MDV 484

special articles Annals of Oncology
Annals of Oncology 27: 16–41, 2016

doi:10.1093/annonc/mdv484
ESMO-ESGO-ESTRO Consensus Conference

on Endometrial Cancer: diagnosis, treatment
and follow-up†
N. Colombo1*, C. Creutzberg2, F. Amant3,4, T. Bosse5, A. González-Martín6,7, J. Ledermann8,
C. Marth9, R. Nout10, D. Querleu11,12, M.R. Mirza13, C. Sessa14 & the ESMO-ESGO-ESTRO
Downloaded from https://academic.oup.com/annonc/article-abstract/27/1/16/2196238 by guest on 20 March 2019

Endometrial Consensus Conference Working Group‡
1
Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; 2Department of Radiation Oncology, Leiden
University Medical Center, Leiden, The Netherlands; 3Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium; 4Center for Gynecological
Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam; 5Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; 6Department
of Medical Oncology, GEICO Cancer Center, Madrid; 7Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain; 8Department of Oncology and
Cancer Trials, UCL Cancer Institute, London, UK; 9Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; 10Department of
Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; 11Department of Surgery, Institut Bergonié, Bordeaux, France; 12Department of Gynecology and
Obstetrics, McGill University Health Centre, Montreal, Canada; 13Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
14
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
Received 17 July 2015; revised 30 September 2015; accepted 5 October 2015
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO)
and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on
11–13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management
of endometrial cancer. Before the conference, the expert panel prepared three clinically relevant questions about endo-
metrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced
and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the
consensus conference, the panel developed recommendations for each specific question and a consensus was reached.
Results of this consensus conference, together with a summary of evidence supporting each recommendation, are
detailed in this article. All participants have approved this final article.
Key words: endometrial neoplasms, practice guideline, consensus, treatment, adjuvant, surgery
introduction than 40 years old [2], many of whom still wish to retain their fer-
tility. The majority of endometrial cancers are diagnosed early
Endometrial cancer is the most common gynaecological cancer (80% in stage I), with 5-year survival rates of over 95%. However,
in developed countries. The number of newly diagnosed cases in 5-year survival rates are much lower if there is regional spread or
Europe was nearly 100 000 in 2012, with an age standardised in- distant disease (68% and 17%, respectively) [3].
cidence of 13.6 per 100 000 women. Cumulative risk for a diag- Historically, endometrial carcinoma has been classified into two
nosis of endometrial cancer is 1.71% [1]. main clinicopathological and molecular types: type I is the much
More than 90% of cases of endometrial cancer occur in women more common endometrioid adenocarcinoma (80%–90%) and
>50 years of age, with a median age at diagnosis of 63 years. type II comprises non-endometrioid subtypes such as serous, clear-
However, 4% of women with endometrial cancer are younger cell and undifferentiated carcinomas, as well as carcinosarcoma/
malignant-mixed Müllerian tumour (10%–20%) [4]. Molecular
data in support of this dichotomous classification have become
*Correspondence to: Prof. Nicoletta Colombo, ESMO Guidelines Committee, ESMO
Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
an integral component of pathologic evaluation, as type I car-
E-mail: clinicalguidelines@esmo.org cinomas are preferentially associated with genetic alterations in
†
PTEN, KRAS, CTNNB1 and PIK3CA and MLH1 promoter
These Guidelines were developed by the European Society for Medical Oncology
(ESMO), the European Society of Gynaecological Oncology (ESGO), and the European
hypermethylation, whereas serous carcinomas prototypically
SocieTy of Radiotherapy and Oncology (ESTRO), and are published jointly in the Annals harbour TP53 mutations. However, this dualistic model has
of Oncology, the International Journal of Gynecological Cancer and Radiotherapy & limitations as considerable molecular heterogeneity exists; for
Oncology. The three societies nominated participants who attended the consensus con- example, 25% of high-grade endometrioid carcinomas express
ference and co-authored the final manuscript.
‡
See appendix for members of the ESMO-ESGO-ESTRO Endometrial Consensus
mutated TP53 and behave like serous carcinomas [5]. Extensive
Conference Working Group. work performed by The Cancer Genome Atlas (TCGA) Research
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology special articles
Network has significantly improved our understanding of the mo- 6. How radical should the surgery be in different stages and
lecular landscape of endometrial cancer, introducing not two, but pathological subtypes of endometrial cancer?
four molecular subtypes including: (i) POLE (ultra-mutated) 7. What is the current best definition of risk groups for adju-
tumours, (ii) microsatellite unstable tumours, (iii) copy-number vant therapy?
high tumours with mostly TP53 mutations and (iv) remaining 8. What are the best evidence-based adjuvant treatment strat-
group without these alterations [6]. Hereditary endometrial adeno- egies for patients with low- and intermediate-risk endomet-
carcinomas are mostly seen in families with hereditary non-polyp- rial cancer?
osis colon cancer [HNPCC, Lynch syndrome (LS)]. Although the 9. What are the best evidence-based adjuvant treatment strat-
majority of endometrial carcinomas related to LS are type I egies for patients with high-risk endometrial cancer?
cancers, the proportion of type II cancers seems to be higher than 10. Does surgery or radiotherapy (RT) have a role in advanced
in the case of sporadic endometrial carcinoma [7]. or recurrent endometrial cancer?
Although the majority of cases of endometrial cancer are diag- 11. What are the optimal systemic therapies for advanced/re-
nosed at an early stage, differences in patient characteristics and current disease?

histopathological features of the disease impact on both patient 12. What are the most promising targeted agents and which study
prognosis and the recommended treatment approach. Given the designs should be used to evaluate their clinical benefit?
large body of literature available that addresses the management
of endometrial cancer, the aim of this consensus conference was Each working group was responsible for reviewing the rele-
to produce multidisciplinary evidence-based guidelines on vant literature in order to draft preliminary recommendations
selected clinically relevant questions in order to complement the relating to each of their assigned questions. No systematic litera-
already available European Society for Medical Oncology ture search was undertaken. During the conference, in parallel
(ESMO) Clinical Practice Guidelines (CPG) for the diagnosis, sessions, the four working groups discussed and reached agree-
treatment and follow-up of patients with endometrial cancer [8]. ment on recommendations relating to each of their assigned
questions. Recommendations from each group were then pre-
sented to the entire panel of experts, where they were discussed
methods and modified as required. An adapted version of the ‘Infectious
In 2014, ESMO decided to update the clinical recommendations Diseases Society of America-United States Public Health Service
for endometrial cancer using a consensus conference approach. Grading System’ was used (Table 1 [9]) to define the level of evi-
The consensus panel comprised 40 experts in the management of dence and strength of each recommendation proposed by the
endometrial cancer, and included representation from the group. Finally, a vote was conducted to determine the level of
European SocieTy for Radiotherapy & Oncology (ESTRO), the agreement among the expert panel for each of the recommenda-
European Society of Gynaecological Oncology (ESGO) and tions. Panel members were allowed to abstain from voting in
ESMO. Each panel member was assigned to one of four working cases where they either had insufficient expertise to agree/
groups, with a working group chair and co-chair appointed for
each group. Three consensus conference chairs (N. Colombo, Table 1. Levels of evidence and grades of recommendation
C. Creutzberg, C. Sessa) were also appointed.
Levels of evidence
Each working group was assigned a subject area as follows:
I Evidence from at least one large randomised, controlled trial of
1. Prevention and screening of endometrial cancer (Chair: F. good methodological quality (low potential for bias) or meta-
Amant; Co-Chair: T. Bosse) analyses of well-conducted, randomised trials without
2. Surgery (Chair: C. Marth; Co-Chair: D. Querleu) heterogeneity
3. Adjuvant treatment (Chair: R. Nout; Co-Chair: M. R. II Small randomised trials or large randomised trials with a suspicion
of bias (lower methodological quality) or meta-analyses of such
Mirza)
trials or of trials with demonstrated heterogeneity
4. Advanced and recurrent disease (Chair: J. Ledermann;
III Prospective cohort studies
Co-Chair: A. González-Martín)
IV Retrospective cohort studies or case–control studies
The consensus conference was held on 11–13 December 2014 in V Studies without control group, case reports, experts opinions
Milan, Italy. Before this consensus conference, three clinically rele- Grades of recommendation
vant questions were identified for each subject area/working group, A Strong evidence for efficacy with a substantial clinical benefit,
giving a total of 12 clinically relevant questions as follows: strongly recommended
B Strong or moderate evidence for efficacy but with a limited clinical
1. Which surveillance should be used for asymptomatic women?
benefit, generally recommended
2. What work-up and management scheme should be under-
C Insufficient evidence for efficacy or benefit does not outweigh the
taken for fertility-preserving therapy in patients with atypical
risk or the disadvantages (adverse events, costs, …), optional
hyperplasia (AH)/endometrial intraepithelial neoplasia D Moderate evidence against efficacy or for adverse outcome,
(EIN) and grade 1 endometrioid endometrial cancer (EEC)? generally not recommended
3. Which (molecular) markers can help distinguish ( pre)can- E Strong evidence against efficacy or for adverse outcome, never
cerous lesions from benign mimics? recommended
4. How does the medical condition influence surgical treatment?
5. What are the indications for and to what extent is lympha- By permission of the Infectious Diseases Society of America-United
denectomy indicated in the surgical management of endo- States Public Health Service Grading System [9].
metrial cancer?
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

disagree with the recommendation or if they had a conflict of Other risk factors for endometrial cancer include unopposed
interest that could be considered as influencing their vote. oestrogen therapy, oestrogen-producing tumours and early menar-
Results of this consensus conference, together with a che/late menopause. Unopposed oestrogen therapy increases the
summary of evidence supporting each recommendation, are risk for endometrial cancer 10- to 30-fold if treatment continues 5
detailed in this article, and a summary of all recommendations years or more [18]. Oestrogen-producing tumours, or ovarian gran-
is included in supplementary Table S1, available at Annals of ulosa, and theca cell tumours carry an increased risk for endomet-
Oncology online. However, these additional recommendations rial cancer, with up to 20% of women with these tumours reported
for specific clinical situations should be read in conjunction as having a simultaneous endometrial cancer [19]. Both early me-
with the ESMO CPG for the diagnosis, treatment and follow-up narche and late menopause are associated with a 2-fold increased
of patients with endometrial cancer [8]. risk for endometrial cancer. The RR is 2.4 for women <12 versus
≥15 years [20] and is 1.8 for women ≥55 versus <50 years [21].
results Studies of women with breast cancer taking tamoxifen with
therapeutic or preventive intent have shown that the RR of devel-

prevention and screening of endometrial cancer oping endometrial cancer is 2.53 times higher than that of an age-
risk factors for endometrial cancer. Most patients with matched population. This risk differs depending on menopausal
endometrial cancer have an identifiable source of excess oestrogen status. Premenopausal women treated with tamoxifen have no
and typically display a characteristic clinical profile comprising a known increased risk of endometrial cancer, while this risk in
high body mass index (BMI) that is considered as overweight postmenopausal women is 4.0 (95% CI 1.70–10.90) [22]. The level
(BMI 25–30) or obese (BMI 30), often with other components of of risk of endometrial cancer is also dose and time dependent.
metabolic syndrome (e.g. hypertension, diabetes). The evidence LS or HNPCC is an autosomal dominant inherited disorder
that greater body fatness (reflected by BMI, measures of abdominal caused by germline mutations in DNA mismatch repair genes.
girth and adult weight gain) is a cause of endometrial cancer is Women with mutations in MLH1, MSH2, MSH6 or PMS2 have
convincing. Glycaemic load is probably a cause of endometrial up to a 40%–60% lifetime risk of developing both endometrial
cancer, while the evidence suggesting that sedentary habits and colorectal cancers, as well as a 9%–12% lifetime risk of
(marked by sitting time) and adult attained height are causes of developing ovarian cancer [23].
endometrial cancer is limited [10].
screening and prevention of endometrial cancer. Most cases of
High BMI correlates with good prognostic features of endo-
endometrial cancer cannot be prevented, but reducing the risk
metrial cancer, including low tumour grade, endometrioid hist-
factors and introducing protective factors into the lifestyle
ology and presentation at early stage. In a small subset of
whenever possible, may lower the risk of developing this disease.
patients, the pathogenesis is related to mismatch repair abnor-
All women should be told about the risks and symptoms of
mality and LS. Tumours associated with mismatch repair abnor-
endometrial cancer and be strongly encouraged to engage in
malities and LS appear to be distinct, with worse prognostic
regular physical activity (exercise) and adopt an active lifestyle
factors and worse clinical outcome [11].
which can help to attain and maintain a healthy weight as well
According to a recent meta-analysis involving 6 studies and
as lowering the risk of other risk factors for endometrial cancer
3132 cancer cases, relative risk (RR) for developing endometrial
such as high blood pressure and diabetes. The use of combined
cancer in women with metabolic syndrome is 1.89 [95% confi-
oral contraceptives is significantly associated with a decrease in
dence interval (CI) 1.34–2.67, P ≤ 0.001]. According to individual
endometrial cancer in ever users, a benefit that is greater with
components of metabolic syndrome, obesity is associated with the
increasing duration of use.
greatest increase in RR of 2.21 (P ≤ 0.001) [12]. The strength of as-
sociation between obesity and cancer risk increases with increasing
BMI: RR for overweight is 1.32 (95% CI 1.16–1.50) and for obesity 1. Which surveillance should be used for asymptomatic
is 2.54 (95% CI 2.11–3.06) [13]. Other components of the meta- women?
bolic syndrome linked to endometrial cancer include hyperten-
sion, with a RR of 1.81 (P = 0.024) [12] or an odds ratio (OR) of women with average risk for endometrial cancer. There is no
1.77 (1.34–2.34) [14]. Hypertriglyceridaemia has a weaker but still indication that population-based screening has a role in the early
significant association (RR 1.17, P < 0.001) [12]. detection of endometrial cancer among women who are at
Diabetes mellitus, in particular type II, has long been held as an average endometrial cancer risk and have no symptoms. There is
independent risk factor for endometrial cancer, with an approxi- also no standard or routine screening test for endometrial cancer.
mate doubling of risk (OR 2.1; 95% CI 1.40–3.41) [14]. However, Screening of asymptomatic women for endometrial carcinoma
the fact that people with type II diabetes mellitus (T2DM) tend to has in general been recommended only for those with LS [24, 25].
be obese is a confounding factor, and a recent epidemiological There is no evidence that screening by ultrasonography (e.g.
study from the United States questioned the independent role of endovaginal or transvaginal ultrasound) reduces mortality from
T2DM as a risk factor for endometrial cancer [15]. endometrial cancer. Moreover, cohort studies indicate that
Nulliparity and infertility are also classical risk factors for endo- screening asymptomatic women will result in unnecessary add-
metrial cancer. Among the causes of infertility, polycystic ovarian itional biopsies because of false-positive test results. Risks asso-
syndrome (PCOS) seems to be the most important, with an ciated with false-positive tests include anxiety and complications
almost threefold increase in risk (OR 2.79–2.89) [16]. However, from biopsies [26].
as with diabetes, obesity seems to be a confounding factor, and At the time of menopause, women should be strongly encour-
the BMI-adjusted OR is lower (2.2; 95% CI 0.9–5.7) [17]. aged to report any vaginal bleeding, discharge or spotting to
 | Colombo et al. Volume 27 | No. 1 | January 2016

their doctor to ensure they receive appropriate treatment of any Recommendation 1.6: Routine screening for endometrial
precancerous disorders of the endometrium. cancer in asymptomatic tamoxifen users is not recommended
Recommendation 1.1: There is no evidence for endometrial Level of evidence: III
cancer screening in the general population Strength of recommendation: B
Level of evidence: II Consensus: 94.6% (35) yes, 5.4% (2) abstain (37 voters)
Strength of recommendation: A
Consensus: 100% yes (37 voters) women with high risk for endometrial cancer. Women with a
high risk for endometrial cancer include known carriers of
women at increased risk for endometrial cancer. Women at HNPCC-associated genetic mutations, those who have a substantial
increased risk for endometrial cancer due to a history of unopposed likelihood of being a mutation carrier (i.e. a mutation is known to
oestrogen therapy, late menopause, tamoxifen therapy, nulliparity, be present in the family) and those without genetic testing results
infertility or failure to ovulate, obesity, diabetes or hypertension but who are from families with a suspected autosomal dominant
should be informed of the risks and symptoms of endometrial

predisposition to colon cancer.
cancer and strongly encouraged to report any unexpected bleeding Findings from a prospective observational cohort study of
or spotting to their physicians. women with LS opting for endometrial cancer screening and
Asymptomatic women with risk factors for endometrial who underwent annual outpatient hysteroscopy and endomet-
cancer who have endometrial thickening and other positive rial sampling (OHES) suggest that, in women with LS, annual
findings on ultrasound, such as increased vascularity, inhomo- OHES is acceptable and has high diagnostic accuracy in screen-
geneity of the endometrium, particulate fluid or thickened endo- ing for endometrial cancer and atypical endometrial hyperplasia
metrium over 11 mm should be managed on a case-by-case (AEH) [29]. However, larger international studies are needed
basis. The potential benefits, risks and limitations of testing for for confirmation.
early endometrial cancer should be explained in order to ensure Women with an HNPCC-associated mutation or with a sub-
informed decision making about testing. stantial likelihood of having an HNPCC-associated mutation
Premenopausal women treated with tamoxifen do not require should be informed of the potential benefits, risks and limita-
additional monitoring beyond routine gynaecological care. tions of testing for early endometrial cancer; they should also be
Postmenopausal women taking tamoxifen should be informed informed that the recommendation for screening is based on
about symptoms of endometrial hyperplasia or cancer [27]. expert opinion in the absence of definitive scientific evidence.
Although findings from a recently published meta-analysis have Although there is insufficient evidence to endorse annual
verified the efficacy of the levonorgestrel intrauterine device screening for endometrial cancer in this group, annual screening
(LNG-IUD) in preventing de novo polyps in breast cancer patients beginning at age 35 is recommended due to the high risk of
treated with tamoxifen, there was insufficient evidence to ascertain endometrial cancer and the potentially life-threatening nature of
whether the LNG-IUD was associated with any benefit in redu- this disease. As screening will be of limited efficacy in gynaeco-
cing the incidence of precancerous or cancerous lesions [28]. logical cancers (endometrial and ovarian), once the family is
Recommendation 1.2: Unopposed oestrogen treatment completed, particularly by age 35–40 years, careful consider-
should not be started or should be discontinued in women with ation must be given to the option of prophylactic hysterectomy
a uterus in situ and bilateral salpingo-oophorectomy [30].
Level of evidence: III In women with LS, the following options are available:
Strength of recommendation: A • Annual screening beginning at age 35 (recommended)
Consensus: 100% yes (37 voters) • Regular hysteroscopy and endometrial biopsies or hysterec-
Recommendation 1.3: Routine surveillance in asymptomatic tomy (current options)
women with obesity, PCOS, diabetes mellitus, infertility, nulli- • The application of local progesterone using the LNG-IUD
parity or late menopause is not recommended • Treatment of premalignant disease (AEH, EIN)
Level of evidence: III • Hysterectomy and bilateral oophorectomy
Strength of recommendation: B
Consensus: 100% yes (37 voters) Evaluating the likelihood of a patient having a gynaecological
Recommendation 1.4: For women with adult granulosa cell cancer predisposition syndrome enables the physician to provide
tumour, if hysterectomy has not been performed, endometrial individualised assessments of cancer risk, as well as the opportunity
sampling is recommended. If this shows no evidence of ( pre) to offer tailored screening and prevention strategies such as surveil-
malignancy, no further screening for endometrial malignancies lance, chemoprevention and prophylactic surgery that may reduce
is required the morbidity and mortality associated with these syndromes.
Level of evidence: IV Recommendation 1.7: Surveillance of the endometrium by
Strength of recommendation: B gynaecological examination, transvaginal ultrasound and aspir-
Consensus: 100% yes (37 voters) ation biopsy starting from the age of 35 years (annually until
Recommendation 1.5: In patients with epithelial ovarian hysterectomy) should be offered to all LS mutation carriers
cancer undergoing fertility-sparing treatment, endometrial sam- Level of evidence: IV
pling is recommended at the time of diagnosis Strength of recommendation: B
Level of evidence: IV Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters)
Strength of recommendation: B Recommendation 1.8: Prophylactic surgery (hysterectomy
Consensus: 100% yes (37 voters) and bilateral salpingo-oophorectomy), preferably using a
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

minimally invasive approach, should be discussed at the age of Level of evidence: IV

40 as an option for LS mutation carriers to prevent endometrial Strength of recommendation: A
and ovarian cancer. All pros and cons of prophylactic surgery Consensus: 100% yes (37 voters)
must be discussed Recommendation 2.4: Pelvic MRI should be performed to
Level of evidence: IV exclude overt myometrial invasion and adnexal involvement.
Strength of recommendation: B Expert ultrasound can be considered as an alternative
Consensus: 100% yes (37 voters) Level of evidence: III
2. What work-up and management scheme should be under- Consensus: 100% yes (37 voters)
taken for fertility-preserving therapy in patients with AH/ Recommendation 2.5: Patients must be informed that fertility-
EIN and grade 1 EEC? sparing treatment is a non-standard treatment and the pros and
cons must be discussed. Patients should be willing to accept close
work-up for fertility-preserving therapy. The diagnosis of follow-up and be informed of the need for future hysterectomy

endometrial carcinoma in young women of childbearing age is Level of evidence: V
rare. Indeed, only 4% of patients with endometrial carcinoma Strength of recommendation: A
are <40 years of age [2]. Younger and premenopausal women Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters)
with endometrial carcinoma seem to have a better prognosis
than older patients, with increased rates of early-stage and low- management schemes for fertility-preserving therapy. Conservative
grade disease reported [2, 31, 32]. medical treatment for endometrial cancer is based on progestins
The standard approach for the management of endometrial with medroxyprogesterone acetate (MPA; 400–600 mg/day) or
cancer in young women of childbearing age is hysterectomy and bi- megestrol acetate (MA; 160–320 mg/day) [33]. Few papers have
lateral salpingo-oophorectomy with or without lymphadenectomy. addressed the use of LNG-IUD but preliminary data using such
Although this is a highly effective approach, carrying a 5-year sur- treatment [added to gonadotropin-releasing hormone (GnRH)
vival rate of 93%, it also results in a permanent loss of reproductive analogues] seem to demonstrate similar remission and recurrence
potential. Conservative management of endometrial carcinoma is rates as oral progestins [37]. Assessment of response must be
based on medical treatment with oral progestins. The most import- performed at 6 months with a new D&C and imaging [38].
ant issues when considering a conservative management approach Response rates associated with the conservative management
are the assessment of clinical and pathological characteristics of the of endometrial carcinoma are ∼75% [39, 40], but recurrence
tumour and selection of the appropriate medical intervention. rates are 30%–40% [39, 41, 42]. Standard surgery with hysterec-
A conservative management approach could be considered in tomy should be proposed to non-responders while maintenance
patients with a histological diagnosis of grade 1 endometrial car- treatment for a further 6 months can be considered in respon-
cinoma (or premalignant disease such as AH) [31]. The optimal ders who wish to delay pregnancy [33].
method to obtain these histologic characteristics is dilatation Although progesterone receptor (PgR) status is a reliable predict-
and curettage (D&C) [33]; this procedure is superior to pipelle ive factor for disease remission, a routine check is not recommended
biopsy in terms of accuracy of the tumour grade [34]. since 50% of PgR-negative patients will respond to treatment [43].
The histological diagnosis should be reviewed by an expert Pregnancy is associated with a reduced risk for endometrial
pathologist to improve the accuracy of histological assessment cancer recurrence [40]. Findings from recent meta-analyses
(endometrial carcinoma or AH) and the reliability of tumour showed that the pooled live birth rate among women receiving
grading [35], whereas the initial stage should be confirmed by fertility-preserving treatment for endometrial cancer was 28%
enhanced pelvic magnetic resonance imaging (MRI) to exclude and reached 39% when assisted reproduction technology was
overt myometrial invasion, as well as adnexal or pelvic nodes in- used [39, 44]. Thus, for patients achieving a complete response
volvement [36]. Patients should be informed that this is a non- at 6 months, conception must be encouraged and these patients
standard approach and they should be willing to accept close should be referred to a fertility clinic.
follow-up during and after the treatment. They should also be For patients with disease recurrence after an initial response, hys-
informed of the need for future hysterectomy in case of failure of terectomy should be proposed as the first option. Moreover, given
the treatment and/or after pregnancies. the high rate of recurrence, after completion of childbearing (or after
Recommendation 2.1: Patients with AH/EIN or grade 1 EEC the age of potential pregnancy), standard treatment with hysterec-
requesting fertility-preserving therapy must be referred to specia- tomy and salpingo-oophorectomy is recommended. Preservation of
lised centres the ovaries can be considered in selected cases, depending on the
Level of evidence: V patient’s age and genetic risk factors.
Strength of recommendation: A Recommendation 2.6: For patients undergoing fertility-preserv-
Consensus: 100% yes (37 voters) ing therapy, MPA (400–600 mg/day) or MA (160–320 mg/day) is
Recommendation 2.2: In these patients, D&C with or without the recommended treatment. However, treatment with LNG-IUD
hysteroscopy must be performed with or without GnRH analogues can also be considered
Level of evidence: IV Level of evidence: IV
Strength of recommendation: A Strength of recommendation: B
Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) Consensus: 100% yes (37 voters)
Recommendation 2.3: AH/EIN or grade 1 EEC must be con- Recommendation 2.7: In order to assess response, D&C, hys-
firmed/diagnosed by a specialist gynaecopathologist teroscopy and imaging at 6 months must be performed. If no
 | Colombo et al. Volume 27 | No. 1 | January 2016

response is achieved after 6 months, standard surgical treatment Level of evidence: IV
should be performed Strength of recommendation: B
Level of evidence: IV Consensus: 100% yes (37 voters)
Another histological entity that may arise in the differential
Consensus: 100% yes (37 voters)
diagnosis of AH/EIN is the rare atypical polypoid adenomyoma
Recommendation 2.8: In case of complete response, concep-
(APA), for which there are no IHC stains with practical value.
tion must be encouraged and referral to a fertility clinic is
Recommendation 3.3: IHC is not recommended to distin-
recommended
guish APA from AH/EIN
Level of evidence: IV
Level of evidence: V
Recommendation 2.9: Maintenance treatment should be con-
sidered in responders who wish to delay pregnancy The putative precursor of serous carcinoma, serous endomet-

Level of evidence: IV rial intraepithelial carcinoma (SEIC), is considered a non-invasive
Strength of recommendation: B cancer rather than a precancer since it may be associated with ex-
Consensus: 100% yes (37 voters) tensive extra-uterine disease [9]. Molecular alterations of serous
Recommendation 2.10: Patients not undergoing hysterec- carcinoma are already present in SEIC, which is especially true
tomy should be re-evaluated clinically every 6 months for p53 expression [52–54]. A completely negative immunoreac-
Level of evidence: IV tive pattern for p53 (all or null) is considered a surrogate for p53
Strength of recommendation: B mutation, and is present in almost all SEIC and invasive serous
Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) carcinomas [55].
Recommendation 2.11: After completion of childbearing, a Recommendation 3.4: p53 by IHC is recommended to distin-
hysterectomy and salpingo-oophorectomy should be recom- guish SEIC from its mimics
mended. The preservation of the ovaries can be considered de- Level of evidence: IV
pending on age and genetic risk factors Strength of recommendation: A
Level of evidence: IV Consensus: 100% yes (37 voters)
In selected cases of endometrial cancer, clinical and radiological
work-up may not be conclusive about the endometrial origin of
3. Which (molecular) markers can help distinguish ( pre)can- the uterine tumour. In addition, endocervical, ovarian and endo-
cerous lesions from benign mimics? metrial adenocarcinomas may show histopathological overlap.
Several IHC markers have been proposed for these differential
Differential diagnosis between benign uterine lesions and diagnoses, but these markers lack sensitivity or specificity to be
endometrial ( pre)carcinomas is based mainly on morphological used as single markers. When endocervical origin is considered,
criteria but may be supported by additional immunohistochem- the use of a panel of markers, including carcinoembryonic antigen
ical (IHC) markers and molecular alterations in problematic (CEA), vimentin, oestrogen receptor (ER) and p16 [as surrogate
cases [45]. for human papilloma virus (HPV)], is recommended [56]. In case
Currently, AH/EIN is the preferred terminology of the pre- of p16 positivity, the staining pattern should be taken into account.
cursor lesion of the most common type of endometrial carcin- Diffuse p16 staining is frequently seen in serous, clear-cell and mu-
oma, endometrioid carcinoma, including its variants. cinous carcinoma endometrial cancers [57, 58]. In cases of scanty
Recommendation 3.1: In case of uncertainty, low threshold tissue with serous carcinoma, an ovarian origin of the serous car-
referral to a specialised gynaecopathologist is recommended cinoma should be considered. The most discriminatory marker for
Level of evidence: V this differential diagnosis is Wilms tumour 1 gene (WT-1) [59],
Strength of recommendation: A which is expressed in 80%–100% of high-grade serous carcinomas
Consensus: 100% yes (37 voters) of the ovary [60, 61] compared with 7%–20% in serous endomet-
The differential diagnosis of AH/EIN includes, in particular, rial carcinomas [62, 63]. In general, the expression profile should
endometrial hyperplasia without atypia, but also includes other be interpreted in the context of the morphological subtype. An in-
mimics, such as glandular and stromal breakdown, focal glandular dividual approach, with close correlation between clinical presenta-
crowding and epithelial metaplasias (e.g. hypersecretory changes). tion and morphological subtype, is therefore recommended.
Loss of PTEN expression, mostly by mutation, and loss of PAX-2 Recommendation 3.5: A panel of markers must be used in
by down-regulation [46–48] are the only IHC markers that have cases where endocervical cancer is suspected. This panel should
been sufficiently studied and can be used on curettage material. include at least ER, vimentin, CEA and p16 by IHC and needs
Loss of PTEN occurs in 40%–50% of AH/EIN cases, whereas loss to be assessed in the histologic and clinical context. In addition,
of PAX-2 occurs in 70% of AH/EIN, and a joint loss of PTEN and HPV analysis can be considered
PAX-2 occurs in ∼30% of AH/EIN [49–51]. Level of evidence: IV
Recommendation 3.2: PTEN and PAX-2 IHC is recom- Strength of recommendation: B
mended to distinguish AH/EIN from benign mimics. Other Consensus: 100% yes (37 voters)
markers that can be used in this context are MLH1 and ARID1a Recommendation 3.6: WT-1 by IHC is the recommended
by IHC marker to determine the origin of serous cancer
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

Level of evidence: IV (of endometrioid tumours; grade 1–3 or a binary system) and
Strength of recommendation: A histotype (endometrioid versus non-endometrioid tumour).
Consensus: 100% yes (37 voters) Recommendation 4.1: Mandatory work-up must include:
Recommendation 3.7: Morphology (and not IHC) should be Family history; general assessment and inventory of comorbid-
used to distinguish AH/EIN from EEC ities; geriatric assessment, if appropriate; clinical examination,
Level of evidence: IV including pelvic examination; transvaginal or transrectal ultra-
Strength of recommendation: A sound; and complete pathology assessment (histotype and
Consensus: 100% yes (37 voters) grade) of an endometrial biopsy or curettage specimen
surgery
4. How does the medical condition influence surgical treat- Recommendation 4.2: Extent of surgery should be adapted to
ment? the medical condition of the patient

mandatory preoperative work-up. The consensus is based on Strength of recommendation: A
current clinical practice. Family history is usually taken to Consensus: 100% yes (37 voters)
identify risk factors associated with LS, including endometrial
cancer, colon cancer and other cancers belonging to the Lynch optional preoperative work-up.
spectrum. General assessment and, if appropriate, geriatric imaging: Additional imaging is considered according to the
assessment are required in patients with comorbidities and clinical situation. Computed tomography (CT) scan and/or
elderly patients, respectively, in order to adapt the surgical positron emission tomography (PET)-CT are options in clinically
strategy. Indeed, endometrial cancer is frequently associated advanced endometrial cancer. In apparent stage I endometrial
with obesity, hypertension and diabetes and, in some patients, cancer, MRI may be useful to complete information regarding
the extent of surgery or staging that is theoretically required myometrial invasion [65]. However, this applies only in institutions
may not be feasible. In such cases, a benefit–risk assessment of where the indication for lymph node dissection (LND) is tailored
surgery may lead to an individualised decision to perform a according to the stratification of patients into low-, intermediate-
‘non-standard’ surgery or a limited staging procedure. and high-risk groups. In this setting, specialised ultrasonography
Pelvic examination and pelvic ultrasonography are manda- and/or intra-operative pathological examination of the uterus may
tory components of clinical staging of endometrial cancer in also be considered [68].
order to establish a tentative International Federation of Recommendation 4.3: In clinical stage I, grade 1 and 2: At
Gynecology and Obstetrics (FIGO) staging before definitive least one of the three following tools should be used to assess
pathology. In addition to being the first imaging technique myometrial invasion if LND is considered: Expert ultrasound
used to evaluate abnormal uterine bleeding, ultrasonography, and/or MRI and/or intra-operative pathological examination
preferably specialised ultrasonography [64], offers the possibil- Level of evidence: IV
ity of evaluating the size of the tumour, ruling out ovarian Strength of recommendation: A
disease and assessing myometrial invasion and cervical stromal Consensus: 100% yes (37 voters)
involvement [65]. Recommendation 4.4: Other imaging methods (thoracic, ab-
Preoperative pathological information is crucial for establishing dominal and pelvic CT scan, MRI, PET scan or ultrasound)
the surgical plan. First, all patients with a risk of cancer, particu- should be considered to assess ovarian, nodal, peritoneal or
larly patients with postmenopausal bleeding and a hyperplastic metastatic disease
endometrium at ultrasound, should be investigated with endo- Level of evidence: IV
metrial biopsy or curettage in order to (i) avoid uterine morcella- Strength of recommendation: C
tion, which poses a risk of spreading unsuspected cancerous Consensus: 94.6% (35) yes, 2.7% (1) abstain, 2.7% (1) no
tissue, notably endometrial carcinomas or sarcomas, beyond the (37 voters)
uterus and may make the pathological assessment of myometrial
invasion extremely difficult; and (ii) prevent the discovery of an serum tumour markers: There is evidence that the serum
unexpected malignancy after inadequate surgery (subtotal hyster- tumour markers cancer antigen 125 (CA 125) and, more recently,
ectomy and/or preservation of the ovaries in a postmenopausal human epididymis protein 4 are significantly correlated with
patient, incomplete staging). Secondly, as grading of EEC has a histological grade, stage, lymph node metastases, myometrial
significant prognostic impact [66] and various histotypes of invasion and cervical involvement [69–71]. However, the
endometrial cancer harbour different natural histories, the appropriate cut-off has not been established and evidence that
primary therapeutic strategy must be adapted to the information serum marker assessment is clinically useful is lacking.
provided by a preoperative pathological examination, despite the Recommendation 4.5: There is no evidence for the clinical
fact that discrepancies between preoperative evaluation and final usefulness of serum tumour markers, including CA 125
pathology exist [67]. Level of evidence: IV
The final therapeutic strategy should be adapted according to Strength of recommendation: B
the information available before surgery, taking into account the Consensus: 91.9% (34) yes, 5.4% (2) abstain, 2.7% (1) no
tentative stage (apparent stage I or more advanced stage), grade (37 voters)
 | Colombo et al. Volume 27 | No. 1 | January 2016

surgical management of apparent stage I endometrial cancer. patients in the laparoscopy and laparotomy groups, respectively
With the exception of patients managed conservatively, extra- (P < 0.0001), there was no difference in the overall detection
fascial total hysterectomy without colpectomy is the mainstay of of advanced stage disease between the two groups. The major
management for patients with endometrial cancer. The rationale shortcoming of this trial is the high conversion rate related to its
for the additional removal of the adnexae is to prevent ovarian multicentric design. Indeed, 25.8% of patients assigned to the lap-
cancer and rule out ovarian metastases. In premenopausal patients, aroscopic group were converted to laparotomy, with a statement of
however, ovarian preservation may be discussed in selected cases. ‘poor visibility’ reported in 14.6% of cases, reflecting the learning
Younger patients with endometrial cancer often have early-stage, curve of some investigators, particularly for LND. In contrast, a
low-grade tumours. Thus, to avoid the short-term and long-term conversion rate of 10.8%, with poor visibility recorded as the main
consequences of surgical menopause, there is a rationale for factor in 4.9% of cases, was reported in a Dutch randomised trial
ovarian preservation in young women. Several retrospective studies in which no lymphadenectomy was performed [74]. However, as
have recently provided evidence that ovarian preservation has no further training or the use of robotic assistance would likely have
statistically significant impact on the overall survival (OS) of young resulted in even better results with laparoscopic surgery, this high

patients with early-stage endometrial cancer [72]. However, conversion rate reported in LAP2 does not weaken the authors’
extreme care must be taken to rule out synchronous concomitant conclusions, and this trial provides evidence that laparoscopic sur-
ovarian malignancy. gical staging for uterine cancer results in fewer complications and
Recommendation 4.6: Standard surgery is total hysterectomy shorter hospital stay.
with bilateral salpingo-oophorectomy without vaginal cuff According to a meta-analysis of data from eight randomised,
Level of evidence: IV controlled trials (RCTs) conducted by Zullo et al. [75], intra-opera-
Strength of recommendation: A tive complication rates were not different between laparoscopy and
Consensus: 100% yes (37 voters) laparotomy (RR 1.25; 95% CI 0.99–1.56) with no significant het-
Recommendation 4.7: Ovarian preservation can be consid- erogeneity across the studies. Estimated blood loss and haemoglo-
ered in patients younger than 45 years old with grade 1 EEC bin or haematocrit changes were consistently less after laparoscopy
with myometrial invasion <50% and no obvious ovarian or in the six studies where this was reported. Operative time was
other extra-uterine disease higher by 34–74 min in the laparoscopy group. The authors also
Level of evidence: IV found a significant advantage of laparoscopy over laparotomy in
Strength of recommendation: B terms of postoperative complications (RR 0.71; 95% CI 0.63–0.79)
Consensus: 100% yes (37 voters) with significant heterogeneity across the studies.
Recommendation 4.8: In cases of ovarian preservation, sal- Aortic dissection can also be achieved in obese patients using
pingectomy is recommended an extra-peritoneal laparoscopic approach [76].
Level of evidence: IV Taken together, these findings provide definitive evidence of
Strength of recommendation: B the short-term benefit and cost-effectiveness of laparoscopic hys-
Consensus: 100% yes (37 voters) terectomy in patients with gynaecological cancer. This includes
Recommendation 4.9: Ovarian preservation is not recom- patients with comorbidities, obesity or advanced age. Regarding
mended for patients with cancer family history involving comorbidity, Tozzi et al. [77] found that the surgical technique is
ovarian cancer risk (e.g. BRCA mutation, LS etc.). Genetic coun- the only significant parameter associated with complication rate,
selling/testing should be offered regardless of risk group, stressing the fact that patients with
Level of evidence: IV serious comorbidities benefit most from laparoscopy. The issue of
Strength of recommendation: B advanced age has also been addressed in the gynaecological on-
Consensus: 100% yes (37 voters) cology literature. Siesto et al. [78] reported outcomes from a
series of 48 patients aged >65 years who had undergone laparo-
minimally invasive surgical techniques. Hysterectomy and scopic surgery for endometrial cancer. Outcomes from this group
bilateral salpingo-oophorectomy can be carried out using the were comparable with younger patients in terms of operative
open, laparoscopic or vaginal approach. time, blood loss, need for blood transfusions, nodal count and
The largest randomised trial comparing laparoscopy with lapar- intra-operative and postoperative complications. The authors
otomy is the LAP2 study [73], which was designed to compare conclude that, in the absence of absolute anaesthesia contraindi-
laparoscopy versus laparotomy for comprehensive surgical staging cations, laparoscopy is feasible and safe in older women with
and management of stage I–IIA uterine cancer, including hysterec- endometrial cancer. However, as cancer in older women was
tomy, salpingo-oophorectomy, pelvic cytology and pelvic and more frequently upstaged than in younger women, they state that
para-aortic lymphadenectomy. In this trial, patients were randomly comprehensive surgical staging should be offered, regardless of
assigned to laparoscopy (n = 1696) or open laparotomy (n = 920). age, to avoid under-staging and to optimise treatment strategies.
A significantly longer operative time was reported for the laparos- Six randomised trials comparing outcomes after laparotomy
copy group compared with the laparotomy group (204 versus 130 with laparoscopy are currently available, four of which have
min, respectively). Intra-operative complication rates were similar been included in a published meta-analysis [79]. However, only
between groups. However, laparoscopy was associated with signifi- two of these four trials reported data for OS, disease-free sur-
cantly fewer moderate-to-severe postoperative adverse events (14% vival and cancer-related survival. Based on the availability of
versus 21%) and a lower frequency of hospitalisations of more new data, this meta-analysis was subsequently updated by
than 2 days (52% versus 94%) than laparotomy. Although pelvic Palomba et al. in 2009 [80] to include a third trial reporting
and para-aortic lymph nodes were not removed in 8% and 4% of these long-term outcomes, resulting in a sample of 359 patients.
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

No significant heterogeneity was observed among these trials, 5. What are the indications for and to what extent is lympha-
and there was no significant adverse effect of a laparoscopic ap- denectomy indicated in the surgical management of endo-
proach on the OS, disease-free survival or cancer-related sur- metrial cancer?
vival (OR 0.96, 0.95 and 0.91, respectively).
Long-term outcomes of the randomised, controlled LAP2 trial
were published in 2012 [81]. The primary end point was non-in- surgical staging in apparent stage I EEC. Collection of
feriority of the recurrence-free interval. Non-inferiority was peritoneal cytology was included as a staging procedure in earlier
defined as no more than a 40% increase in the risk of recurrence recommendations, but it is no longer considered mandatory.
with laparoscopy compared with laparotomy. The estimated However, since retrospective studies indicate that positive
hazard ratio (HR) for recurrence-free survival with laparoscopy peritoneal cytology has prognostic value, collection of this
versus laparotomy was 1.14 (90% CI 0.92–1.46). Actual recur- information could be considered, especially in patients with
rence rates were substantially lower than anticipated; the esti- tumours of non-endometrioid histology [83, 84].
mated 3-year recurrence rate was 11.4% with laparoscopy and Recommendation 5.1: Peritoneal cytology is no longer con-

10.2% with laparotomy, and the estimated 5-year OS was almost sidered mandatory for staging
identical in both arms (89.8%). Level of evidence: IV
Recommendation 4.10: Minimally invasive surgery is recom- Strength of recommendation: A
mended in the surgical management of low- and intermediate- Consensus: 100% yes (37 voters)
risk endometrial cancer
Level of evidence: I lymphadenectomy. Lymphadenectomy is an integral part of the
Strength of recommendation: A comprehensive surgical staging of endometrial cancer. However,
Consensus: 100% yes (37 voters) the role of lymphadenectomy in early endometrial cancer is unclear
and controversy remains regarding the indications for, the anatomic
In a retrospective, multi-institutional trial of patients with
extent of, and the therapeutic value of lymphadenectomy in the
high-grade endometrial cancer, outcomes of 191 patients who
management of the disease.
underwent laparotomy were compared with 192 patients
The definition of an adequate lymphadenectomy has not
who underwent minimal invasive surgery. In this trial, women
been standardised: current approaches include pelvic lymphade-
with high-grade endometrial cancer staged by minimally invasive
nectomy, para-aortic lymphadenectomy to the inferior mesen-
techniques experienced fewer complications and similar survival
teric artery (IMA) and para-aortic lymphadenectomy up to the
outcomes compared with those staged by laparotomy [82].
renal vessels. Lymph node counts have become a marker for ad-
Recommendation 4.11: Minimally invasive surgery can be
equacy of lymph node evaluation in a variety of solid tumour
considered in the management of high-risk endometrial cancer
disease sites. In endometrial cancer, two retrospective reviews
have shown that patients had improved survival when at least
Strength of recommendation: C
10–12 lymph nodes were removed during lymphadenectomy
[85, 86]. Lymph node counts therefore provide a surrogate way
alternative approaches for patients unsuitable for standard of measuring the adequacy of a LND and, as such, more than 10
surgical therapy. Although advances in surgical techniques, nodes should be removed [87, 88].
anaesthesiology and perioperative management mean that the vast Sampling of lymph nodes has a low sensitivity in endometrial
majority of patients with endometrial cancer are amenable cancer [89]. Indeed, it has been shown that para-aortic nodes
to standard surgical therapy, a small proportion of patients are may be positive in the absence of positive pelvic nodes [90, 91],
still medically unfit for laparoscopic surgery or laparotomy. suggesting that para-aortic lymph nodes should be removed in
However, these patients can still be managed either surgically cases where a lymphadenectomy is indicated. In the Mayo
by vaginal hysterectomy, whenever possible, with bilateral Clinic experience of 281 patients with endometrial cancer who
salpingo-oophorectomy, or by definitive RT, combining external underwent lymphadenectomy, 22% of patients with high-risk
beam radiation therapy (EBRT) and brachytherapy, or by disease had lymph node metastases: 51% had both positive
hormonal treatment. In addition, vaginal hysterectomy is an pelvic and para-aortic nodes, 33% had positive pelvic lymph
acceptable minimally invasive surgical option in some low-risk nodes only and 16% had isolated para-aortic lymphadenopathy
patients who do not need LND (see section 4). [92]. As the majority (77%) of patients with para-aortic lymph
Recommendation 4.12: Vaginal hysterectomy with salpingo- node involvement had metastases above the IMA, para-aortic
oophorectomy can be considered in patients unfit for the lymphadenectomy up to the renal vessels is recommended.
recommended surgery and in selected patients with low-risk The concept of sentinel lymph node (SLN) dissection (SLND)
endometrial cancer was first developed in cervical cancer as a tool to select patients
Level of evidence: IV most suitable for surgical management. In low- and intermedi-
Strength of recommendation: C ate-risk endometrial cancer, the rationale is different as the need
Consensus: 100% yes (37 voters) for SLND is controversial. However, SLND could represent a
Recommendation 4.13: In medically unfit patients, RT or compromise between no dissection (leaving a small proportion
hormone treatment can be considered of node-positive patients) and full dissection (adding a useless
Level of evidence: IV procedure for the majority of node-negative patients). In add-
Strength of recommendation: C ition, ultra-staging of the SLNs detects micrometastases other-
Consensus: 100% yes (37 voters) wise undiagnosed by conventional histology, even in patients
 | Colombo et al. Volume 27 | No. 1 | January 2016

considered at low risk, on the basis of grade and depth myome- the average frequency of LND was 31%, 40%, 47% and 53% for
trial invasion [93]. However, these large series only use the the years 1988–1991, 1992–1995, 1996–1999 and 2000–2003, re-
cervix as the injection site. The question of alternative injection spectively (P < 0.0001) [98]. On multivariate analysis, the pres-
sites in the endometrium or uterine fundus, which are anatom- ence of LND was associated with OS and uterine-specific
ically more logical, is still a topic for investigation. Injection survival benefits with HRs of 0.81 (P < 0.0001) and 0.78
under hysteroscopic, ultrasound, laparoscopic or open guidance (P < 0.0001), respectively, and removal of >11 lymph nodes was
in patients with endometrial cancer has been addressed, without associated with HRs of 0.74 (P < 0.0001) and 0.69 (P < 0.0001),
evidence of benefit of the more demanding and less practical mo- respectively. On the basis of these findings, the authors con-
dalities. Nevertheless, evidence is accumulating that the SLND cluded that the presence of LND and increased number of
may be useful in the management of endometrial cancers [94]. nodes dissected predicted for improved OS and uterine-specific
Recommendation 5.2: If a lymphadenectomy is performed, survival in women with adenocarcinoma of the endometrium.
systematic removal of pelvic and para-aortic nodes up to the Retrospective single-institution studies advocate lymphade-
level of the renal veins should be considered nectomy for all grades of tumour [87, 88]. In contrast, a series

Level of evidence: IV using a US database supports lymphadenectomy for high-grade
Strength of recommendation: B tumours only [99]. This was confirmed by the SEPAL trial in a
Consensus: 91.9% (34) yes, 2.7% (1) abstain, 5.4% (2) no series of intermediate- or high-risk patients with pelvic lympha-
(37 voters) denectomy with or without para-aortic LND [100]. Patients
Recommendation 5.3: SLND is still experimental, but large who underwent para-aortic lymphadenectomy had a superior
series suggest that it is feasible. SLND increases the detection of survival compared with those who did not.
lymph nodes with small metastases and isolated tumour cells; In addition to risk factors, the number of lymph nodes
however, the importance of these findings is unclear removed also seems to be important, with higher node count
Level of evidence: IV associated with improved survival [85, 101]. Kim et al. recently
Strength of recommendation: D analysed data from nine trials (two RCTs and seven observa-
Consensus: 100% yes (37 voters) tional studies) involving 16 995 patients with endometrial
cancer and showed that the efficacy of systematic lymphadenect-
indications for lymphadenectomy. Although the therapeutic omy, defined as removal of ≥10–11 lymph nodes, was associated
effect of lymphadenectomy is unclear, it is an integral part of with limited survival benefit in patients with low-risk endomet-
comprehensive staging. The advantages of comprehensive surgical rial cancer, but resulted in improved OS in patients with inter-
staging are a better definition of prognosis and appropriate triage mediate- or high-risk endometrial cancer [102]. However,
of patients for adjuvant therapy. patients with low-risk disease (i.e. grade 1 and 2 endometrioid
Data from two RCTs do not support the therapeutic benefit lesions with <50% myometrial invasion) have a very low prob-
of lymphadenectomy in early-stage endometrial cancer. ability of lymphadenopathy and therefore derive no benefit
Benedetti Panici et al. randomised 514 women with clinical from a systematic lymphadenectomy [103].
stage I endometrial cancer to either systematic pelvic lymphade- Recommendation 5.4: Lymphadenectomy is a staging pro-
nectomy or no LND and found no improvement in disease-free cedure and allows tailoring of adjuvant therapy
survival or OS between the two groups [95]. Similarly, the Level of evidence: III
ASTEC trial, which included 1408 patients with stage I endo- Strength of recommendation: B
metrial cancer who were randomised to receive surgical staging Consensus: 100% yes (37 voters)
with or without pelvic lymphadenectomy, failed to show a bene- Recommendation 5.5: Patients with low-risk endometrioid
ficial effect of lymphadenectomy [96]. Although these trials re- carcinoma (grade 1 or 2 and superficial myometrial invasion
present the best data available, controversy still exists, partly due <50%) have a low risk of lymph node involvement, and two
to criticisms of the ASTEC trial, in which the number of lymph RCTs did not show a survival benefit. Therefore, lymphadenect-
nodes removed was low and systematic para-aortic lymphade- omy is not recommended for these patients
nectomy was not performed. A mathematical model applied to Level of evidence: II
the ASTEC trial suggested a survival difference of <2% between Strength of recommendation: A
the experimental and control arms under all circumstances [97]. Consensus: 100% yes (37 voters)
This model suggested that, even if LND was therapeutic, this Recommendation 5.6: For patients with intermediate risk
trial would have been negative due to the trial design. In the (deep myometrial invasion >50% or grade 3 superficial myome-
Italian trial [95], median node counts were 26, or 30 for the 26% trial invasion <50%), data have not shown a survival benefit.
of patients who also had para-aortic lymphadenectomy, and Lymphadenectomy can be considered for staging purposes in
there were no differences in relapse rates, disease-free survival these patients
and OS. Level of evidence: II
In contrast, retrospective data, which are prone to selection Strength of recommendation: C
bias and stage migration, suggest that patients who underwent Consensus: 100% yes (37 voters)
systematic lymphadenectomy had improved survival over those Recommendation 5.7: For patients with high risk (grade 3
who had limited or no sampling performed [88]. Data from with deep myometrial invasion >50%), lymphadenectomy
42 184 patients with endometrial cancer, obtained from the should be recommended
Surveillance, Epidemiology and End Results Program of the US Level of evidence: IV
National Cancer Institute for the years 1988–2003, showed that Strength of recommendation: B
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

Consensus: 73.0% (27) yes, 8.1% (3) abstain, 18.9% (7) no Recommendation 6.5: Multimodality management should be
(37 voters) considered for the treatment of advanced endometrial cancer
Recommendation 5.8: Lymphadenectomy to complete when surgery may significantly impair vaginal function
staging could be considered in previously incompletely operated Level of evidence: IV
high-risk patients to tailor adjuvant therapy Strength of recommendation: B
Level of evidence: V Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters)
Consensus: 100% yes (37 voters) surgical management of non-EEC. The standard of surgical
therapy in non-EEC is not different from EEC (see sections 3 and
6. How radical should the surgery be in different stages and 5). Hysterectomy and bilateral salpingo-oophorectomy is the
pathological subtypes of endometrial cancer? mainstay of therapy in apparent stage I disease. Radical
hysterectomy is not recommended in stage II disease, whereas
complete cytoreduction is required in advanced disease stages.

surgical management of stage II–IV endometrial cancer. In a
However, there is no documentation on ovarian preservation.
recent study from Japan, radical surgery in stage II endometrial
Bilateral salpingo-oophorectomy is mandatory.
cancer did not result in any survival benefit compared with simple
Comprehensive surgical staging of more advanced disease
hysterectomy but was associated with more perioperative and late
stages is mandatory (see section 5). Although no data from rando-
adverse events [104]. Another recent study found that parametrial
mised trials are available in non-EEC, the staging of apparent
spread cannot be predicted by cervical involvement alone but
stage I disease are similar to high-risk EEC. Omentectomy is also
may be predicted by various lymphovascular space invasion
considered in apparent stage I papillary serous carcinoma, in
(LVSI)-related histopathological factors [105]. However, radical
which peritoneal implants are not uncommon. However, omen-
hysterectomy is considered in cases of obvious involvement of the
tectomy is not mandatory in cases of clear-cell carcinoma [108],
parametrium. Surgery should then be tailored according to the
but should be considered where there is a serous component since
recent classification of radical hysterectomy [106] in order to
uterine serosal spread has a negative impact on survival [109].
obtain free margins. Lymphadenectomy is recommended.
Recommendation 6.6: In non-EEC (apparent stage I), lym-
Recommendation 6.1: Radical hysterectomy is not recom-
phadenectomy is recommended
mended for the management of stage II endometrial cancer
Consensus: 91.9% (34) yes, 8.1% (3) abstain (37 voters)
Recommendation 6.7: Staging omentectomy is not manda-
Recommendation 6.2: Modified (type B) or type A radical
tory in clear-cell or undifferentiated endometrial carcinoma and
hysterectomy should be considered only if required for obtain-
carcinosarcoma
ing free margins
Recommendation 6.8: Staging omentectomy should be con-
Recommendation 6.3: Lymphadenectomy is recommended
sidered in serous carcinoma
for clinical or intra-operative stage II endometrial cancer
adjuvant treatment
surgical management of stage III–IV endometrial cancer. 7. What is the current best definition of risk groups for
Although there is no evidence from randomised trials for stage adjuvant therapy?
III–IV endometrial cancer, there is consensus that multimodality
therapy is required, generally starting with radical cytoreductive The majority of patients with endometrial cancer have a low
surgery. Several retrospective studies have shown a statistically risk of recurrence and are managed by surgery alone [110]. Risk
significant advantage in progression-free survival (PFS) and OS groups have been devised based on clinicopathological prognos-
when optimal cytoreduction can be achieved [107]. However, not tic factors to identify patients at risk of recurrence who may
all patients are amenable to optimal cytoreduction as a result of benefit from adjuvant therapy.
poor general condition or tumour extent. In addition, the surgical In order to have clinical value, a definition of risk groups
management of metastatic vaginal disease may impair the vaginal should have both prognostic value and consequences for the in-
function. Primary RT is therefore preferable in some cases. dication of adjuvant therapy. Well-defined clinicopathological
Recommendation 6.4: Complete macroscopic cytoreduction prognostic factors include: age, FIGO stage, depth of myometrial
and comprehensive staging is recommended in advanced endo- invasion, tumour differentiation grade, tumour type (endome-
metrial cancer trioid versus serous and clear cell) and LVSI [89]. Compared
Level of evidence: IV with the ESMO risk group classification [8], the adverse prog-
Strength of recommendation: A nostic role of both LVSI and tumour grade 3 within the inter-
Consensus: 100% yes (37 voters) mediate-risk group (stage IA grade 3 or stage IB grade 1–2) has
 | Colombo et al. Volume 27 | No. 1 | January 2016

Table 2. New risk groups to guide adjuvant therapy use of routine lymphadenectomy for nodal staging purposes in
low- and intermediate-risk endometrial cancer [95, 96]. Given
Risk group Description LOE
the absence of a survival benefit and its associated side-effects,
Low Stage I endometrioid, grade 1–2, <50% I routine lymphadenectomy is not recommended for low- and
myometrial invasion, LVSI negative (high)intermediate-risk disease in most national and internation-
Intermediate Stage I endometrioid, grade 1–2, ≥50% I al guidelines for these patients. The value of lymphadenectomy in
myometrial invasion, LVSI negative high-risk endometrial cancer is the subject of ongoing investiga-
High- Stage I endometrioid, grade 3, <50% I tions. Recommendations regarding what defines adequate (lymph
intermediate myometrial invasion, regardless of LVSI
node) staging are detailed in the chapter on surgery.
status
Compared with the ESMO CPG on endometrial cancer [8],
Stage I endometrioid, grade 1–2, LVSI II
the current recommendations are specified to address both
unequivocally positive, regardless of depth
scenarios that surgical nodal staging is performed and is not
of invasion
performed, and to specifically address non-endometrioid histo-

High Stage I endometrioid, grade 3, ≥50% I
myometrial invasion, regardless of LVSI
logical subtypes. In addition, the roles of vaginal brachytherapy,
status EBRT and chemotherapy or combinations of these treatments
Stage II I have been specified in more detail for each of these situations.
Stage III endometrioid, no residual disease I
Non-endometrioid (serous or clear-cell or I low-risk endometrial cancer. Some patients now considered as
undifferentiated carcinoma, or low risk were included in the large randomised trials of adjuvant
carcinosarcoma) RT, and no benefit of RT was found in this subgroup [116–119].
Advanced Stage III residual disease and stage IVA I A randomised trial of 645 patients with low-risk endometrial
Metastatic Stage IVB I cancer treated with vaginal brachytherapy also showed no
advantage for the use of adjuvant brachytherapy, likely because
FIGO 2009 staging used; molecular factors were considered but not the risk of recurrence after surgery alone is <5% [125].
included; tumour size was considered but not included; nodal status may Therefore, no adjuvant treatment is indicated for patients with
be considered for treatment recommendations. low-risk endometrial cancer.
LOE, level of evidence; LVSI, lymphovascular space invasion. Recommendation 8.1: In patients with low-risk endometrial
cancer (stage I endometrioid, grade 1–2, <50% myometrial inva-
sion, LVSI negative), no adjuvant treatment is recommended
been recognised [111–115]. This has led to a new subdivision of Level of evidence: I
low risk, intermediate risk and high-intermediate risk in the Strength of recommendation: A
current classification, which is different from the risk classifica- Consensus: 100% yes (37 voters)
tion used in many clinical trials. Historically, low-risk endomet-
rial cancer was defined as endometrioid adenocarcinoma FIGO intermediate-risk endometrial cancer. Patients considered
stage I and grade 1 with superficial invasion or grade 2 without intermediate risk in the current classification were included in
invasion, and high-risk as stage I, grade 3 with deep myometrial the large randomised trials evaluating the role of adjuvant RT in
invasion, with other combinations of grade and invasion early-stage endometrial cancer [116–119]. In these trials, patients
defined as intermediate risk. Against this background, the large were randomised after total hysterectomy with bilateral salping-
trials evaluating the role of RT for intermediate-risk endometrial oophorectomy to pelvic EBRT or observation after surgery. All
cancer (PORTEC-1, GOG99, ASTEC/EN5, described below three trials and a meta-analysis by Kong et al. [119] found that
[116–118]) were conducted and, based on the results of these EBRT reduced the risk of pelvic recurrence by threefold (from
trials and a subsequent meta-analysis [119], a refined classifica- 14% to 4%), but did not lead to an OS benefit and came at the
tion of low risk, intermediate risk and high-intermediate risk cost of increased risk of (predominantly gastrointestinal) toxicity.
has been introduced. In contrast to the PORTEC-1 trial [117], surgical staging lym-
Factors such as tumour size and several molecular factors (e.g. phadenectomy was mandatory in the GOG99 trial [118],
TP53, L1CAM) have been reported as having prognostic value in showing that for node-negative disease, EBRT still reduced the
observational studies but have not been incorporated into this risk of recurrence. This risk reduction was mainly caused by pre-
classification since they are still under investigation and currently vention of local (vaginal) recurrence. Both PORTEC-1 and
not in clinical use [120–124]. A definition of risk groups to iden- GOG99 defined a subgroup of patients who derived the greatest
tify patients at risk of recurrence who may benefit from adjuvant benefit of adjuvant EBRT, a so-called high-intermediate-risk
therapy has been devised by the consensus panel and is shown in group. In the PORTEC-1 trial, the definition of risk groups was
Table 2. based on risk factors for locoregional recurrence [age >60 years,
deep (≥50%) myometrial invasion, grade 3], with high-inter-
8. What are the best evidence-based adjuvant treatment strat- mediate-risk patients defined as having two of three of these risk
egies for patients with low- and intermediate-risk endo- factors. In this subgroup, the 5-year risk of locoregional recur-
metrial cancer? rence was 20% for observation versus 5% for adjuvant RT, and
only in this subgroup was the risk of relapse deemed high
Although the 1988 FIGO staging system included surgical enough to consider adjuvant RT [117]. In the GOG99 trial, the
staging, two large randomised trials have since found no benefit definition of risk groups was based on risk factors for overall
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

recurrence identified in previous Gynecologic Oncology Group In the GOG249 study, both high-intermediate- and high-risk
(GOG) studies, with high-intermediate-risk patients defined as: patients were randomised between pelvic EBRT and vaginal
age <50 years and one risk factor, age 50–70 years and two risk brachytherapy followed by chemotherapy (three cycles of carbo-
factors and age >70 and all three risk factors. Similar results platin and paclitaxel). Results have been presented (abstract
were found in the ASTEC trial, which reported a lower risk of only) that showed no PFS benefit of adjuvant chemotherapy
vaginal and pelvic relapse in the no-EBRT group (7% versus 4% over the standard EBRT [131].
in the EBRT arm). In the ASTEC trial, vaginal brachytherapy Recommendation 8.3: In patients with high-intermediate-
was allowed in both study arms, and more than 50% of patients risk endometrial cancer (stage I endometrioid, grade 3, <50%
in the observation arm received vaginal brachytherapy. myometrial invasion, regardless of LVSI status; or stage I endo-
The randomised PORTEC-2 trial included only patients with the metrioid, grade 1–2, LVSI unequivocally positive, regardless of
high-intermediate-risk factors defined in PORTEC-1, and showed depth of invasion):
that vaginal brachytherapy provided excellent vaginal control com- 1: Surgical nodal staging performed, node negative:
pared with EBRT, and had a more favourable toxicity and quality- A. Adjuvant brachytherapy is recommended to decrease

of-life profile [126]. These results have been confirmed in a Swedish vaginal recurrence
trial in which vaginal brachytherapy was compared with combined Level of evidence: III
EBRT and a vaginal brachytherapy boost [127]. Strength of recommendation: B
Multiple cohort studies have identified LVSI and grade 3 as B. No adjuvant therapy is an option
risk factors for disease recurrence [111–115]. This finding was Level of evidence: III
confirmed in a recent pooled analysis of data from the PORTEC- Strength of recommendation: C
1 and -2 trials, which showed that both LVSI and grade 3 are risk Consensus: 100% yes (37 voters)
factors for regional nodal recurrence and for distant metastasis 2: No surgical nodal staging:
[128]. EBRT decreased the risk of regional nodal recurrence in A. Adjuvant EBRT recommended for LVSI unequivocally
this small subgroup (5%) of patients, while vaginal brachytherapy positive to decrease pelvic recurrence
did not. As the vast majority of patients in PORTEC-2 had grade Level of evidence: III
1–2 tumours with deep (≥50%) myometrial invasion and Strength of recommendation: B
without LVSI, this population is now considered intermediate B. Adjuvant brachytherapy alone is recommended for grade
risk in the current consensus classification. These patients have a 3 and LVSI negative to decrease vaginal recurrence
low risk of regional and distant recurrence, while their risk of Level of evidence: III
local (vaginal) recurrence is significantly decreased with adjuvant Strength of recommendation: B
vaginal brachytherapy. In addition, others have validated the Consensus: 100% yes (37 voters)
added prognostic value of the incorporation of LVSI in the 3: Systemic therapy is of uncertain benefit; clinical studies are
ESMO risk classification [129]. encouraged
Because adjuvant RT does not improve OS and combined Level of evidence: III
EBRT and brachytherapy for recurrent disease is associated with Strength of recommendation: C
a high chance of complete remission, not performing routine Consensus: 94.6% (35) yes, 5.4% (2) abstain (37 voters)
adjuvant RT is also an option [130]. However, combined EBRT
and brachytherapy for recurrent disease is associated with a
higher rate of side-effects compared with adjuvant vaginal 9. What are the best evidence-based adjuvant
brachytherapy alone. treatment strategies for patients with high-risk
Recommendation 8.2: In patients with intermediate-risk endometrial cancer?
endometrial cancer (stage I endometrioid, grade 1–2, ≥50% In general, high-risk endometrial cancer is characterised by
myometrial invasion, LVSI negative): an increased risk of pelvic recurrence and distant metastases
1: Adjuvant brachytherapy is recommended to decrease vaginal that contribute to the inferior outcomes of this group.
recurrence However, high-risk endometrial cancer represents a heteroge-
Level of evidence: I neous group of patients, including both endometrioid and
Strength of recommendation: B non-endometroid tumour types such as serous and clear cell,
2: No adjuvant treatment is an option, especially for patients and ranges from stage IB grade 3 (with or without LVSI and
aged <60 years with or without nodal staging) to more advanced FIGO
Level of evidence: II stages. Regardless of tumour type, the estimated 5-year OS
Strength of recommendation: C according to the 26th FIGO annual report is 85%–90% for
Consensus: 100% yes (37 voters) stage I, 75%–85% for stage II, 50%–65% for stage III and
20%–25% for stage IV [132]. Among FIGO stage I patients,
high-intermediate-risk endometrial cancer. Patients with grade those with deep myometrial invasion and grade 3 histology
1–2 tumours with deep (≥50%) myometrial invasion and are at increased risk of pelvic and distant relapse [133–135].
unequivocally positive (substantial, not focal) LVSI, and those Estimated 5-year OS rates in patients with ≥50% myometrial
with grade 3 tumours with <50% myometrial invasion regardless invasion and grade 3 tumours (without nodal staging) were
of LVSI status are referred to as high-intermediate risk in the only 58%. Regarding non-endometrioid tumour types,
current classification. ∼60%–70% of patients with uterine serous cancer have
 | Colombo et al. Volume 27 | No. 1 | January 2016

disease outside the uterus at the time of presentation. The 1: Surgical nodal staging performed, node negative:
5-year OS rate for patients with uterine serous cancer is A. Adjuvant EBRT with limited fields should be considered
20%–25% versus 80% for all patients with endometrial cancer to decrease locoregional recurrence
[136]. For these reasons, recommendations were made for the Level of evidence: I
following subgroups: endometrioid stage I, grade 3 and >50% Strength of recommendation: B
myometrial invasion; endometrioid stage II; endometrioid B. Adjuvant brachytherapy may be considered as an alterna-
stage III without residual disease and non-endometrioid tive to decrease vaginal recurrence
tumour types. Recommendations for patients with advanced Level of evidence: III
non-resectable or residual disease are provided separately in Strength of recommendation: B
the ‘Advanced and Recurrent Endometrial Cancer’ section of C. Adjuvant systemic therapy is under investigation
this article. Level of evidence: II
External beam pelvic RT is the standard therapy for high-risk Strength of recommendation: C
patients and is indicated to maximise pelvic control. The add- Consensus: 100% yes (37 voters)

ition of chemotherapy, or replacement of RT by chemotherapy, 2: No surgical nodal staging:
has been studied in several randomised trials. A historic GOG A. Adjuvant EBRT is generally recommended for pelvic
randomised trial that included patients with high-risk stage I control and relapse-free survival
and occult stage II disease found no benefit of adjuvant doxo- Level of evidence: III
rubicin after surgery and postoperative pelvic EBRT [137]. A Strength of recommendation: B
Japanese (JGOG 2033) and an Italian trial randomised patients B. Sequential adjuvant chemotherapy may be considered to
with high-risk endometrial cancer between pelvic EBRT and improve PFS and cancer-specific survival (CSS)
adjuvant cyclophosphamide, doxorubicin, cisplatin (CAP) Level of evidence: II
chemotherapy (three and five cycles, respectively), and both Strength of recommendation: C
trials found no difference in OS or disease-free survival (5-year C. There is more evidence to support giving chemotherapy
OS: 85% versus 87% and 69% versus 66%, respectively) and EBRT in combination rather than either treatment
[138, 139]. modality alone
Results of a combined analysis of the NSGO 9501/EORTC Level of evidence: II
55991 and MaNGO-ILIADE III randomised trials have been Strength of recommendation: B
published [140]. In this pooled analysis, the addition of adjuvant Consensus: 100% yes (37 voters)
chemotherapy (four cycles of platinum-based chemotherapy
given either before or after RT) to adjuvant EBRT was associated high-risk, stage II endometrial cancer. The definition of stage II
with a significant improvement in 5-year PFS (78% versus 69%, endometrial cancer was changed in the most recent FIGO 2009
P = 0.009), and a trend towards improved OS (82% versus 75%, staging system; tumours with endocervical glandular involvement
P = 0.07). Findings from a subgroup analysis suggested that the (previously stage IIA) were moved to stage I as this has no
benefit of adjuvant chemotherapy was restricted to patients prognostic impact [142, 143]. As a result, stage II now only
with endometrioid tumours rather than the 36% with serous or includes tumours with cervical stromal invasion [144].
clear-cell tumours. However, as this was an unplanned and Stage II tumours have been associated with an increased fre-
small subgroup analysis, no definite conclusions can be drawn quency of deep myometrial invasion and grade 3 histology,
on the efficacy of adjuvant chemotherapy for serous or clear-cell making it difficult to conclude if cervical invasion alone is the
cancers. reason for the observed higher risk of recurrence and lower OS
Promising results were found in the RTOG 9708 phase II compared with stage I disease [145]. In a SEER analysis that
study in 46 patients using concurrent pelvic RT and two included 1577 patients with stage II endometrial cancer, of
cycles of cisplatin (50 mg/m2 days 1 and 28) followed by four which half had stromal invasion, a multivariate analysis demon-
additional courses at 28-day intervals of cisplatin (50 mg/m2) strated no OS benefit for radical compared with simple hysterec-
and paclitaxel (175 mg/m2) as a 24-h infusion [141]. tomy, while RT (independently of the type of surgery) was
Reported 4-year OS rates were 85% for the whole group and associated with a survival benefit [146].
77% for stage III patients. This concurrent and adjuvant Controversy exists regarding the role of additional vaginal
chemotherapy schedule formed the rationale for the treat- brachytherapy boost in combination with EBRT [147]. The indi-
ment arms included in recently completed trials that investi- cation for a brachytherapy boost is clear in the rare situation of a
gated the role of combined cisplatin-based chemoradiation plus tumour with positive vaginal margin. However, in the adjuvant
adjuvant chemotherapy compared with either RT alone setting, it has historically been performed largely for stage II
(PORTEC-3) or chemotherapy alone (GOG258) for patients with disease. In randomised trials conducted in patients with inter-
high-risk and advanced stage endometrial cancer. The ongoing mediate-risk stage I endometrial cancer, there is no clear benefit
ENGOT-EN2-DGCG/EORTC55102 trial is evaluating the role of in terms of vaginal control among trials that included a vaginal
chemotherapy versus observation in patients with high-risk, node- brachytherapy boost compared with those that did not, with low
negative endometrial cancer. recurrence rates of ∼2% at 5 years after EBRT or vaginal brachy-
Recommendation 9.1: In patients with high-risk endometrial therapy alone [126, 127]. A SEER analysis conducted in patients
cancer (stage I endometrioid, grade 3, ≥50% myometrial inva- with stage IIIC endometrial cancer suggested a survival benefit
sion, regardless of LVSI status): for patients with ‘direct extension’ of the tumour, but no vaginal
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

recurrence rates are available [148]. Other studies have found no and chemotherapy, as also evaluated in PORTEC-3, does indeed
difference in local recurrence or OS rates among patients with improve PFS and OS compared with chemotherapy alone.
stage II endometrial cancer treated with or without vaginal Recommendation 9.3: In patients with high-risk, stage III
brachytherapy in addition to EBRT, but it was associated with endometrial cancer and no residual disease:
increased risk of side-effects [149–153]. 1: EBRT is recommended to:
Recommendation 9.2: In patients with high-risk, stage II A. Decrease pelvic recurrence
endometrial cancer: Level of evidence: I
1: Simple hysterectomy, surgical nodal staging performed, node Strength of recommendation: B
negative: B. Improve PFS
A. Grade 1–2, LVSI negative: Recommend vaginal brachy- Level of evidence: I
therapy to improve local control Strength of recommendation: B
Level of evidence: III C. Improve survival
Strength of recommendation: B Level of evidence: IV

B. Grade 3 or LVSI unequivocally positive: Strength of recommendation: B
i. Recommend limited field EBRT 2: Chemotherapy is recommended to improve PFS and CSS
Level of evidence: III Level of evidence: II
Strength of recommendation: B Strength of recommendation: B
ii. Consider brachytherapy boost 3: There is more evidence to give chemotherapy and EBRT in
Level of evidence: IV combination than either alone in stage III disease:
Strength of recommendation: C A. IIIA: Chemotherapy AND EBRT to be considered
iii. Chemotherapy is under investigation B. IIIB: Chemotherapy AND EBRT to be considered
Level of evidence: III C. IIIC1: Chemotherapy AND EBRT to be considered
Strength of recommendation: C D. IIIC2: Chemotherapy AND extended field EBRT to be
Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) considered
2: Simple hysterectomy, no surgical nodal staging: Level of evidence: II
A. EBRT is recommended Strength of recommendation: B
Level of evidence: III Consensus: 94.6% (35) yes, 5.4% (2) abstain (37 voters)
B. Consider brachytherapy boost
Level of evidence: IV high-risk, non-endometrioid cancers. For the purpose of
Strength of recommendation: C these recommendations, serous, clear-cell, carcinosarcoma,
C. Grade 3 or LVSI unequivocally positive: Sequential adju- undifferentiated and mixed (>10%) tumours are regarded as
vant chemotherapy should be considered high-risk non-endometrioid-type cancers. These tumours
Level of evidence: III represent an infrequent subset of patients; hence, most studies are
Strength of recommendation: B retrospective and have included a limited number of patients. The
Consensus: 100% yes (37 voters) largest retrospective study conducted to date suggested a survival
benefit for the combination of chemotherapy and RT in uterine
serous cancer [159]. However, a subgroup analysis of the NSGO
high-risk, stage III endometrial cancer. In patients with stage 9501/EORTC 55991 and MaNGO-ILIADE III trials did not show
IIIC endometrial cancer, pelvic and/or extended field RT have a survival benefit for patients with serous or clear-cell tumours
been associated with increased OS and locoregional control rates, [140]. Given the high rates of distant metastasis observed in
while a higher rate of pelvic recurrence was found after adjuvant patients with uterine serous and clear-cell tumours, adjuvant
chemotherapy alone [154, 155]. In the GOG122 trial [156], chemotherapy can be considered and clinical trials addressing
women with advanced stage III/IV endometrial cancer were these rare subtypes are encouraged [136, 160]. One retrospective
randomised between whole abdominal irradiation and eight cycles study investigated the role of vaginal brachytherapy for stage I
of doxorubicin/cisplatin chemotherapy. Both adjusted PFS and serous or clear-cell cancers. The majority were either non-
OS were higher in the group who received chemotherapy invasive (26%) or had <50% myometrial invasion (58%), and
(predicted 5-year rates of 50% versus 38% and 55% versus 42%, 34% received adjuvant chemotherapy. The 5-year rate of isolated
respectively). However, event rates were high in both arms (50% pelvic recurrence was 4% and locoregional recurrence was 7%; the
and 54%). Patients with up to 2 cm residual disease were included 5-year OS rate was 84%, suggesting that vaginal brachytherapy
in this trial, suggesting that the dose delivered with whole alone is sufficient in patients with stage IA disease [161].
abdominal irradiation is not effective for macroscopic disease and Carcinosarcomas are regarded as metaplastic carcinomas con-
is toxic. In view of findings from the pooled NSGO/EORTC/Iliace taining both sarcomatous and carcinomatous elements [162].
trials [140] as well as results from prospective and retrospective They are rare and aggressive tumours with more than 35% of
trials [141, 154, 155, 157, 158], the use of combined RT and patients presenting with extra-uterine disease at diagnosis and
chemotherapy is recommended as opposed to either alone. are associated with a 5-year OS rate of 50% for patients with
Results of the recently completed GOG258 for stage III–IV stage I disease [163]. In the EORTC-55874 trial, patients with
endometrial cancer are awaited to see if the combination of EBRT stage I–II uterine sarcomas were randomised to receive adjuvant
 | Colombo et al. Volume 27 | No. 1 | January 2016

RT after surgery. Of the 224 patients included, 91 had carcino- cases, palliative surgery can be performed to alleviate symptoms
sarcoma. In both groups, RT significantly reduced the risk of (e.g. bleeding or bowel obstruction).
local relapse but there was no difference in the rate of distant For patients with oligometastases or isolated retroperitoneal
metastasis and OS [164]. Three analyses of SEER data have been lymph node metastases, surgical resection is an option that can
reported in this setting, which initially showed a survival benefit be considered but the evidence of its benefit is limited.
for patients who received RT but who did not undergo lympha- Recommendation 10.1: For patients with advanced or recur-
denectomy [165, 166]. However, in a subsequent analysis, this rent disease, surgery is recommended only if optimal cytoreduc-
survival benefit was not maintained [167], thus limiting the con- tion (no residual disease) can be achieved. In selected cases,
clusions that can be drawn from these analyses. Finally, the palliative surgery is recommended to alleviate specific symptoms
GOG performed a trial in which whole abdominal irradiation Level of evidence: IV
was compared with three courses of ifosfamide and cisplatin Strength of recommendation: C
after complete resection. In this trial, chemotherapy was asso- Consensus: 100% yes (37 voters)
ciated with a numerically lower risk of recurrence and better Recommendation 10.2: Exenteration can be considered in

survival but the differences were not statistically significant selected patients with locally advanced tumours, and for isolated
[168]. central local relapse after radiation, if clear margins are expected
Recommendation 9.4: In patients with high-risk, non-endo- Level of evidence: IV
metrioid cancers: Strength of recommendation: C
1: Serous and clear cell after comprehensive staging: Consensus: 100% yes (37 voters)
A. Consider chemotherapy; clinical trials are encouraged Recommendation 10.3: Complete resection of distant oligo-
Level of evidence: III metastases and pelvic or retroperitoneal lymph node relapse can
Strength of recommendation: B be considered if technically possible according to localisation of
B. Stage IA, LVSI negative: Consider vaginal brachytherapy disease
only without chemotherapy Level of evidence: V
Level of evidence: IV Strength of recommendation: C
Strength of recommendation: C Consensus: 100% yes (37 voters)
C. Stage ≥IB: EBRT may be considered in addition to
chemotherapy, especially for node-positive disease
histology. Uterine serous cancer and clear-cell cancer account for
Level of evidence: III
∼10% and 3% of advanced endometrial cancer cases, respectively
[170]. Patients with advanced disease have a worse prognosis than
those with endometrioid type, but there is no evidence that
2: Carcinosarcoma and undifferentiated tumours: histology should influence the decision regarding surgery.
A. Chemotherapy is recommended Recommendation 10.4: Histological type should not influ-
Level of evidence: II ence the decision whether or not to proceed with surgery
Strength of recommendation: B Level of evidence: IV
B. Consider EBRT; clinical trials are encouraged Strength of recommendation: B
Level of evidence: III Consensus: 100% yes (37 voters)
RT for isolated vaginal relapse in early-stage endometrial
cancer. RT is an effective therapeutic modality for improving
local disease control. However, fewer patients now receive
advanced and recurrent endometrial cancer adjuvant radiation for early disease. Observation after surgery
10. Does surgery or RT have a role in advanced or recurrent particularly applies to those with early-stage, grade 1–2 disease
endometrial cancer? without LVSI, as salvage RT in those who have a localised vaginal
relapse is associated with good local control [171]. In the
surgical cytoreduction. Patients with advanced disease (defined as PORTEC1 trial, 35 of 39 patients with a vaginal recurrence after
bulky FIGO stage IIIA-IV), or recurrent disease should only be surgery alone were treated with radical intent, mostly with
considered for surgery if it is anticipated that cytoreduction with no combinations of EBRT and brachytherapy, and in some cases with
macroscopic residual disease can be achieved. Cytoreduction also surgery. The complete remission rate was 89%, and 77% remained
includes removal of enlarged lymph nodes, but as there is no disease free with a median follow-up of 44 months [130]. Survival
evidence that a systematic pelvic and para-aortal lymphadenectomy after relapse was better in patients who did not receive primary
will influence PFS or OS, it should not be routinely performed. In a adjuvant RT; among patients who had received adjuvant RT, most
meta-analysis of 14 publications containing retrospective data from relapses were at distant sites. There is currently no evidence to
672 patients, median OS time was positively associated with an suggest that modern techniques of image-guided brachytherapy
increasing proportion of patients with no residual disease (each and intensity-modulated RT (IMRT) are superior to conventional
10% increase improved survival by 9.3 months, P = 0.04); the approaches, although a single-institution retrospective study of RT
change in survival for patients with between 0 and ≤2 cm of disease [EBRT predominantly using an IMRT technique followed by
after surgery was not significant [169]. Exenteration may be image-guided high dose rate (HDR) brachytherapy] for vaginal
considered for FIGO stage IIIA and central local relapse. In selected recurrence has also reported high tumour control rates [172].
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

Recommendation 10.5: RT with curative intent is indicated in Recommendation 10.10: RT may be indicated for primary
patients with isolated vaginal relapse after surgery tumours that are unresectable, or where surgery cannot be per-
Level of evidence: III formed or is contraindicated for medical reasons
Strength of recommendation: A Level of evidence: IV
Consensus: 100% yes (34 voters) Strength of recommendation: B
chemotherapy with RT for recurrence. RT can be considered for
patients with vaginal or pelvic nodal recurrence. Improvements 11. What are the optimal systemic therapies for advanced/
in RT techniques allow for better means of localised treatment, recurrent disease?
or possibly retreatment of patients who have previously received The majority of patients with advanced or recurrent disease
RT. Whether chemotherapy has an additional benefit is unclear. will be candidates for systemic palliative therapy. The choice
The ongoing randomised phase II GOG0238 (NCT00492778) between hormonal treatment and chemotherapy relies on
trial is comparing pelvic irradiation of 45 Gy in 25 fractions plus

several factors, including histopathological and clinical features
either brachytherapy or external beam boost with the same of the individual patient.
schedule plus concomitant cisplatin (40 mg/m2 weekly) in
women with vaginal/pelvic relapse who have not received
prior RT.
Recommendation 10.6: For vaginal or pelvic nodal recur- hormonal therapy: which patient and when? Hormonal therapy
rence, chemotherapy with RT could be considered in patients is indicated for patients with advanced or recurrent endometrial
with high-risk features for systemic relapse cancer and endometrioid histology. This statement is based on
Level of evidence: IV several clinical trials that have shown clinical activity with a
Strength of recommendation: C favourable toxicity profile [176, 177].
Consensus: 97.1% (33) yes, 2.9% (1) abstain (34 voters) Recommendation 11.1: Hormone therapy is indicated in
advanced or recurrent EEC
combined approaches to recurrence and re-irradiation. The use Level of evidence: II
of systemic therapy or surgery before RT for vaginal or pelvic Strength of recommendation: A
node recurrence could be considered in certain patients with Consensus: 100% yes (34 voters)
more bulky disease. As the techniques for image-guided RT
Response to hormonal therapy is quite variable, and a
have improved, there are situations where re-irradiation can be
number of pathological factors contributing to this variation
considered, although evidence from clinical trials is lacking.
have been identified. For example, hormonal therapy is more
Recommendation 10.7: Use of systemic therapy or surgery
likely to be effective in grade 1 or 2 endometrioid tumours. In a
before RT for vaginal or pelvic node recurrence could be consid-
large clinical trial of MPA, the response rate was 37% for grade
ered in certain patients
1, 23% for grade 2 and 9% for grade 3 tumours [176]. Others
have reported similar findings [177]. Patients with hormone re-
ceptor-positive disease have also been shown to have a higher
chance of responding to endocrine therapy. In a randomised
Recommendation 10.8: Re-irradiation could be considered in
trial, the response rate observed in patients with ER- and PgR-
highly selected patients using specialised techniques
positive disease was ∼25% and 37%, respectively, but was only
7%–8% in patients with ER/PgR-negative disease [176, 177].
Based on these results, it seems that positivity of ER and/or PgR
could be a predictive factor of response to endocrine therapy and
so should be determined before initiating hormonal therapy.
palliative RT. RT can be effectively used to palliate symptoms
Recommendation 11.2: Hormone therapy is more likely to be
such as bleeding, bone metastases or painful nodal recurrence.
effective in grade 1 or 2 endometrioid tumours
No randomised trials have been conducted comparing RT with
palliative chemotherapy.
Recommendation 10.9: RT is indicated for palliation of symp-
toms related to local recurrence or systemic disease
Recommendation 11.3: Hormone receptor status should be
determined before hormone therapy is initiated, as it is more
likely to be effective in patients with positive PgR and ER status
Level of evidence: III
radical RT for primary endometrial cancer. RT can be used as a
primary treatment in patients with unresectable disease, or where
there are medical contraindications to surgery [173, 174]. Treatment Biopsy of recurrent disease can be considered, since there may
involves intrauterine brachytherapy alone or in combination with be differences in hormone receptor status in the primary and
EBRT. Image-guided brachytherapy may improve outcomes [175]. metastatic tumour. In a prospective collection of 686 primary
Two-year local control rates of more than 90% can be achieved for endometrial tumours and 171 metastatic lesions, loss of PgR
medically inoperable stage I disease. expression increased with disease progression, with 23% of
 | Colombo et al. Volume 27 | No. 1 | January 2016

primary tumours and 76% of metastatic lesions demonstrating alone in terms of response rate (43%–41% versus 17%–25%) but
PgR loss [178]. with no benefit in terms of OS [185, 186]. The combination also
Recommendation 11.4: Biopsy of recurrent disease could be resulted in a higher incidence of grade 3–4 myelotoxicity and
considered as there may be differences in hormone receptor nausea/vomiting.
status in the primary and metastatic tumour In another GOG trial, conducted in patients with measurable
Level of evidence: III FIGO III–IV endometrial cancer, the addition of paclitaxel to
Strength of recommendation: C cisplatin and doxorubicin was associated with a higher response
Consensus: 100% yes (34 voters) rate and PFS than cisplatin and doxorubicin alone [objective re-
sponse rate (ORR): 57% versus 34%, respectively, P < 0.01;
Hormone therapy is the preferred front-line systemic therapy
median PFS: 8.3 versus 5.3 months, respectively, P < 0.01], and a
for patients with hormone receptor-positive grade 1 or 2
small but significant improvement in OS (median 15.3 versus
tumours in the absence of rapidly progressive disease, as it pro-
12.3 months, respectively, P = 0.037) [187]. However, toxicity,
vides an excellent benefit/risk ratio and convenient toxicity
especially peripheral neuropathy, was significantly higher (grade

profile. However, patients with visceral involvement and rapidly
2–3: 39% versus 5%, respectively). For this reason, it has not
progressive disease are not candidates for hormone therapy as it
been widely adopted as a standard of care.
is not usually associated with a rapid response.
Finally, GOG209 was a randomised, non-inferiority trial that
Recommendation 11.5: Hormone therapy is the preferred
compared the combination of paclitaxel 160 mg/m2, cisplatin
front-line systemic therapy for patients with hormone receptor-
60 mg/m2 and doxorubicin 50 mg/m2 (TAP) with paclitaxel
positive tumours—grade 1 or 2 and without rapidly progressive
175 mg/m2 and carboplatin AUC 6 (TC), both administered
disease
every 3 weeks. A total of 1305 patients were included in this
trial, and preliminary data (not yet fully published) indicate a
similar response rate (51.3% versus 51.2%) and PFS (median
13.5 versus 13.3 months) [188]. The median OS ( primary study
The progestogens, MPA 200 mg or MA 160 mg, are generally end point) was 40.3 months for TAP and 36.5 months for TC,
recommended. They have shown clear activity for the front-line which met the criteria of non-inferiority. TC had a more favour-
treatment of non-selected patients with recurrent or persistent able toxicity profile than TAP in this trial, with fewer patients
endometrioid tumours not suitable for surgery or RT, with re- discontinuing therapy due to toxicity (12% versus 18%). In add-
sponse rates of ∼25% and PFS times of 3 months [176, 179]. ition, TC can be administered in the outpatient setting whereas
Data from a randomised trial comparing low-(200 mg/day) with TAP is given in the inpatient setting in most countries. This
high-(1000 mg/day) dose MPA in 299 patients with advanced aspect may be important in terms of logistical, financial and
or recurrent endometrial carcinoma showed that low-dose MPA quality-of-life considerations in the palliative setting.
was more active than the high dose in terms of response rate Recommendation 11.8: The standard of care is six cycles of 3-
(25% versus 15%, respectively) and OS (11.0 versus 7.0 months, weekly carboplatin and paclitaxel. This is based on the prelimin-
respectively) [176]. ary communication of a randomised trial showing similar efficacy
Recommendation 11.6: Progestogens (e.g. MPA 200 mg or and less toxicity compared with cisplatin/doxorubicin/paclitaxel
MA 160 mg) are generally recommended Level of evidence: I
Level of evidence: III Strength of recommendation: A
Strength of recommendation: A Consensus: 100% yes (34 voters)
Evidence supporting the use of second-line chemotherapy
Other endocrine therapies have also demonstrated activity in after platinum-containing therapy in patients with endometrial
phase II trials among patients with advanced or recurrent endo- cancer is limited, especially in cases where the treatment-free
metrial cancer, with tamoxifen, anastrozole and fulvestrant all interval following first-line chemotherapy is <6–12 months.
associated with response rates of ∼10% [180–182]. Interestingly, Although various regimens have been evaluated in this setting
patients included in the anastrozole trial had not received prior [189–192], no randomised trials have been published. Therefore,
progestin therapy [182]. The combination of tamoxifen and no specific regimen can be recommended as a standard of care
MPA is associated with response rates and PFS similar to MPA for second-line chemotherapy.
alone [183, 184]. Recommendation 11.9: There is no standard of care for
Recommendation 11.7: Other hormonal agents to consider second-line chemotherapy
after progestins include tamoxifen, fulvestrant and aromatase Level of evidence: V
inhibitors Strength of recommendation: C
Level of evidence: III Consensus: 100% yes (34 voters)
Consensus: 100% yes (34 voters) 12. What are the most promising targeted agents and which
chemotherapy: is there any standard of care? Endometrial study designs should be used to evaluate their clinical
cancer is a relatively chemo-sensitive disease, with anthracyclines, benefit?
platinum-based drugs and taxanes shown to be the most active
agents. Two clinical trials showed that the combination of potentially ‘druggable’ molecular alterations in endometrial
cisplatin and doxorubicin was more active than doxorubicin cancer. According to the WHO classification of endometrial
Volume 27 | No. 1 | January 2016 doi:10.1093/annonc/mdv484 | 

carcinoma, there are seven different types of tumours; however, usually modest and of short duration. Currently, several
endometrioid carcinoma, grade 3 and serous carcinomas different targeted therapies are undergoing clinical evaluation
account for the vast majority of aggressive tumours. Molecular but none are currently licensed for use. EGFR, human
genetic alterations involved in the development of endometrioid epidermal growth factor receptor-2 (HER2), mTOR and
cancers differ from those of serous tumours and this must be VEGFR inhibitors have been tested in phase I and II trials, with
taken into account when designing clinical trials to evaluate the modest response rates [200–203]. However, since this consensus
efficacy of molecular targeted agents. conference was held, findings from two randomised phase II
Over the last 15 years, it has been demonstrated that endomet- trials evaluating the addition of bevacizumab to TC in advanced
rial cancer shows microsatellite instability (MSI) and mutations or recurrent endometrial cancer suggest that this might be a
in PTEN, PIK3CA and KRAS, and that β-catenin genes are the promising approach worthy of further evaluation in phase III
most common molecular abnormalities in endometrioid carcin- clinical trials [204, 205]. GOG-86P was a three-arm trial
omas, whereas serous tumours have alterations of p53 and loss of evaluating the addition of bevacizumab, temsirolimus or
heterozygosity on several chromosomes, as well as other molecu- ixabepilone to first-line TC in 349 patients with advanced or

lar alterations (STK15, p16, E-cadherin and C-erbB2) [193]. recurrent endometrial cancer [204]. No differences in PFS were
Recently, the TCGA Research Network performed an integrated seen when the three arms were compared with historical data
genomic characterisation of endometrial carcinoma [5]. for TC from GOG 209 [188]. However, bevacizumab appeared
The PI3K/AKT pathway is one of the most frequently altered superior when the median OS results were compared with these
signalling pathways in endometrioid tumours, often resulting historical control data (34.0 versus 22.7 months, P < 0.039). In
from mutations in PTEN, PIK3CA and PIK3RI [194]. Of par- the MITO END-2 trial, which included 108 patients with
ticular interest is the downstream effector, mammalian target of advanced or recurrent endometrial cancer who had received 0
rapamycin (mTOR), and inhibitors of mTOR are now undergo- or 1 prior lines of chemotherapy, bevacizumab was added to six
ing evaluation in clinical trials. The RAS-RAF-MEK-ERK sig- to eight cycles of TC and then continued as maintenance
nalling pathway also plays an important role in these tumours, therapy. This approach resulted in a significant improvement in
with frequent mutations in KRAS, but also inactivation of median PFS (13 versus 8.7 months, P = 0.036) and a numerical
tumour suppressors such as RASF1A [195, 196]. Fibroblast increase in median OS (23.5 versus 18 months, P = 0.24),
growth factor-2 (FGFR2) is mutated in 10%–14% of endome- although these OS data are not yet mature [205].
trioid tumours and is a target for receptor tyrosine kinase inhi- Despite these promising results, few clinical trials of new tar-
bitors [197]. Angiogenesis also plays a role in endometrial geted therapies are molecularly driven [206] and the prevalence
tumorigenesis [198]. In addition, tumour homologous recom- of potential targets in metastatic lesions has been studied less
bination and mismatch repair deficiencies are seen in endome- than in primary tumours [178].
trioid tumours, the latter of which is particularly associated with Taken together, these findings suggest that PI3Kinase, mTOR
LS, and these pathways could be interesting targets. and angiogenesis inhibitors are the most promising classes of
Although there are a large number of specific gene abnormal- drugs to investigate in endometrial cancer [207], and progress in
ities and aberrant signalling pathways that appear to be promis- this area is likely to be faster if studies are biomarker driven with
ing targets, the frequency of each abnormality is small and this biopsy at entry.
presents a challenge to evaluating therapies in clinical trials Recommendation 12.2: Drugs targeting PI3K/mTOR
[199]. Examples include known tumour markers such L1CAM, pathway signalling and angiogenesis have shown modest activity
Anexin 2, other tyrosine kinase receptors [insulin-like growth but no agent has been approved for clinical use, and further bio-
factor receptor (IGFR), epidermal growth factor receptor marker-driven studies are warranted
(EGFR)] and signalling pathways involved in epithelial to mes- Level of evidence: III
enchymal transition [transforming growth factor-beta (TGF-β), Strength of recommendation: A
wnt] or stem cell-ness (Notch). PI3K/PTEN/AKT/mTOR Consensus: 100% yes (34 voters)
pathway, PTEN, MAPK-KRAS, angiogenesis [especially FGFR2
and vascular endothelial growth factor (VEGF)/VEGF receptor clinical trial design. While clinical trial end points such as OS
(VEGFR)], ER/PgR and homologous recombination deficiency and PFS are desirable, it may not be possible to make progress
(HRD)/MSI are altered in endometrial cancer, and the relevance unless novel trial design and end points are used. There should be
of these potential targets should be studied in clinical trials with better selection of patients, using a more systematic approach to
targeted agents. integration of biomarkers as well as earlier characterisation and
Recommendation 12.1: PI3K/PTEN/AKT/mTOR pathway, standardisation of diagnostic imaging and biomarker assessments.
PTEN, RAS-MAPK, angiogenesis (especially FGFR2 and Tumour response to biological agents may not occur to the same
VEGF/VEGFR), ER/PgR and HRD/MSI are altered in endomet- degree as with chemotherapy and alternative early end points,
rial cancer and their relevance should be studied in clinical trials such as the percentage of patients free from progression at 18
with targeted agents weeks [208], have been used. Trial designs that include different
Level of evidence: III gynaecological cancers of the same histotype should also be
Strength of recommendation: B considered, an approach that is being taken in the ongoing phase
Consensus: 100% yes (34 voters) III GOG0261 trial of paclitaxel plus carboplatin versus paclitaxel
plus ifosfamide in patients with different types of gynaecological
new agents in recurrent or metastatic endometrial cancer. The carcinosarcomas (NCT00954174), and a randomised phase II trial
benefit of standard chemotherapy and hormonal therapies is of nintedanib versus chemotherapy in patients with recurrent
 | Colombo et al. Volume 27 | No. 1 | January 2016

clear-cell carcinoma of the ovary or endometrium (EudraCT property rights for some aspects relating to STMN/pSTMN1 as a
2013-002109-73). There is also an argument for not being too prognostic marker for endometrial cancer [US 127962,946 (HS)
selective, as the presence of a specific biomarker target may not be and US 147155,412 (HS)]). All remaining authors have declared
reflective of the probability of response. In a recent analysis of no conflicts of interest.
phase II studies of mTOR inhibitors, there was no correlation
between response and the presence of mutations in the PI3K/AKT
pathway [209], a result that could be explained by a variety of
reasons, including the presence of multiple mutations, cross-talk
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Villejuif, France; H. W. Nijman, Department of Gynaecologic First Department of Obstetrics and Gynecology, Athens
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special articles Annals of Oncology

Annals of Oncology 27: 16–41, 2016

ESMO-ESGO-ESTRO Consensus Conference

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Received 17 July 2015; revised 30 September 2015; accepted 5 October 2015

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minimally invasive approach, should be discussed at the age of Level of evidence: IV

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carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to appendix

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