin Oncol 2006; 24: 36–44.
109 Morrow CP, Bundy BN, Homesley HD, et al. Doxorubicin as an
adjuvant following surgery and radiation therapy in patients with
high-risk endometrial carcinoma, stage I and occult stage II:
a Gynecologic Oncology Group Study. Gynecol Oncol 1990; 36: 166–71.
110 Kuoppala T, Mäenpää J, Tomas E, et al. Surgically staged high-risk
endometrial cancer: randomized study of adjuvant radiotherapy alone
vs sequential chemo-radiotherapy. Gynecol Oncol 2008; 110: 190–95.
111 Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant
chemotherapy and radiotherapy in endometrial cancer—results
from two randomised studies. Eur J Cancer 2010; 46: 2422–31.
112 McMeekin DS, Filiaci VL, Thigpen JT, Gallion HH, Fleming GF,
Rodgers WH, and the Gynecologic Oncology Group study. The
relationship between histology and outcome in advanced and
recurrent endometrial cancer patients participating in first-line
chemotherapy trials: a Gynecologic Oncology Group study.
Gynecol Oncol 2007; 106: 16–22.
113 Fader AN, Drake RD, O’Malley DM, et al, and the Uterine Papillary
Serous Carcinoma (UPSC) Consortium. Platinum/taxane-based
chemotherapy with or without radiation therapy favorably impacts
survival outcomes in stage I uterine papillary serous carcinoma.
Cancer 2009; 115: 2119–27.
114 McMeekin DS, Filiaci VL, Aghajanian C, et al. A randomized phase
III trial of pelvic radiation therapy (PXRT) versus vaginal cuff
brachytherapy followed by paclitaxel/carboplatin chemotherapy
(VCB/C) in patients with high risk (HR), early stage endometrial
cancer (EC): a Gynecologic Oncology Group trial. Gynecol Oncol
2014; 134: 438 (abstr).
115 Barakat RR, Goldman NA, Patel DA, Venkatraman ES, Curtin JP.
Pelvic exenteration for recurrent endometrial cancer. Gynecol Oncol
1999; 75: 99–102.
116 Bradford LS, Rauh-Hain JA, Schorge J, Birrer MJ, Dizon DS.
Advances in the management of recurrent endometrial cancer.
Am J Clin Oncol 2015; 38: 206–12.
117 Landrum LM, Moore KN, Myers TK, et al. Stage IVb endometrial
cancer: does applying an ovarian cancer treatment paradigm result
in similar outcomes? A case-control analysis. Gynecol Oncol 2009;
112: 337–41.
118 Barlin JN, Puri I, Bristow RE. Cytoreductive surgery for advanced or
recurrent endometrial cancer: a meta-analysis. Gynecol Oncol 2010;
118: 14–18.
119 Eto T, Saito T, Kasamatsu T, et al. Clinicopathological prognostic
factors and the role of cytoreduction in surgical stage IVb
endometrial cancer: a retrospective multi-institutional analysis of
248 patients in Japan. Gynecol Oncol 2012; 127: 338–44.
120 Eto T, Saito T, Shimokawa M, et al. Status of treatment for the
overall population of patients with stage IVb endometrial cancer,
and evaluation of the role of preoperative chemotherapy:
a retrospective multi-institutional study of 426 patients in Japan.
Gynecol Oncol 2013; 131: 574–80.
121 Despierre E, Moerman P, Vergote I, Amant F. Is there a role for
neoadjuvant chemotherapy in the treatment of stage IV serous
endometrial carcinoma? Int J Gynecol Cancer 2006;
16 (suppl 1): 273–77.
122 Whitney CW, Brunetto VL, Zaino RJ, et al, and the Gynecologic
Oncology Group study. Phase II study of medroxyprogesterone
acetate plus tamoxifen in advanced endometrial carcinoma:
a Gynecologic Oncology Group study. Gynecol Oncol 2004; 92: 4–9.
123 Asbury RF, Brunetto VL, Lee RB, Reid G, Rocereto TF, and the
Gynecologic Oncology Group. Goserelin acetate as treatment for
recurrent endometrial carcinoma: a Gynecologic Oncology Group
study. Am J Clin Oncol 2002; 25: 557–60.
1107
 Seminar
124 Lindemann K, Malander S, Christensen RD, et al. Examestane in
advanced or recurrent endometrial carcinoma: a prospective phase
II study by the Nordic Society of Gynecologic Oncology (NSGO).
BMC Cancer 2014; 5: 14–68.
125 Colombo N, McMeekin DS, Schwartz PE, et al. Ridaforolimus as a
single agent in advanced endometrial cancer: results of a single-arm,
phase 2 trial. Br J Cancer 2013; 108: 1021–26.
126 Tsoref D, Welch S, Lau S, et al. Phase II study of oral ridaforolimus
in women with recurrent or metastatic endometrial cancer.
Gynecol Oncol 2014; 135: 184–89.
127 Oza A, Pignata S, Poveda A, et al. Randomized phase II trial of
ridaforolimus in advanced endometrial carcinoma. J Clin Oncol
2015; published online June 15. DOI:10.1200/JCO.2014.58.8871.
128 Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral
mammalian target of rapamycin inhibitor, everolimus, in patients
with recurrent endometrial carcinoma. Cancer 2010; 116: 5415–19.
129 Oza AM, Elit L, Tsao MS, 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: 3278–85.
130 Slomovitz BM, Jiang Y, Yates MS, et al. Phase II study of everolimus
and letrozole in patients with recurrent endometrial carcinoma.
J Clin Oncol 2015; published online Jan 26. DOI:10.1200/
JCO.2014.58.3401.org.
131 Matulonis U, Vergote I, Backes F, et al. Phase II study of the PI3K
inhibitor pilaralisib (SAR245408; XL147) in patients with advanced
or recurrent endometrial carcinoma. Gynecol Oncol 2015;
136: 246–53.
132 Makker V, Recio FO, Ma L, et al. Phase II trial of GDC-0980 (dual
PI3K/mTOR inhibitor) in patients with advanced endometrial
carcinoma: final study results. J Clin Oncol 2014;
32 (suppl): 5513 (abstr).
133 Coleman RL, Sill MW, Thaker PH, et al. A phase II evaluation of
selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2
inhibitor in the treatment of recurrent or persistent endometrial
cancer: an NRG Oncology/Gynecologic Oncology Group study.
Gynecol Oncol 2015; 138: 30–35.
134 Teplinsky E, Muggia F. Targeting HER2 in ovarian and uterine
cancers: challenges and future directions. Gynecol Oncol 2014;
135: 364–70.
135 Febbraro T, Lengyel E, Romero IL. Old drug, new trick:
repurposing metformin for gynecologic cancers? Gynecol Oncol
2014; 135: 614–21.
136 Dedes KJ, Wetterskog D, Ashworth A, Kaye SB, Reis-Filho JS.
Emerging therapeutic targets in endometrial cancer.
Nat Rev Clin Oncol 2011; 8: 261–71.
137 Castonguay V, Lheureux S, Welch S, et al. A phase II trial of
sunitinib in women with metastatic or recurrent endometrial
carcinoma: a study of the Princess Margaret, Chicago and California
Consortia. Gynecol Oncol 2014; 134: 274–80.
138 Powell MA, Sill MW, Goodfellow PJ, et al. A phase II trial of brivanib
in recurrent or persistent endometrial cancer: an NRG Oncology/
Gynecologic Oncology Group Study. Gynecol Oncol 2014; 135: 38–43.
139 Vergote I TM, Powell MA, et al. A phase II trial of lenvatinib in
patients with advanced or recurrent endometrial cancer:
angiopoietin-2 as a predictive marker for clinical outcomes.
J Clin Oncol 2013; 31 (suppl): 5520 (abstr).
140 Alvarez EA, Brady WE, Walker JL, 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: 22–27.
141 Emons G, Gorchev G, Sehouli J, et al. Efficacy and safety of AEZS-108
(INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to
doxorubicin in women with platinum refractory or resistant ovarian
cancer expressing LHRH receptors: a multicenter phase II trial of the
ago-study group (AGO GYN 5). Gynecol Oncol 2014; 133: 427–32.
142 Swisher EBJ, Kaufmann S, et al. ARIEL2. A phase 2 study to
prospectively identify ovarian cancer patients likely to respond to
rucaparib. 26th EORTC-NCI-AACR symposium on molecular
therapeutics; Barcelona, Spain; Nov 18–21, 2014. Abstract 215.
1108
143 Forster MD, Dedes KJ, Sandhu S, et al. Treatment with olaparib in a
patient with PTEN-deficient endometrioid endometrial cancer.
Nat Rev Clin Oncol 2011; 8: 302–06.
144 Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1
(PD-1) and its ligand (PD-L1) in common cancers and their
correlation with molecular cancer type.
Cancer Epidemiol Biomarkers Prev 2014; 23: 2965–70.
145 Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase
e-mutated and microsatellite-instable endometrial cancers with
neoantigen load, number of tumor-infiltrating lymphocytes, and
expression of PD-1 and PD-L1. JAMA Oncol 2015; published online
July 9. DOI:10.1001/jamaoncol.2015.2151.
146 Moir-Meyer GL, Pearson JF, Lose F, et al, and the Australian
National Endometrial Cancer Study Group, and the Hunter
Community Study, and the Studies of Epidemiology and Risk
Factors in Cancer Heredity. Rare germline copy number deletions
of likely functional importance are implicated in endometrial
cancer predisposition. Hum Genet 2015; 134: 269–78.
147 Lancaster JM, Powell CB, Kauff ND, et al, and the Society of
Gynecologic Oncologists Education Committee. Society of
Gynecologic Oncologists Education Committee statement on risk
assessment for inherited gynecologic cancer predispositions.
Gynecol Oncol 2007; 107: 159–62.
148 Buchanan DD, Tan YY, Walsh MD, et al. Tumor mismatch repair
immunohistochemistry and DNA MLH1 methylation testing of
patients with endometrial cancer diagnosed at age younger than
60 years optimises triage for population-level germline mismatch
repair gene mutation testing. J Clin Oncol 2014; 32: 90–100.
149 Bonadona V, Bonaïti B, Olschwang S, et al, and the French Cancer
Genetics Network. Cancer risks associated with germline mutations
in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA
2011; 305: 2304–10.
150 Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to
reduce the risk of gynecologic cancers in the Lynch syndrome.
N Engl J Med 2006; 354: 261–69.
151 Chen LM, Yang KY, Little SE, Cheung MK, Caughey AB.
Gynecologic cancer prevention in Lynch syndrome/hereditary
nonpolyposis colorectal cancer families. Obstet Gynecol 2007;
110: 18–25.
152 Renkonen-Sinisalo L, Bützow R, Leminen A, Lehtovirta P,
Mecklin JP, Järvinen HJ. Surveillance for endometrial cancer in
hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer
2007; 120: 821–24.
153 Lécuru F, Le Frère Belda MA, Bats AS, et al. Performance of office
hysteroscopy and endometrial biopsy for detecting endometrial
disease in women at risk of human non-polyposis colon cancer:
a prospective study. Int J Gynecol Cancer 2008; 18: 1326–31.
154 Crosbie E, Morrison J. The emerging epidemic of endometrial
cancer: Time to take action. Cochrane Database Syst Rev 2014;
12: ED000095.
155 Arem H, Park Y, Pelser C, et al. Prediagnosis body mass index,
physical activity, and mortality in endometrial cancer patients.
J Natl Cancer Inst 2013; 105: 342–49.
156 Liao C, Zhang D, Mungo C, Tompkins DA, Zeidan AM. Is diabetes
mellitus associated with increased incidence and disease-specific
mortality in endometrial cancer? A systematic review and
meta-analysis of cohort studies. Gynecol Oncol 2014; 135: 163–71.
157 Committee on Gynecologic Practice. Committee opinion no. 619:
Gynecologic surgery in the obese woman. Obstet Gynecol 2015;
125: 274–78.
158 Robbins JR, Gayar OH, Zaki M, Mahan M, Buekers T, Elshaikh MA.
Impact of age-adjusted Charlson comorbidity score on outcomes for
patients with early-stage endometrial cancer. Gynecol Oncol 2013;
131: 593–97.
www.thelancet.com Vol 387 March 12, 2016