Seminar

Endometrial cancer
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 Published Online
increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often September 7, 2015
http://dx.doi.org/10.1016/
diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and S0140-6736(15)00130-0
bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node
Department of Gynecologic
surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space), Surgery (Prof P Morice MD),
disease stage (including myometrial invasion), patients’ characteristics (age and comorbidities), and national and Department of Medical
international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are Oncology (A Leary MD),
Translational Research Lab
used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival
U981 (A Leary), Gustave
ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence Roussy, Villejuif, France; Unit
(including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that INSERM U 1030, Gustave
best balance optimisation of survival with the lowest adverse effects on quality of life. Roussy, Villejuif, France
(Prof P Morice); Université
Paris-Sud (Paris XI), Le Kremlin
Introduction of life), 14% of cases are diagnosed in premenopausal Bicêtre, France (Prof P Morice);
Endometrial cancer—a tumour originating in the women, 5% of whom are younger than 40 years.6–8 The Department of Radiation
endometrium—is the most common gynaecological increased incidence of endometrial cancer in Europe and Oncology, Leiden University
Medical Center, Leiden,
tumour in developed countries, and its prevalence is North America could be related to a greater overall Netherlands
increasing.1 As the disease is frequently symptomatic at prevalence of obesity and metabolic syndromes in these (Prof C Creutzberg MD);
an early stage, endometrial cancer is often diagnosed regions, in addition to the ageing of the population.8–11 Memorial Sloan-Kettering
at stage I. Historically, standard treatment consisted of Projections show that the number of cases will increase Cancer Center, New York, NY,
USA (Prof N Abu-Rustum MD);
hysterectomy, bilateral salpingo-oophorectomy, and pelvic to 42·13 per 100 000 in 2030 in the USA.10 Department of Obstetrics and
lymph node dissection followed by adjuvant therapy The main risk factor is exposure to endogenous and Gynaecology, Hôpital Tenon,
tailored on the basis of final histology. exogenous oestrogens associated with obesity, diabetes, Paris, France (Prof E Darai MD);
Management of endometrial cancer has become more early age at menarche, nulliparity, late-onset menopause, INSERM UMRS 938, Paris,
France (Prof E Darai); and
complex during the past 5–10 years for several reasons: older age (≥55 years), and use of tamoxifen.12–17 The Université Pierre et Marie Curie
changes in histological classification that affect surgical relation between diabetes and endometrial cancer is (Paris VI), Paris, France
management, adjuvant therapies, and prognosis; controversial.18 Of the four cohort studies in which (Prof E Darai)
changes in the indications and modalities of adjustments were made for body-mass index (BMI), an Correspondence to:
lymphadenectomy; de-escalation of adjuvant therapy independent association between endometrial cancer and Dr Philippe Morice, Department
of Gynecologic Surgery, Gustave
based on data from randomised trials; and discrepancies diabetes was noted in only one.18–21 The levonorgestrel- Roussy, 114 rue Edouard Vaillant,
between the various classifications used to characterise releasing intrauterine system might have a protective 94805 Villejuif Cedex, France
recurrence risk factors. effect against endometrial malignant transformation.22 philippe.morice@
These modifications have led national scientific gustaveroussy.fr

societies to review the emerging data and unanswered
questions, and to publish specific recommendations for
endometrial cancer.2–4
This Seminar focuses on the epidemiology and the
histological and molecular classification of endometrial
cancer. We also describe current practice and trials of
surgery, adjuvant treatment, and novel targeted therapies.
Pathogenesis and histological or molecular
classifications
In the past 30 years, endometrial cancer has been broadly
classified into two subtypes on the basis of histological
characteristics, hormone receptor expression, and grade
(table 1).23 The most common subtype is low-grade,

Epidemiology and risk factors Search strategy and selection criteria

In 2012, around 320 000 new cases of endometrial cancer
were diagnosed worldwide. Endometrial cancer is the
fifth most common cancer in women (4·8% of cancers in
women), who have a cumulative risk of 1% of developing
the disease by age 75 years.1 It is the 14th cancer in terms
of mortality (76 000 deaths); cumulative risk of death by
age 75 years is 0·2%.1 The highest incidences in 2012 are
estimated in the USA and Canada (19·1/100 000) and
northern (12·9/100 000) and western Europe
(15·6/100 000).1,5 Although endometrial cancer is
conventionally thought to be a cancer of the
postmenopausal period (ie, the sixth and seventh decades
We searched MEDLINE, Current Contents, and PubMed with the
terms “endometrial cancer”, “hysterectomy”,
“lymphadenectomy”, “sentinel node”, “chemotherapy”,
“radiation therapy”, “targeted therapy”, “fertility sparing
management”, “ovarian preservation”, and “molecular
classification” for articles published in English between
Jan 1, 1990, and Jan 1, 2015. We also reviewed the reference
lists of articles identified by this search. We focused our search
strategy on systematic reviews, meta-analyses, and clinical
trials registered on http://clinicaltrials.gov, and selected articles
on the basis of their representativeness and relevance.

www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0 1

 Seminar

endometrioid, diploid, hormone-receptor-positive more than 90% of lesions.26 KRAS mutations are also
endometrial cancer, which has a good prognosis. Type II common (reported in about 20% of tumours), and 12%
endometrial cancers are described as non-endometrioid, of tumours harbour an FGFR2 mutation.27 Type II
high grade, aneuploid, TP53-mutated, hormone-receptor- endometrial cancers include a range of histological
negative tumours that are associated with a higher risk of subtypes, each showing distinct molecular and genomic
metastasis and a poor prognosis (table 1).23 Although this features (table 2).26–28 Serous disease shares genomic
dualistic classification has started to become incorporated features with triple-negative basal-like breast cancer and
into clinical decision-making algorithms defining high-grade serous ovarian cancer, suggesting possible
high-risk patients, its prognostic value remains limited overlap in therapeutic opportunities.25 Clear-cell
because 20% of endometrioid (ie, type I) endometrial endometrial cancer resembles its ovarian clear-cell
cancers relapse, whereas 50% of non-endometrioid counterpart, with inactivating mutations in the
(ie, type II) endometrial cancers do not.23 Additionally, chromatin remodelling gene ARID1A in 20–40% of
15–20% of endometrioid tumours are high-grade lesions, cases and universal expression of hepatocyte nuclear
and where they fit into the dualistic model is unclear.24,25 factor-1β.29–31
That endometrial cancer comprises a range of diseases Analyses of the Cancer Genome Atlas focusing on
with distinct genetic and molecular features is becoming endometrioid and serous endometrial cancer further
increasingly clear.26 emphasise the disease’s heterogeneity by identifying four
Within type I endometrial cancer, the PIK3CA pathway distinct molecular subgroups: POLE ultramutated,
is the most frequently altered: mutations are noted in microsatellite instability hypermutated, copy-number-low
microsatellite stable, and copy-number-high serous-like
(figure 1),26 showing increasing grade, TP53, and somatic
Type I Type II copy number alterations, but decreasing mutation rates
Associated clinical features Metabolic syndrome: obesity, None (figure 1A). The newly identified POLE ultramutated
hyperlipidaemia, hyperglycaemia, and category is the smallest subgroup, but defines a unique
increased oestrogen concentrations
subset that is characterised by mutations in the
Grade Low High
exonuclease domain of POLE, high mutation load, and
Hormone receptor expression Positive Negative
an excellent prognosis (figure 1B).32 60% of POLE
Histology Endometrioid Non-endometrioid (serous,
ultramutated endometrial cancers are high-grade
clear-cell carcinoma)
endometrioid lesions, and 35% harbour TP53 mutations.
Genomic stability Diploid, frequent microsatellite instability Aneuploid
(40%) Roughly 30–40% of endometrioid endometrial cancers
TP53 mutation No Yes show loss of DNA mismatch repair proteins (MLH1,
Prognosis Good (overall survival 85% at 5 years) Poor (overall survival 55% at MSH2, MSH6, and PMS2); in sporadic cases this is
5 years) secondary to MLH1 promoter hypermethylation, and in
hereditary Lynch syndrome it can be caused by mutations
Table 1: Dualistic classification of endometrial cancers, by Bokhman subtype
in any of the DNA mismatch repair genes.33 The

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

2 www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0


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
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
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
www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0
Seminar
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
(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
3
 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
5

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

4 www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0

 Seminar

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.

the core variables of these risk stratification systems are Survival

very similar, the combination of defining variables varies.
Results of a 2014 study—a simultaneous comparison of
five risk stratification systems in the same cohort—
suggested that the European Society for Medical
Oncology modified system was the most accurate in the
prediction of lymph node status and survival.58
Because of the limits of the conventional methods
used for histological classification of endometrial
cancer subtypes, Murali and colleagues54 suggested
incorporation of molecular and genetic characteristics
into classifications for better appraisal of prognostic
and predictive factors. Novel candidate prognostic
markers, such as stathmin or L1 cell adhesion molecule
(L1CAM), and POLE mutations have been identified.
Stathmin, a regulator of microtubule dynamics, is
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)
and outperformed risk stratification systems.60 These
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.
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 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

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.

www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0 5

 Seminar
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
(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
6 www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0
cancer includes careful assessment of the peritoneal
TNM category
surfaces. Omental and peritoneal biopsies are commonly
TX done in high-risk disease.
T0
Tis† Lymphadenectomy and sentinel node biopsy
T1 Surgical assessment of lymph nodes for staging at
T1a primary surgery remains one of the most varied practices
worldwide, ranging from no nodal assessment, to
T1b
sentinel node mapping, to complete pelvic and aortic
T2
lymphadenectomy up to the renal vessels. Most
T3 or N1–2, or both
clinicians agree that excision or biopsy of suspicious or
T3a enlarged lymph nodes in the pelvic or para-aortic regions
T3b is important to exclude nodal metastatic disease. Pelvic
nodal dissection and pathological assessment continue
N1 to be important aspects of surgical staging for apparent
N2 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.
T4
Para-aortic nodal assessment from the intramesenteric
and infrarenal regions is also done for staging selected
M1
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.
 Seminar

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

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
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 See Online for appendix
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

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 Seminar
invasion tended to achieve better local control and
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
8 www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0
cancer and older 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
 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

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 Seminar
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
10 www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0
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,

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
www.thelancet.com Published online September 7, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00130-0
Seminar
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.
11
 Seminar
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