ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

ConcinN, etal. Int J Gynecol Cancer 2021;31:12–39. doi:10.1136/ijgc-2020-002230

ESGO/ESTRO/ESP guidelines for the management

of patients with endometrialcarcinoma

Nicole Concin ,

1,2

Xavier Matias- Guiu,

3,4

Ignace Vergote,

David Cibula,

Mansoor Raza Mirza,

Simone Marnitz,

Jonathan Ledermann ,

Tjalling Bosse,

Cyrus Chargari,

Anna Fagotti,

Christina Fotopoulou

Antonio Gonzalez Martin,

Sigurd Lax,

15,16

Domenica Lorusso,

Christian Marth,

Philippe Morice,

Remi A Nout,

Dearbhaile O'Donnell,

Denis Querleu ,

12,21

Maria Rosaria Raspollini,

Jalid Sehouli,

Alina Sturdza,

Alexandra Taylor,

Anneke Westermann,

Pauline Wimberger,

Nicoletta Colombo,

François Planchamp,

Carien L Creutzberg

For numbered afliations see

end of article.

Correspondence to

Nicole Concin, Department of

Gynecology and Obstetrics,

Innsbruck Medical University,

Innsbruck 6020, Austria; nicole.

concin@ i- med. ac. at

For ‘Presented at statement’

see end of article.

Received 7 November 2020

Accepted 16 November 2020

Published Online First

18December2020

To cite: ConcinN,

Matias- GuiuX, VergoteI,

etal. Int J Gynecol Cancer

2021;31:12–39.

Joint statement

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INTERNATIONAL JOURNAL OF

GYNECOLOGICAL CANCER

ABSTRACT

A European consensus conference on endometrial

carcinoma was held in 2014 to produce multi- disciplinary

evidence- based guidelines on selected questions.

Given the large body of literature on the management

of endometrial carcinoma published since 2014, the

European Society of Gynaecological Oncology (ESGO), the

European SocieTy for Radiotherapy and Oncology (ESTRO),

and the European Society of Pathology (ESP) jointly

decided to update these evidence- based guidelines and

to cover new topics in order to improve the quality of care

for women with endometrial carcinoma across Europe and

worldwide.

INTRODUCTION

Endometrial carcinoma is the most common gyneco-

logical cancer in Europe, with a 5- year prevalence of

34.7% (445 805 cases).

The estimated number of

new endometrial carcinoma cases in Europe in 2018

was 121 578 with 29 638 deaths, and the incidence

has been rising with aging and increased obesity of

the population. The EUROCARE-5 study, published in

2015, reported a 5- year relative survival of 76% for

European women diagnosed with endometrial carci-

noma in 2000–2007, ranging from 72.9% in Eastern

Europe to 83.2% in Northern Europe.

The observed

geographic difference might be partially attributable

to tangible differences in the prevalence of endome-

trioid sub- types among regions. Furthermore, differ-

ences in patient characteristics and histopathologic

features of the disease impact both on patient prog-

nosis and the recommended treatment approach.

A consensus conference including representa-

tion from the European Society of Medical Oncology

(ESMO), the European Society of Gynaecological

Oncology (ESGO), and the European SocieTy for

Radiotherapy and Oncology (ESTRO) was held in

2014 with the aim to produce multi- disciplinary

evidence- based guidelines on 12 selected questions

in order to complement the ESMO clinical practice

guidelines previously published.

3–6

ESGO, ESTRO,

and the European Society of Pathology (ESP) jointly

decided to update these evidence- based guidelines

and, moreover, to cover new topics in order to provide

comprehensive guidelines on all relevant issues of

diagnosis and treatment in endometrial carcinoma

in a multi- disciplinary setting. These guidelines

are intended for use by gynecological oncologists,

general gynecologists, surgeons, radiation oncolo-

gists, pathologists, medical and clinical oncologists,

radiologists, general practitioners, palliative care

teams, and allied health professionals.

RESPONSIBILITIES

These guidelines are a statement of evidence and

consensus of the authors regarding their views of

currently accepted approaches for the management

of patients with endometrial carcinoma. Any clinician

applying or consulting these guidelines is expected

to use independent medical judgment in the context

of individual clinical circumstances to determine any

patient’s care or treatment. These guidelines make no

warranties of any kind regarding their content, use, or

application, and the authors disclaim any responsi-

bility for their application or use in any way.

METHODS

The guidelines were developed using a ve- step

process as dened by the ESGO Guideline Committee

(see Figure1). The strengths of the process include

creation of a multi- disciplinary international devel-

opment group, use of scientic evidence and inter-

national expert consensus to support the guidelines,

and use of an international external review process

(physicians and patients). This development process

involved three meetings of the international devel-

opment group chaired by Professor Nicole Concin

(Medical University of Innsbruck, Innsbruck, Austria/

Evangelische Kliniken Essen- Mitte, Essen, Germany,

for ESGO), Professor Carien L Creutzberg (Leiden

University Medical Center, Leiden, the Nether-

lands, for ESTRO), and Professor Xavier Matias- Guiu

(Department of Pathology, Hospital Universitari Arnau

de Vilanova and Hospital Universitari de Bellvitge,

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Joint statement

Irblleida, Idibell, Universities of Lleida and Barcelona, CIBERONC,

Spain, for ESP).

ESGO/ESTRO/ESP nominated practising clinicians who are

involved in the management of patients with endometrial carcinoma

and have demonstrated leadership in the clinical management of

patients through research, administrative responsibilities, and/or

committee membership to serve on the expert panel. The objective

was to assemble a multi- disciplinary panel and it was therefore

essential to include professionals from relevant disciplines (gyne-

cological oncology and gynecology, medical, clinical and radiation

oncology, pathology) to contribute to the validity and acceptability of

the guidelines. To ensure that the statements were evidence based,

the current literature was reviewed and critically appraised. A

systematic literature review of relevant studies published between

January 2014 and June 2019 was carried out using the MEDLINE

database (see online supplemental appendix 1). The literature

search was limited to publications in English. Priority was given to

high- quality systematic reviews, meta- analyses, and randomized

controlled trials, but studies of lower levels of evidence were also

evaluated. The search strategy excluded editorials, letters, and in

vitro studies. The reference list of each identied article was also

reviewed for other potentially relevant articles.

The development group developed guidelines for all the topics.

The guidelines were retained if they were supported by a suf-

ciently high level of scientic evidence and/or when a large

consensus among experts was obtained. An adapted version of the

'Infectious Diseases Society of America- United States Public Health

Service Grading System' was used to dene the level of evidence

and grade of recommendation for each of the recommendations

(see Table1). In the absence of any clear scientic evidence, judg-

ment was based on the professional experience and consensus of

the development group.

ESGO/ESTRO/ESP established a large multi- disciplinary panel

of practicing clinicians who provide care to patients with endo-

metrial carcinoma to act as independent expert reviewers for the

guidelines developed. These reviewers were selected according to

their expertise, had to be still involved in clinical practice, and were

from different European and non- European countries to ensure

global perspective. Patients with endometrial carcinoma were also

included. These independent reviewers were asked to evaluate

each recommendation according to its relevance and feasibility in

clinical practice (only physicians), so that comprehensive quantita-

tive and qualitative evaluations of the guidelines were completed.

Patients were asked to evaluate qualitatively each recommen-

dation (according to their experience, personal perceptions, etc).

Figure 1 Development process.

Table 1 Levels of evidence and grades of

recommendations

Levels of evidence

I Evidence from at least one large randomized

controlled trial of good methodological quality

(low potential for bias) or meta- analyses of well-

conducted randomized trials without heterogeneity

II Small randomized trials or large randomized trials

with a suspicion of bias (lower methodological

quality) or meta- analyses of such trials or of trials

with demonstrated heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case–control studies

V Studies without control group, case reports, expert

opinions

Grades of recommendations

A Strong evidence for efcacy with a substantial clinical

benet, strongly recommended

B Strong or moderate evidence for efcacy but with a

limited clinical benet, generally recommended

C Insufcient evidence for efcacy or benet does not

outweigh the risk or the disadvantages (adverse

events, costs, etc), optional

D Moderate evidence against efcacy or for adverse

outcome, generally not recommended

E Strong evidence against efcacy or for adverse

outcome, never recommended

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Joint statement

Evaluations of the external reviewers (n=191) were pooled and

discussed by the international development group before nalising

the guidelines. The list of the 191 external reviewers is available in

online supplemental appendix 2.

GENERAL RECOMMENDATIONS

► Planning of staging and treatment should be made on a

multi- disciplinary basis (generally at a tumor board meeting,

composed according to local guidelines) and based on the

comprehensive and precise knowledge of prognostic and

predictive factors for outcome, morbidity, and quality of life (V,

A).

► Patients should be carefully counseled about the suggested

diagnostic and treatment plan and potential alternatives,

including risks and benets of all options (V, A).

► Treatment should be undertaken in a specialized center by a

dedicated team of specialists in the diagnosis and manage-

ment of gynecological cancers, especially in high- risk and/or

advanced stage disease (V, A).

IDENTIFICATION AND SURVEILLANCE OF WOMEN WITH A

PATHOGENIC GERMLINE VARIANT IN A LYNCH SYNDROME-

ASSOCIATED GENE

Approximately 3% of all endometrial carcinomas and about 10%

of mismatch repair decient (MMRd)/microsatellite unstable endo-

metrial carcinomas are causally related to germline mutations of

one of the MMR genes MLH1, PMS2, MSH2 and MSH6.

Testing

for MMR status/microsatellite instability (MSI) in endometrial carci-

noma patients has been shown to be relevant for four reasons: (1)

diagnostic, as MMRd/MSI is considered a marker for endometrioid-

type endometrial carcinoma; (2) pre- screening to identify patients at

higher risk for having Lynch syndrome; (3) prognostic, as identied

by The Cancer Genome Atlas (TCGA, see below for molecular clas-

sication); and (4) predictive for potential utility of immune check-

point inhibitor therapy. The International Society of Gynecological

Pathology (ISGyP) has recommended testing for MMR status/MSI in

all endometrial carcinoma samples, irrespective of age.

This has

also been recommended in other society statements and recom-

mendations, such as the Manchester International Consensus

Group recommendations, whenever resources are available.

The preferred approach (widely available and cost- effective) to

identifying patients with a higher chance of having Lynch syndrome

is by MMR- immunohistochemistry (IHC) on well preserved tumor

tissue. MMR- IHC is a reliable method to assess MMR status, and

in addition provides information on the altered gene/protein. ISGyP

guidelines therefore recommend MMR- IHC as the preferred test.

MMR- IHC consists of the assessment of the expression of four

MMR proteins (MLH1, PMS2, MSH6, and MSH2). A simplied two-

antibody (PMS2 and MSH6) approach has been proposed as a cost-

effective alternative.

11–13

This procedure still requires performing

MLH1 and MSH2 IHC in cases with any abnormal staining of PMS2

and/or MSH6. Molecular analyses for the microsatellite status

(MSI- test) are an alternative, but are more laborious, require non-

neoplastic tissue, are more expensive, and do not provide infor-

mation on the gene affected. For optimal pre- selection of patients

at risk for having Lynch syndrome, both approaches require the

analysis of MLH1 promoter methylation status in cases with loss of

MLH1/PMS2 expression. Testing for MMRd by IHC or MSI by PCR-

based methods does not allow direct identication of patients with

Lynch syndrome since MMRd/MSI is frequently due to sporadic

events such as bi- allelic somatic mutations or hypermethylation.

In the absence of hypermethylation, referral to genetic counseling

is recommended to evaluate the presence of a germline muta-

tion. When familial history is highly suspicious of Lynch syndrome,

genetic counseling is recommended independent of the MMR

status.

The cumulative incidences for cancer depend on the specic

mutation in women with Lynch sydrome. For endometrial carci-

noma, the cumulative incidences at 70 years are 34%, 51%,

49%, and 24% for MLH1, MSH2, MSH6, and PMS2 mutation

carriers, respectively, and for ovarian cancer 11%, 15%, 0%,

and 0%, respectively.

Furthermore, the age of cancer onset in

Lynch syndrome varies among specic mutated genes and types

of mutations.

Ryan et al suggest gynecological surveillance to

be appropriate from age 30 years for those with MSH2 mutations,

from age 35 years for those with nontruncating MLH1 mutations,

and from age 40 years for those with MSH6 and truncating MLH1

mutations. Women with heterozygous PMS2 mutations do not

warrant gynecological surveillance because their absolute risk of

gynecological cancer is very low. As part of a retrospective study,

Lachiewicz et al reported a risk of any occult malignancy during

prophylactic surgery for women with Lynch syndrome or heredi-

tary non- polyposis colorectal cancer to be up to 17%.

Thus, these

patients should be counseled about the risk of detection of gyneco-

logical cancer at prophylactic surgery.

Recommendations

► To identify patients with Lynch syndrome and triage for germline

mutational analysis, MMR IHC (plus analysis of MLH1 promotor

methylation status in case of immunohistochemical loss of

MLH1/PMS2 expression) or MSI tests should be performed in

all endometrial carcinomas, irrespective of histologic subtype

of the tumor (III, B).

► Endometrial carcinoma patients identied as having an

increased risk of Lynch syndrome should be offered genetic

counseling (III, B).

► Surveillance for endometrial carcinoma in Lynch syndrome

mutation carriers should in general start at the age of 35 years;

however, individual factors need to be taken into consideration

(tailored surveillance programs). The decision on the starting

age of surveillance should integrate knowledge on the specic

mutation and history of onset of events in the family (IV, B).

► Surveillance of the endometrium by annual transvaginal ultra-

sound (TVUS) and annual or biennial biopsy until hysterectomy

should be considered in all Lynch syndrome mutation carriers

(IV, B).

► Hysterectomy and bilateral salpingo- oophorectomy to prevent

endometrial and ovarian cancer should be performed at the

completion of childbearing and preferably before the age of

40 years. All the pros and cons of prophylactic surgery must

be discussed including the risk of occult gynecological cancer

detection at prophylactic surgery. Estrogen replacement

therapy should be suggested if bilateral salpingo- oophorectomy

is performed in pre- menopausal women (IV, B).

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Joint statement

MOLECULAR MARKERS FOR ENDOMETRIAL CARCINOMA

DIAGNOSIS AND AS DETERMINANTS FOR TREATMENT

DECISIONS

Different types of endometrial carcinoma have specic histolog-

ical and molecular features, precursor lesions and natural histo-

ries. Conventional pathologic analysis remains an important tool

for tumor stratication, but suffers from inter- observer varia-

tion. Different groups have applied a diagnostic algorithm using

three immunohistochemical markers (p53, MSH6 and PMS2)

and one molecular test (mutation analysis of the exonuclease

domain of POLE) to identify prognostic groups analogous to the

TCGA molecular- based classication.

17–21

The feasibility of this

approach was conrmed by a large number of publications that

have all consistently reported prognostic relevance particularly in

high- grade and high- risk tumors in several independent cohorts

and prospective clinical trials.

To apply this molecular classica-

tion, all these diagnostic tests need to be performed. Performing

one of the surrogate marker tests in isolation is insufcient, as a

combination of positive tests can occur in approximatively 5% of

all carcinomas. The diagnostic algorithm to classify these so- called

'multiple classiers' has been described recently.

23 24

In addition,

endometrial carcinoma should only be classied as POLE- mutated

(POLEmut) when pathogenic variants of POLE are identied in the

gene’s exonuclease domain.

25 26

This surrogate marker approach to the molecular- based classi-

cation has been demonstrated to be prognostically informative in

low-, intermediate-, and high- risk endometrial carcinoma. Smaller

studies showed that the molecular classication is also applicable

to non- endometrioid tumors including serous, clear cell, undiffer-

entiated carcinomas, and uterine carcinosarcomas. For adjuvant

treatment recommendations, the molecular classication seems to

be particularly relevant in the context of high- grade and/or high- risk

endometrial carcinomas. Application of the molecular classication

in high- grade and/or high- risk endometrial carcinomas shows that

there is a group of patients with an excellent prognosis—that is,

the POLEmut tumors—and a group with a poor prognosis—that is,

the p53- abnormal (p53abn) tumors. Endometrial carcinomas with

MMRd or non- specic molecular prole (NSMP) have an interme-

diate prognosis. However, the molecular surrogate is not perfect.

Immunohistochemical demonstration of p53abn is a good but not

perfect surrogate of TP53 mutation. Furthermore, a small propor-

tion of high copy number tumors do not show TP53 mutations. To

minimize these limitations, an integrated analysis combining tradi-

tional pathologic and molecular results seems ideal. In low- risk

endometrioid carcinomas, the molecular classication may not be

required.

27 28

The proposed molecular classication of endometrial carcinoma

is clinically feasible using a limited set of diagnostic tests. Using

this novel classication is encouraged. All diagnostic tests should

be performed in conjunction due to the occurrence of 'double clas-

siers'.

Clinical management may be particularly impacted by the

molecular classication in scenarios where adjuvant chemotherapy

is considered (high- grade/high- risk disease). Thus, these cases

should be prioritized when there is a lack of sufcient resources to

perform this classication on all endometrial carcinomas. If molec-

ular classication tools are not available, endometrial carcinoma

classication should be based on traditional pathologic features.

There is still room for other biomarkers that may be potentially

useful in the big group of low- grade endometrioid carcinoma with

NSMP, such as L1CAM expression or mutations in CTNNB1.

29–32

Recommendations

► Molecular classication is encouraged in all endometrial carci-

nomas, especially high- grade tumors (IV, B).

► POLE mutation analysis may be omitted in low- risk and

intermediate- risk endometrial carcinoma with low- grade

histology (IV, C).

DEFINITION OF PROGNOSTIC RISK GROUPS INTEGRATING

MOLECULAR MARKERS

There is overwhelming evidence that traditional pathologic features,

such as histopathologic type, grade, myometrial invasion, and

lymphovascular space invasion (LVSI), are important in assessing

prognosis, as recommended in the ISGyP guidelines.

Histopatho-

logic typing should be performed according to the WHO Classica-

tion of Tumors (5th edition).

A binary International Federation of

Gynecology and Obstetrics (FIGO) grading is recommended, which

considers grade 1 and grade 2 carcinomas as low- grade and grade

3 carcinomas as high- grade. For the assessment of myometrial

invasion, account needs to be taken of the endo- myometrial junc-

tion which is undulating.

Focal LVSI is dened by the presence

of a single focus around the tumor, substantial LVSI as multifocal

or diffuse arrangement of LVSI or the presence of tumor cells in

ve or more lymphovascular spaces. The molecular classication

adds another layer of information to the conventional morphologic

features and therefore should be integrated in the pathologic report.

Recommendations

► Histopathologic type, grade, myometrial invasion, and LVSI (no/

focal/substantial) should be recorded in all patients with endo-

metrial carcinoma (V, A).

► The denition of prognostic risk groups is presented in Table2

for both situations when molecular classication is known or

unknown.

PRE- AND INTRA-OPERATIVE WORK-UP

Risk group allocation on biopsy according to the WHO Classication

of Tumors (5th edition) and FIGO grading of endometrial carcinoma

is required for adequate planning of therapy.

Histopathologic

grade has prognostic relevance. A modied binary FIGO grading is

recommended lumping together grade 1 and grade 2 endometrioid

carcinomas as low- grade and grade 3 as high- grade.

Magnetic resonance imaging (MRI) techniques are highly specic

in the assessment of deep myometrial invasion, cervical stromal

involvement, and lymph node metastasis.

35–82

The diagnostic

performance of TVUS and MRI for detecting myometrial invasion

in endometrial carcinoma are quite similar.

39 44 56 83–88

Of note, pre-

operative ultrasound assessment of deep myometrial and cervical

stromal invasion in endometrial carcinoma is best performed by an

expert sonographer as, compared with gynecologists, they show

a greater degree of agreement with histopathology and greater

inter- observer reproducibility.

Positron emission tomography

(PET) scanning has an excellent specicity for the pre- operative

assessment of lymph node metastases in patients with endome-

trial carcinoma. Its moderate sensitivity for detecting lymph node

metastases during preo- perative staging probably reects the need

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Joint statement

for a sufcient number of neoplastic cells to induce

F- uoro-

2- deoxy- D- glucose hypermetabolism.

89–100

The usefulness of

maximal standardized uptake value in classifying patients into pre-

dened risk groups is limited.

101

A pre- operative CT scan has a

clinical utility in patients with endometrial carcinoma in detecting

metastatic disease.

102 103

Frozen section of endometrial biopsy material is obsolete.

Myometrial invasion should not be assessed by frozen section

because of poor reproducibility and agreement with denitive

parafn sections. Since sentinel node biopsy is increasingly used,

the need for intra- operative assessment of myometrial invasion has

become less important. Moreover, some of the biomarkers that have

been proposed require optimal management of the surgical spec-

imen with high quality pre- analytical issues such as appropriate

xation conditions. Performing frozen sections can lead to incor-

rect control of pre- analytical conditions, sometimes even leading

to incorrect assessment of LVSI due to artifactual displacement of

tumor cells into vascular spaces during processing. In addition, the

freezing of tissue before xation and further processing interferes

with an optimal pre- analytical procedure required for standardized

histopathologic diagnosis.

Recommendations

► Histopathologic tumor type and grade in endometrial biopsy is

required (IV, A).

► Pre- operative mandatory work- up includes: family history;

general assessment and inventory of co- morbidities; geriatric

assessment, if appropriate; clinical examination, including

pelvic examination; expert transvaginal or transrectal ultra-

sound or pelvic MRI (IV, C).

► Depending on clinical and pathologic risk, additional imaging

modalities (thoracic, abdominal and pelvic CT scan, MRI, PET

scan, or ultrasound) should be considered to assess ovarian,

nodal, peritoneal, and other sites of metastatic disease (IV, C).

Table 2 Denition of prognostic risk groups

Risk group Molecular classication unknown Molecular classication known*†

Low

► Stage IA endometrioid + low- grade‡ +

LVSI negative or focal

► Stage I–II POLEmut endometrial carcinoma,

no residual disease

► Stage IA MMRd/NSMP endometrioid

carcinoma + low- grade‡ + LVSI negative or focal

Intermediate

► Stage IB endometrioid + low- grade‡ +

LVSI negative or focal

► Stage IA endometrioid + high- grade‡ +

LVSI negative or focal

► Stage IA non- endometrioid (serous,

clear cell, undifferentiared carcinoma,

carcinosarcoma, mixed) without myometrial

invasion

► Stage IB MMRd/NSMP endometrioid

carcinoma + low- grade‡ + LVSI negative or focal

► Stage IA MMRd/NSMP endometrioid

carcinoma + high- grade‡ + LVSI negative or

focal

► Stage IA p53abn and/or non- endometrioid

(serous, clear cell, undifferentiated carcinoma,

carcinosarcoma, mixed) without myometrial

invasion

High–intermediate

► Stage I endometrioid + substantial LVSI

regardless of grade and depth of invasion

► Stage IB endometrioid high- grade‡

regardless of LVSI status

► Stage II

► Stage I MMRd/NSMP endometrioid

carcinoma + substantial LVSI regardless of grade

and depth of invasion

► Stage IB MMRd/NSMP endometrioid

carcinoma high- grade‡ regardless of LVSI status

► Stage II MMRd/NSMP endometrioid

carcinoma

High

► Stage III–IVA with no residual disease

► Stage I–IVA non- endometrioid (serous,

clear cell, undifferentiated carcinoma,

carcinosarcoma, mixed) with myometrial

invasion, and with no residual disease

► Stage III–IVA MMRd/NSMP endometrioid

carcinoma with no residual disease

► Stage I–IVA p53abn endometrial carcinoma

with myometrial invasion, with no residual

disease

► Stage I–IVA NSMP/MMRd serous,

undifferentiated carcinoma, carcinosarcoma with

myometrial invasion, with no residual disease

Advanced

metastatic

► Stage III–IVA with residual disease

► Stage IVB

► Stage III–IVA with residual disease of any

molecular type

► Stage IVB of any molecular type

*For stage III–IVA POLEmut endometrial carcinoma and stage I–IVA MMRd or NSMP clear cell carcinoma with myometrial invasion,

insufcient data are available to allocate these patients to a prognostic risk group in the molecular classication. Prospective registries are

recommended.

†See text on how to assign double classiers (eg, patients with both POLEmut and p53abn should be managed as POLEmut).

‡According to the binary FIGO grading, grade 1 and grade 2 carcinomas are considered as low- grade and grade 3 carcinomas are

considered as high- grade.

LVSI, lymphovascular space invasion; MMRd, mismatch repair decient; NSMP, non- specic molecular prole; p53abn, p53 abnormal;

POLEmut, polymerase- mutated.

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Joint statement

► Intra- operative frozen section is not encouraged for myometrial

invasion assessment because of poor reproducibility and inter-

ference with adequate pathologic processing (IV, A).

EARLY STAGE DISEASE

Surgical management of apparent stage I/II endometrial

carcinomas

Minimally invasive approach

Two randomized prospective studies comparing minimally invasive

with open surgeries showed similar survival with quicker recovery

with the minimally invasive approach.

104 105

More recently, pooled

analyses of randomized prospective studies including, notably, these

two studies and multiple retrospective and prospective studies also

support the use of minimally invasive surgery for patients including

those with high- risk endometrial carcinoma.

106–171

Recommendations

► Minimally invasive surgery is the preferred surgical approach,

including patients with high- risk endometrial carcinoma (I, A).

► Any intra- peritoneal tumor spillage, including tumor rupture or

morcellation (including in a bag), should be avoided (III, B).

► If vaginal extraction risks uterine rupture, other measures

should be taken (eg, mini- laparotomy, use of endobag) (III, B).

► Tumors with metastases outside the uterus and cervix

(excluding lymph node metastases) are relative contra-

indications for minimally invasive surgery (III, B).

Standard surgical procedures

In a randomized controlled trial comparing modied radical (Piver–

Rutledge class II) hysterectomy to the standard extrafascial (Piver–

Rutledge class I) or simple total hysterectomy in stage I endometrial

carcinoma, Signorelli et al showed no differences in locoregional

control and survival.

172

The high risk of microscopic omental metas-

tases in stage I serous and undifferentiated endometrial carcinoma

and in carcinosarcoma suggests that omentectomy should be part

of staging surgery in these patients.

173

The low rate of omental

metastases in apparent clinical stage I endometrioid and clear cell

carcinoma does not justify the procedure.

174

Although the risk of

having occult (microscopic) omental metastases in carcinosarcoma

is around 6%, staging omentectomy in these women is suggested.

Identication of these cases will allow inclusion of patients with

advanced stage disease into clinical trials.

175

Positive peritoneal

cytology correlates with poor prognostic factors and poor survival;

however, it is not part of FIGO staging and unclear if this should

inuence treatment decisions.

176–178

Recommendations

► Standard surgery is total hysterectomy with bilateral salpingo-

oophorectomy without vaginal cuff resection (II, A).

► Staging infracolic omentectomy should be performed in clinical

stage I serous endometrial carcinoma, carcinosarcoma, and

undifferentiated carcinoma. It can be omitted in clear cell and

endometrioid carcinoma in stage I disease (IV, B).

► Surgical re- staging can be considered in previously incom-

pletely staged patients with high– intermediate- risk/high- risk

disease if the outcome might have an implication for adjuvant

treatment strategy (IV, B).

Lymph node staging

Sentinel node biopsy has been introduced as an alternative to lymph

node dissection for lymph node staging and, if done according to

state- of- art principles, a negative sentinel node is accepted to

conrm pN0. Multiple studies, including prospective cohort ones,

conrmed high sensitivity of sentinel lymph node status for lymph

node staging in patients with early- stage endometrial carcinoma

and support the impact of sentinel lymph node biopsy on surgical

management and indications for adjuvant therapies.

179–241

intensive pathologic assessment of sentinel lymph node (sentinel

lymph node ultrastaging) supports the detection of small metas-

tases which could be missed by standard evaluation.

214 232

Sentinel

lymph node biopsy without dissection of other pelvic lymph nodes is

associated with subtantially lower risk of post- operative morbidity,

especially lower leg lymphedema.

242

In a large group of patients

with low- risk (myometrial invasion <50%, low- grade) endometrial

carcinoma with sentinel lymph node biopsy, lymph node involve-

ment was found in 6% of patients, half of them identied by patho-

logic ultrastaging.

243

Patients with tumors without myometrial inva-

sion did not have any positive sentinel lymph nodes. Four prospec-

tive cohort trials have shown high sensitivity to detect pelvic lymph

node metastases and a high negative predictive value by applying

a sentinel lymph node algorithm in high- risk/high- grade endome-

trial carcinomas in the hands of experienced surgeons.

181 182 237 244

Recently, a randomized controlled trial highlighted that the use

of indocyanine green instead of methylene blue dye resulted in

a signicant increase in sentinel lymph node detection rates per

hemipelvis in women with endometrial carcinoma undergoing mini-

mally invasive surgery.

245

Retrospective studies showed a similar

prognosis for patients after full lymphadenectomy and sentinel

lymph node biopsy only.

179 201 220

High bilateral pelvic sentinel

lymph node detection can be achieved when the tracer is injected

into the cervix.

180 246

A higher sentinel lymph node detection rate

has been reported using near- infrared uorescence in comparison

to other techniques.

247

A worse prognosis is associated with the

presence of nodal micrometastases, especially in patients who do

not receive adjuvant treatment.

248

There is no evidence that the

presence of isolated tumor cells (ITCs) has an impact on prognosis,

and similar to other tumor sites, the stage would be pN0(i+). If

pelvic lymph node involvement is reported either by sentinel lymph

node frozen section or by the nal pathology, para- aortic staging

can be considered, either by imaging (with all limitations of the

imaging modalities) or by surgery. It should be noted that, based on

data from two large randomized trials, lymph node staging does not

have a therapeutic value but is done to assess the extent of disease

and to provide information for adjuvant treatment decisions.

249 250

Frozen section on specimens regarded as sentinel lymph nodes

can conrm the presence of lymph nodes and macrometastases

but should not replace adequate pathologic processing and ultrast-

aging.

Recommendations

► Sentinel lymph node biopsy can be considered for staging

purposes in patients with low- risk/intermediate- risk disease. It

can be omitted in cases without myometrial invasion. System-

atic lymphadenectomy is not recommended in this group (II, A).

► Surgical lymph node staging should be performed in patients

with high–intermediate- risk/high- risk disease. Sentinel

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Joint statement

lymph node biopsy is an acceptable alternative to systematic

lymphadenectomy for lymph node staging in stage I/II (III, B).

► If sentinel lymph node biopsy is performed (II, A):

– Indocyanine green with cervical injection is the preferred

detection technique.

– Tracer re- injection is an option if sentinel lymph node is not

visualized upfront.

– Side- specic systematic lymphadenectomy should be per-

formed in high–intermediate- risk/high- risk patients if senti-

nel lymph node is not detected on either pelvic side.

– Pathologic ultrastaging of sentinel lymph nodes is

recommended.

► When a systematic lymphadenectomy is performed, pelvic and

para- aortic infrarenal lymph node dissection is suggested (III,

B).

► Presence of both macrometastases and micrometastases

(<2 mm, pN1(mi)) is regarded as a metastatic involvement (IV,

C).

► The prognostic signicance of ITCs, pN0(i+), is still uncertain

(IV, C).

► If pelvic lymph node involvement is found intra- operatively,

further systematic pelvic lymph node dissection should be

omitted. However, debulking of enlarged lymph nodes and

para- aortic staging can be considered (IV, B).

Option for ovarian preservation and salpingectomy in stage I/II

A meta- analysis showed that there was no signicant difference

in overall survival between patients treated with ovarian preser-

vation and bilateral salpingo- oophorectomy.

251

A similar result

was achieved in young and pre- menopausal women. Disease- free

survival of patients whose ovaries were preserved was slightly

compromised, but this was not statistically signicant. Ovarian

preservation can be cautiously considered in specic clinical situa-

tions when treating young and pre- menopausal women with early

stage endometrial carcinoma because it is not associated with a

signicant adverse impact on survival.

252–254

Salpingectomy during

hysterectomy is recommended to decrease the risk of high- grade

serous ovarian carcinoma.

255

Ovarian preservation is not recom-

mended in patients with cancer family history involving ovarian

cancer risk (eg, BRCA mutation, Lynch syndrome, etc), but oocyte

cryopreservation might be considered.

256

Recommendations

► Ovarian preservation can be considered in pre- menopausal

patients aged <45 years with low- grade endometrioid endo-

metrial carcinoma with myometrial invasion <50% and no

obvious ovarian or other extra- uterine disease (IV, A).

► In cases of ovarian preservation, salpingectomy is recom-

mended (IV, B).

► Ovarian preservation is not recommended for patients with

cancer family history involving ovarian cancer risk (eg, BRCA

mutation, Lynch syndrome, etc) (IV, B).

Radicality of surgery for clinical stage II

Radicality of hysterectomy (simple vs modied radical hysterec-

tomy (type II)) in stage I–III endometrial carcinoma has no impact

on local recurrence rate, disease- free survival, and overall survival.

In a meta- analysis enrolling 2866 patients with stage II endometrial

carcinoma, radical hysterectomy did not show a signicant survival

benet for either overall survival or progression- free survival

compared with simple hysterectomy.

257

The result remained

consistent after it was adjusted for the possible impact of adjuvant

radiotherapy.

Recommendations

► Total hysterectomy with bilateral salpingo- oophorectomy and

lymph node staging is the surgical standard of care in patients

with stage II endometrial carcinoma (IV, B).

► More extensive procedures should only be performed if required

to achieve free surgical margins (IV, B).

Medically unt patients

It is rare for patients to be unt for surgery, but medical co- morbidi-

ties, which increasingly include morbid obesity, can preclude surgery

due to high operative and peri- operative risks. Ideally, assessment

should be undertaken in a center with specialist anesthetic experi-

ence in managing these high- risk patients. Denitive radiotherapy

with brachytherapy, external beam radiation therapy (EBRT) or the

combination of both modalities can be considered.

258–262

Recommendations

► Medical contra- indications to the standard surgical manage-

ment by minimally invasive surgery are rare. Vaginal hyster-

ectomy, with bilateral salpingo- oophorectomy if feasible, can

be considered in patients unt for the recommended standard

surgical therapy (IV, C).

► Denitive radiotherapy can be considered for primary tumors

where surgery is contra- indicated for medical reasons:

– The combination of EBRT and brachytherapy should be used

for high- grade tumors and/or deep myometrial invasion (II,

B).

– For low- grade tumors, brachytherapy alone can be consid-

ered (II, B).

– In medically unt patients unsuitable for curative surgery or

radiotherapy, systemic treatment (including hormonal ther-

apy) can be considered (IV, B).

Fertility preservation

Work-up for fertility preservation treatments

Fertility- sparing treatments should be considered in patients with

atypical hyperplasia/endometrioid intra- epithelial neoplasia (AH/

EIN) or grade 1 endometrioid carcinoma without myometrial inva-

sion.

263–269

There are very few published data on patients with

stage IA grade 2 endometrioid carcinoma without myometrial

invasion who received fertility- sparing treatment with combined

oral medroxyprogesterone acetate/levonorgestrel intrauterine

system.

270

Although results are encouraging, this treatment should

only be considered by experienced gynecological oncologists using

well- dened protocols with detailed patient information and close

follow- up.

Hysteroscopic biopsy is suggested, based on its higher agree-

ment with the nal diagnosis compared with dilatation and curet-

tage.

271 272

Although hysteroscopy seems to be associated with a

higher rate of positive peritoneal cytology, it seems not to have a

negative impact on survival.

273

Expert vaginal ultrasound examina-

tion can be used instead of pelvic MRI. Its high diagnostic perfor-

mance allows the detection of myometrial invasion and cervical

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Joint statement

stromal invasion with respect to nal pathologic examination.

Ultrasound should be performed by an expert sonographer (a prac-

titioner who spends a signicant part of her/his time undertaking

ultrasound examinations in gynecology and gynecologic oncology

and has fullled the minimum training requirements for level 3

following the recommendations of the European Federation of Soci-

eties for Ultrasound in Medicine and Biology).

274

There is currently a lack of high- quality evidence regarding the

correlation between weight loss and reduction of risk of recurrence/

increased survival in patients with endometrial carcinoma, espe-

cially with respect to fertility- sparing treatment.

275

Diabetes mellitus

does not seem to affect the outcome of conservative treatment in

women with AH/EIN or early endometrial carcinoma.

276

Conversely,

the use of metformin seems associated with an improvement in

overall survival for patients with endometrial carcinoma and a

reduced risk of cancer relapse.

277

In addition, metformin is associ-

ated with improvement in the overall survival of patients with endo-

metrial carcinoma with diabetes.

Recommendations

► Patients who are candidates for fertility- preserving treatment

must be referred to specialized centers. Fertility- sparing treat-

ment should be considered only in patients with AH/EIN or

grade 1 endometrioid endometrial carcinoma without myome-

trial invasion and without genetic risk factors (V, A).

► In these patients, endometrial biopsy, preferably through

hysteroscopy, must be performed (III, A).

► AH/EIN or grade 1 endometrioid endometrial carcinoma must

be conrmed/diagnosed by a pathologist experienced in gyne-

cological pathology (V, A).

► Radiologic imaging to assess the extension of the disease must

be performed. An expert ultrasound examination can substitute

pelvic MRI scan (III, B).

► Patients must be informed that fertility- sparing treatment is

not a standard treatment. Only patients who strongly desire

to preserve fertility should be treated conservatively. Patients

must be willing to accept close follow- up and be informed of

the need for future hysterectomy in case of failure of treatment

and/or after pregnancies (V, A).

Management and follow-up for fertility preservation

To date, there are no available randomized controlled trials

comparing different methods of conservative treatment in women

with AH/EIN or presumed stage IA grade 1 endometrioid carci-

noma. Existing data suggest that patients who received hystero-

scopic resection followed by progestin therapy achieve the highest

complete remission rate compared with other existing fertility-

preserving treatments.

263–269 278–295

Intrauterine progestin therapy

such as levonorgestrel- releasing intrauterine system combined with

gonadotropin- release hormone receptor agonist/progestin have a

satisfactory pregnancy rate and low recurrence rate. Patients who

received oral progestin only might be more likely to recur and have

more systemic adverse effects.

Recommendations

► All patients should be evaluated before and after the fertility-

sparing treatment at a fertility clinic (IV, C).

► Hysteroscopic resection prior to progestin therapy can be

considered (III, B).

► Medroxyprogesterone acetate (400–600 mg/day) or megestrol

acetate (160–320 mg/day) is the recommended treatment.

Treatment with levonorgestrel intrauterine device in combina-

tion with oral progestins with or without gonadotropin- releasing

hormone analogs can also be considered (IV, B).

► In order to assess response, hysteroscopic guided biopsy

and imaging at 3–4 and 6 months must be performed. If no

response is achieved after 6 months, standard surgical treat-

ment is recommended (IV, B).

► Continuous hormonal treatment should be considered in

responders who wish to delay pregnancy (IV, B).

► Strict surveillance is recommended every 6 months with TVUS

and physical examination. During follow- up, hysteroscopic

and endometrial biopsy should be performed only in case of

abnormal uterine bleeding or atypical ultrasound ndings (IV,

B).

► Fertility- sparing treatment can be considered for intrauterine

recurrences only in highly selected cases under strict surveil-

lance (IV, C).

► Hysterectomy and bilateral salpingo- oophorectomy is recom-

mended after childbearing due to a high recurrence rate. Pres-

ervation of the ovaries can be considered depending on age

and genetic risk factors (IV, B).

Synchronous presentation of low-grade endometrioid

endometrial and ovarian carcinomas

Adnexal involvement by endometrial carcinoma is currently a

parameter important in FIGO staging and has an impact on overall

survival rate.

296

It was shown that patients with simultaneous

involvement of the endometrium and ovary by low- grade endo-

metrioid carcinoma had a favorable outcome. This suggested that

they were synchronous primary tumors rather than metastatic

sites. Several criteria have been used in the past to distinguish

between endometrial carcinoma with ovarian metastasis and

synchronous primary tumors.

297 298

However, these were not easy

to apply.

Recent studies have shown that, for low- grade endometrioid

carcinomas, there is a clonal relationship between endometrial and

ovarian carcinomas in the vast majority of cases, indicating that

the carcinoma arises in the endometrium and extends secondarily

to the ovary.

299 300

In the most recent edition of WHO (2020) it is

mentioned that patients with clonally related low- grade endome-

trioid carcinomas should be managed without adjuvant treatment

(as if they were two independent primaries) when fullling the

following criteria: (1) low- grade endometrioid morphology, (2) no

more than supercial myometrial invasion, (3) absence of LVSI, and

(4) absence of additional metastases.

33 301

Recommendation

► If all WHO 2020 criteria mentioned above are met and the

ovarian carcinoma is pT1a, no adjuvant treatment is recom-

mended (III, B).

ADJUVANT TREATMENT

Adjuvant treatment recommendations for endometrial carcinoma

strongly depend on the prognostic risk group (see Table 2 for

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Joint statement

denitions of the prognostic risk groups with and without known

molecular classication).

Low risk

For patients with low- risk endometrial carcinoma, no adjuvant treat-

ment is recommended based on data from multiple randomized

trials.

302–305

For patients with stage I–II POLEmut endometrial carci-

nomas, no adjuvant treatment seems justiable based on the data

from independent series showing very few recurrences and also

in cases of observation.

21 25

For stage III patients, however, there

are only indirect data to support this, as all cases with advanced

disease had adjuvant treatment. In the molecular analysis of the

PORTEC-3 trial of high- risk endometrial carcinoma, those with

POLEmut endometrioid carcinoma had an excellent outcome in both

arms.

However, both trial arms included EBRT. Prospective regis-

tration (preferably in national or international studies) of POLEmut

endometrial carcinoma cases with treatment and outcome data is

strongly recommended.

Recommendations

► For patients with low- risk endometrial carcinoma, no adjuvant

treatment is recommended (I, A).

► When molecular classication is known:

– For patients with endometrial carcinoma stage I–II, low- risk

based on pathogenic POLE- mutation, omission of adjuvant

treatment should be considered (III, A).

– For the rare patients with endometrial carcinoma stage

III–IVA and pathogenic POLE-mutation, there are no out-

come data with the omission of the adjuvant treatment.

Prospective registration is recommended (IV, C).

Intermediate risk

Adjuvant brachytherapy provides excellent vaginal control and

high survival rates, similar to those after adjuvant EBRT in this

intermediate- risk population, as shown in large randomized trials,

particularly the PORTEC-2 trial and Swedish trial.

306–314

It was also

shown that only the small minority of patients with higher risk

based on substantial LVSI, p53abn, or L1CAM overexpression had a

slightly higher risk of pelvic recurrence with vaginal brachytherapy

than those who had EBRT. Therefore, the intermediate- risk category

only includes those with none or only focal LVSI and no p53abn. In

a Danish population study it was conrmed that the risk of locore-

gional relapse was higher (about 14%) with omission of vaginal

brachytherapy, but that overall survival was not different due to

treatment of relapse.

315

Therefore, no adjuvant treatment is an

option in this group, especially for patients aged <60 years who

have a lower risk of relapse.

MMRd and, especially, NSMP cancers form the majority of

endometrioid carcinomas and have an intermediate prognosis, in

between POLEmut (excellent prognosis) and p53abn carcinomas

(unfavorable prognosis). Findings of prior large randomized trials

in high–intermediate- risk endometrial carcinoma are therefore

mainly applicable to MMRd and NSMP endometrioid carcinomas in

this intermediate- risk category.

It has to be stressed that p53abn carcinomas restricted to

a polyp or without myometrial invasion were not included in the

randomized trials and the value of chemotherapy and of EBRT are

uncertain. Since the studies mentioned above did not include and/

or did not address non- endometrioid (and/or p53abn) carcinomas

without myometrial invasion, there are very few specic available

data on the best treatment for stage IA non- endometrioid carci-

nomas (serous, clear cell, undifferentiated carcinoma, carcinosar-

coma, mixed) without myometrial invasion. Some case series and

a recent analysis using the US National Cancer Data Base suggest

that adjuvant chemotherapy (with or without vaginal brachytherapy)

might improve survival, while other reports showed good outcomes

with vaginal brachytherapy only.

306

Therefore, these carcinomas

have been grouped in the intermediate- risk category and adjuvant

therapy should be discussed on a case- by- case basis until more

prospective data are available.

Recommendations

► Adjuvant brachytherapy can be recommended to decrease

vaginal recurrence (I, A).

► Omission of adjuvant brachytherapy can be considered (III, C),

especially for patients aged <60 years (II, A).

► When molecular classication is known, POLEmut and p53abn

with myometrial invasion have specic recommendations (see

respective recommendations for low- and high- risk).

► For p53abn carcinomas restricted to a polyp or without myome-

trial invasion, adjuvant therapy is generally not recommended

(III, C).

High–intermediate risk (pN0 after lymph node staging)

The denition of high–intermediate risk has changed in compar-

ison with the ESMO- ESGO- ESTRO consensus conference. In the

current prognostic risk group classication (see Table2), stage IA

endometrioid carcinomas are only included if there is substantial

LVSI.

3–5

This high–intermediate- risk group also includes stage IB

low- grade endometrioid with substantial LVSI, and stage IB high-

grade endometrioid carcinomas regardless of LVSI, and stage II

endometrioid carcinomas. In view of the higher risk of recurrence

in this newly classied group (even with negative nodes), adjuvant

brachytherapy can be recommended to decrease vaginal recur-

rence. In the case of substantial LVSI and/or stage II, EBRT can be

considered as it has been shown to reduce the risk of pelvic and

para- aortic nodal relapse.

316

In two older randomized controlled trials

317 318

there was no

difference between adjuvant chemotherapy alone and EBRT

alone in recurrence- free and overall survival. In the NSGO/EORTC

trial and the PORTEC-3 trials, the combination of chemotherapy

and radiotherapy seemed to provide better recurrence- free and

overall survival outcomes respectively compared with radiotherapy

alone.

319 320

The GOG-249 trial did not nd benet in recurrence-

free or overall survival from three cycles of chemotherapy with

brachytherapy compared with EBRT alone.

316

Molecular analysis

of PORTEC-3 trial tissues suggested no benet of chemotherapy

for MMRd carcinomas.

320 321

Omission of adjuvant treatment is an

option and this should be considered only when close follow- up

is guaranteed to ensure detection and prompt treatment of recur-

rence at an early stage.

Recommendations

► Adjuvant brachytherapy can be recommended to decrease

vaginal recurrence (II, B).

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Joint statement

► EBRT can be considered for substantial LVSI and for stage II

(I, B).

► Adjuvant chemotherapy can be considered, especially for high-

grade and/or substantial LVSI (II, C).

► Omission of any adjuvant treatment is an option (IV, C).

► When molecular classication is known, POLEmut and p53abn

have specic recommendations (see respective recommenda-

tions for low- and high- risk).

High–intermediate risk cN0/pNx (lymph node staging not

performed)

In view of the recent randomized trials GOG-249 (for stage I and II

endometrial carcinomas with high- risk factors or serous or clear

cell histology), the PORTEC-3 trial and the older GOG-99 trial, adju-

vant EBRT is recommended in case of substantial LVSI or stage

II.

302 316 319 320 322

Additional chemotherapy can be considered, espe-

cially for high- grade carcinomas, based on the PORTEC-3 trial, but

the question remains whether the benet outweighs the toxicity for

stage I–II endometrioid carcinomas, and multi- disciplinary shared

decision- making is needed.

320

Molecular analysis of PORTEC-3 trial

tissues suggested no benet of chemotherapy for MMRd carci-

nomas.

320 321

Adjuvant brachytherapy alone can be considered for

LVSI negative cases and for stage II grade 1 disease.

Recommendations

► Adjuvant EBRT is recommended, especially for substantial LVSI

and/or for stage II (I, A).

► Additional adjuvant chemotherapy can be considered, espe-

cially for high- grade and/or substantial LVSI (II, B).

► Adjuvant brachytherapy alone can be considered for high- grade

LVSI negative and for stage II grade 1 endometrioid carcinomas

(II, B).

► When molecular classication is known, POLEmut and p53abn

have specic recommendations (see respective recommenda-

tions for low- and high- risk).

High risk

The risk category changes also have a substantial impact on this

category. Some carcinomas designated as high risk in the ESMO-

ESGO- ESTRO consensus conference are not included anymore in

the high- risk sub- group in these ESGO- ESTRO- ESP guidelines.

3–5

High- risk carcinomas are now either stage III–IVA without residual

disease or stage I–IVA p53abn or non- endometrioid carcinomas

without residual disease with myometrial invasion (for specics see

Table2).

In 2019 the updated results of the PORTEC-3 trial, with a longer

median follow- up of 72 months and with 75% of participants

having reached 5 years of follow- up, were published.

323

In this

trial comparing combined chemotherapy and radiotherapy (two

cycles of cisplatin during radiotherapy followed by four cycles

of carboplatin- paclitaxel) with radiotherapy alone, a statistically

signicant 5% overall survival benet at 5 years and a 7% failure-

free survival benet was seen in the combined therapy group

compared with radiotherapy alone. The greatest overall survival

difference was seen in stage III carcinomas and in serous carci-

nomas regardless of stage. The GOG-258 trial compared the same

chemotherapy- radiotherapy schedule used in PORTEC-3 with six

cycles of carboplatin- paclitaxel chemotherapy alone and found

overlapping relapse- free and overall survival rates.

324

However, the

chemotherapy alone arm had signicantly higher rates of pelvic

and peri- aortic nodal relapse. Therefore, chemotherapy alone is

an alternative option based on the GOG-258 results for stage III–

IV disease. The nal analysis of the GOG-249 trial highlighted that

a post- operative adjuvant strategy of vaginal cuff brachytherapy

followed by three cycles of paclitaxel and carboplatin chemotherapy

did not signicantly increase 5- year recurrence- free survival or

5- year overall survival compared with pelvic radiotherapy.

325

Vaginal and distant recurrence rates were similar between arms.

However, pelvic or para- aortic nodal recurrences were signicantly

less common with pelvic radiotherapy. The older pooled analysis

of the NSGO- EORTC and MANGO- ILIADE trials used sequential

chemotherapy and radiotherapy (either sequence) and reported

signicantly longer recurrence- free survival compared with radio-

therapy alone.

319

Multiple retrospective studies indicated a survival

benet in patients with advanced stage endometrial carcinoma

treated with post- operative combined treatment including radio-

therapy and chemotherapy, delivered by either the sandwich or

sequential method, compared with radiotherapy alone or chemo-

therapy alone.

326–344

The benet of added chemotherapy is unclear for patients with

stage I–II clear cell carcinomas. These have often been included

with serous as 'non- endometrioid carcinomas'. Of note, in the

PORTEC-3 trial it was specically in those with serous histology

that a signicant benet of added chemotherapy was seen.

323

However, this was not observed in the NSGO- EORTC and MANGO-

ILEADE trials. Extended eld radiotherapy is used in the case of

involved para- aortic nodes or involvement of high common iliac

nodes, both with or without chemotherapy. The combination of

extended eld radiotherapy with chemotherapy using modern

intensity- modulated radiation therapy/volumetric modulated arc

therapy (IMRT/VMAT) techniques has been shown feasible in the

PORTEC-3 and GOG-258 trials. An additional brachytherapy boost

can be considered, especially for substantial LVSI, endocervical

stromal invasion, and/or stage IIIB–IIIC.

MMRd and NSMP carcinomas are included in the high- risk cate-

gory if stage III–IVA with no residual disease. The p53abn carci-

nomas can be of endometrioid, serous, undifferentiated, and clear

cell histologic type, but all consistently show a poor outcome and

should therefore be regarded as high risk. Based on the current

data, it is more difcult to draw conclusions regarding carcino-

sarcomas and undifferentiated carcinomas that are NSMP endo-

metrial carcinomas due to the lack of large series. For clear cell

carcinomas, the available data suggest some prognostic infor-

mation may lie in the molecular classication. About 40–50% of

clear cell carcinomas are p53abn. While serous carcinomas in the

PORTEC-3 trial had an unfavorable outcome and signicant benet

of added adjuvant chemotherapy, those with clear cell carcinomas

seemed to have an outcome similar to high- grade carcinomas in

general and were more favorable if not p53abn.

321 323

The ndings

of the randomized trials for endometrioid carcinomas cited above

are therefore largely applicable to stage III MMRd and NSMP carci-

nomas and to stage I–III p53abn carcinomas. This was also seen

in the molecular analysis of the PORTEC-3 trial, which showed a

statistically signicant survival advantage for p53abn carcinomas

with combined therapy for stage I–III. In contrast, POLEmut carci-

nomas had almost no recurrences in both arms. There was no clear

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Joint statement

benet of added chemotherapy for MMRd, while the NSMP carci-

nomas had some benet of added chemotherapy especially in case

of stage III. Prospective evaluation of the molecular characteristics

in randomized trials is highly recommended.

Recommendations

► EBRT with concurrent and adjuvant chemotherapy (I, A) or

alternatively sequential chemotherapy and radiotherapy is

recommended (I, B).

► Chemotherapy alone is an alternative option (I, B).

► Carcinosarcomas should be treated as high- risk carcinomas

(not as sarcomas) (IV, B).

► When the molecular classication is known, p53abn carci-

nomas without myometrial invasion and POLEmut have specic

recommendations (see respective recommendations for low-

and intermediate- risk) (III, C).

ADVANCED DISEASE

Surgery for clinically overt stage III and IV disease

In stage III and IV endometrial carcinoma (including carcinosarcoma),

maximal cytoreduction should be considered only if macroscopic

complete resection is feasible with acceptable morbidity.

345–350

Surgery should be performed in a specialized center. Pre- operative

complete staging and multi- disciplinary discussion within a tumor

board should be performed. Suspicious enlarged lymph nodes

should be resected if complete resection is possible.

351 352

A full

systematic pelvic and para- aortic lymphadenectomy of non-

suspicious lymph nodes should not be performed because there

is no evidence of a therapeutic impact. If upfront surgery is not

feasible or acceptable and therefore primary systemic therapy is

given, delayed surgery can be considered in case of a meaningful

response to chemotherapy.

353–360

Recommendations

► In stage III and IV endometrial carcinoma (including carcino-

sarcoma), surgical tumor debulking including enlarged lymph

nodes should be considered when complete macroscopic

resection is feasible with an acceptable morbidity and quality of

life prole, following full pre- operative staging and discussion

by a multi- disciplinary team (IV, B).

► Primary systemic therapy should be used if upfront surgery is

not feasible or acceptable (IV, A).

► In cases of a good response to systemic therapy, delayed

surgery can be considered (IV, C).

► Only enlarged lymph nodes should be resected. Systematic

lymphadenectomy is not recommended (IV, B).

Unresectable primary tumor due to local extent of disease

For patients presenting with unresectable locally advanced disease

and no evidence of multiple distant metastases, treatment options

include denitive radiotherapy or neoadjuvant chemotherapy

followed by surgery or denitive radiotherapy, depending on

response.

261 354–356 361

Denitive radiotherapy comprises EBRT to

the pelvis followed by image- guided brachytherapy. Concurrent

chemotherapy may be considered to enhance the radiation effect.

Brachytherapy should boost sites of macroscopic disease in the

uterus, parametrium, or vagina using the ESTRO principles. Adju-

vant chemotherapy should also be considered following primary

local treatment (surgery or radiotherapy) to reduce the risk of

distant metastases.

Recommendations

► For unresectable tumors, multi- disciplinary team discussion

should consider denitive radiotherapy with EBRT and intra-

uterine brachytherapy, or neoadjuvant chemotherapy prior

to surgical resection or denitive radiotherapy, depending on

response (IV, C).

► Image- guided brachytherapy is recommended to boost intrau-

terine, parametrial, or vaginal disease (IV, A).

► Chemotherapy should be considered after denitive radio-

therapy (IV, B).

Residual pelvic or para-aortic lymph nodes following surgery

Residual lymph node disease can be treated with EBRT using an

integrated or sequential boost to escalate the nodal dose. An IMRT

technique reduces the risk of toxicity to surrounding tissue.

362

Adjuvant chemotherapy reduces the risk of distant metastases for

patients with lymph node involvement.

320 323 324

Recommendations

► Residual lymph node disease should be treated with a combi-

nation of chemotherapy and EBRT (III, B) or chemotherapy

alone (IV, B).

► EBRT should be delivered to pelvis and para- aortic nodes

with dose escalation to involved nodes using an integrated or

sequential boost (IV, B).

Residual pelvic disease (positive resection margin, vaginal

disease, pelvic side wall disease)

Patients with residual pelvic disease following surgery have a high

risk of both local and distant recurrence. Radiotherapy can achieve

long- term local control while chemotherapy reduces the risk of

distant metastases. An individualized approach with either (chemo)-

radiotherapy to the pelvis followed by chemotherapy or adjuvant

chemotherapy followed by radiotherapy to the pelvis±para- aortic

nodes should be considered.

Recommendation

► An individualized approach with either radiotherapy or chemo-

therapy or a combination of both modalities should be consid-

ered by a multi- disciplinary team (V, B).

RECURRENT DISEASE

Radiotherapy naïve patients

Treatment of patients with recurrent endometrial carcinoma

involves a multi- disciplinary approach with surgery, radiotherapy,

and/or systemic therapy depending on the tness and wishes of

the patient, the tumor dissemination patterns, and prior treatment.

A decision about surgery needs to take account of patient morbidity

and wishes, available non- surgical treatments, and resources. The

interval between primary treatment and recurrence should also be

taken into consideration. Patients with recurrent disease, including

resectable peritoneal and lymph node relapse, should be consid-

ered for surgery only if it is anticipated that complete resection of

macroscopic disease can be achieved with a reasonable morbidity

prole.

363–369

The extent of the operation will depend on the degree

of tumor dissemination pattern.

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Joint statement

Locoregional recurrence of endometrial carcinoma is rare. With

the advent of modern image- guided radiation therapy, including

IMRT and image- guided adaptive brachytherapy, radiotherapy

has become the treatment of choice in previously non- irradiated

patients with isolated vaginal recurrence or locoregional recur-

rence.

363 364 370–379

Consideration should be given to remove solitary

easily accessible vaginal relapses, for better local symptom control

prior to radiotherapy.

Recommendations

► Patients with recurrent disease (including peritoneal and lymph

node relapse) should be considered for surgery only if it is

anticipated that complete removal of macroscopic disease can

be achieved with acceptable morbidity. Systemic and/or radia-

tion therapy should be considered post- operatively depending

on the extent and pattern of relapse and the amount of residual

disease (IV, C).

► In selected cases, palliative surgery can be performed to alle-

viate symptoms (eg, bleeding, stula, bowel obstruction) (IV, B).

► For locoregional recurrence, the preferred primary therapy

should be EBRT±chemotherapy with brachytherapy (IV, A).

► An easily accessable supercial vaginal tumor can be resected

vaginally prior to radiotherapy (IV, C).

► For vaginal cuff recurrence:

– Pelvic EBRT+intracavitary (±interstitial) image- guided

brachytherapy is recommended (IV, A).

– In case of supercial tumors, intracavitary brachytherapy

alone can be considered (IV, A).

► Systemic treatment can be considered before or after radio-

therapy (IV, C).

Radiotherapy pre-treated patients with locoregional

recurrence

In patients who have previously received EBRT±brachytherapy,

radical surgery with the intention of complete resection with clear

margins should be considered in specialized centers after ruling out

metastatic disease with modern imaging. Pelvic exenteration may

be considered for central local relapse.

349 380 381

Otherwise, further

radiation should be considered as radical therapy with or without

systemic therapy. Interstitial brachytherapy (low- dose rate or high-

dose rate) as the sole modality of treatment or combined with EBRT

can result in high local control over 1–5 years.

374

375 382 383

Other

techniques like permanent seed implant or post- operative elec-

tron irradiation, protons and stereotactic body radiotherapy may be

recommended in highly selected patients.

384–386

The appropriate

dose for each case needs to be individualized. Some low- dose rate

data suggest improved outcomes with doses >50 Gy. The high- dose

rate data are more varied, suggesting improved local control with

doses >40 Gy. In general, a longer time interval between the rst

and second course of radiation as well as recurrences <2–4 cm

tend to have improved outcomes. Multi- disciplinary management is

critical to develop individualized plans and to clearly communicate

potential side effects and expected treatment outcomes.

Recommendations

► In patients with a history of previous radiation, radical surgery,

including exenteration, should be considered when the inten-

tion is complete resection with clear margins (IV, B).

► Additional options to consider include intra- operative electron

radiation therapy or other forms of radiation therapy (IV, C).

► If surgery is not feasible, radical re- irradiation options include

stereotactic body radiotherapy targeting the recurrence,

permanent seed implants, or proton therapy. In selected cases,

limited volume re- irradiation with EBRT and brachytherapy

boost may be an option (especially if longer interval from the

rst irradiation) (IV, C).

► In patients who only had previous brachytherapy,

EBRT+brachytherapy boost is recommended (IV, C).

► In patients where re- irradiation with ERBT is not an option,

image- guided interstitial brachytherapy only is recommended

(may improve outcome) (IV, C).

Oligometastatic recurrent disease

Oligometastases is a disease concept that is dened by a state of

limited metastatic tumors for which local ablative therapy could be

curative. It refers in general to cancer patients with 1–5 metastases

or recurrences.

387–389

In recent years the concept of oligometastatic

relapse has evolved and has led to a change in the approach to

treatment. A prolonged disease- free interval and perhaps even cure

may be achieved in some situations where the primary cancer site

(if still present) is controlled and metastatic sites are ablated (surgi-

cally or with radiation).

390–393

Multi- disciplinary management is

critical to develop individualized plans and to communicate poten-

tial side effects and expected treatment outcomes. The additional

benet of chemotherapy is uncertain.

Recommendations

► Patients with oligometastatic disease should be considered for

radical local therapy (IV, B).

► Treatment options include (IV, B):

– Surgery

– Radiation therapy including stereotactic radiotherapy

– Local ablating techniques

► The additional benet of chemotherapy is uncertain (IV, B).

Systemic treatment for recurrent disease

Hormonal treatment results in a response rate of up to 55% in

advanced/recurrent endometrial carcinoma.

394

Low- grade, slowly

progressing, hormone receptor- positive tumors appear to gain

the greatest benet from treatment; however, clinical benet has

also been observed in patients with hormone receptor- negative

tumors.

395

Progestogens are generally recommended.

395

Alterna-

tive options include aromatases inhibitors, tamoxifen, and fulves-

trant. In the PARAGON trial a response rate of 7% and a clinical

benet rate of 44% was reported with anastrazole in a cohort of

82 patients with recurrent, receptor positive, endometrial carci-

noma.

396

A single- arm phase II trial demonstrated a high response

rate and clinical benet rate with the combination of letrozole and

everolimus.

397

Conrmation of hormone receptor status by biopsy

should be considered at the time of recurrence because of a poten-

tial change in hormone receptor expression between primary tumor

and recurrence. In patients undergoing hormonal therapy, the risk

of thrombo- embolic events needs to be taken into account. Proph-

ylaxis with low molecular weight heparin should be considered in

patients at high risk for thrombosis and be given according to local

guidelines. There are no universally agreed recommendations to

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Joint statement

predict a response to hormonal therapy in endometrial carcinoma

based on estrogen and progesterone receptor immunohistochem-

ical status. Some of the following should be taken into account:

(1) a wide range of hormonal agents are used, including medroxy-

progesterone acetate and synthetic progestational agents, lutein-

izing hormone releasing hormone antagonists, tamoxifen, and new

generations of selective estrogen receptor modulators; each has a

different molecular action and may therefore have different activity;

(2) receptor- negative status is not an absolute contra- indication to

hormone treatment; (3) in some reports, response rates to various

hormonal treatments for patients with endometrial carcinoma are

higher for those with progesterone receptor expression; (4) the

methodology for assessing and scoring hormone receptor expres-

sion in endometrial carcinoma is variable in the reported series;

(5) assessment of estrogen and progesterone receptor status in

the primary tumor may not reect the status in the recurrent or

metastatic tumor and thus a biopsy of recurrent or metastatic carci-

nomas for hormone receptor analysis may be helpful; (6) from a

pragmatic viewpoint, it seems reasonable to interpret a carcinoma

as receptor positive when immunoreactivity for estrogen receptor

or progesterone receptors is found in more than 1% of carcinoma

cells, until stronger validated scientic evidence is provided.

The combination of carboplatin and paclitaxel is the standard

chemotherapy treatment of advanced/recurrent endometrial carci-

noma based on a randomized phase 3 trial comparing carboplatin-

paclitaxel versus carboplatin- paclitaxel- anthracyclines that

reported overlapping progression- free survival and overall survival

between the two arms but an increased toxicity for the triple combi-

nation.

398

No standard treatment has been identied as second- line

therapy; a response rate of about 10–15% has been seen among

all the available treatment options. Thus, enrollment of patients in

clinical trials is strongly encouraged. Weekly paclitaxel and anthra-

cyclines (including pegylated liposomal doxorubicin when available)

are considered to be active drugs. The re- introduction of carbo-

platin may be considered after a prolonged interval from the last

platinum treatment, based on the results of a single- center retro-

spective series in patients treated with a median platinum- free

interval of 25 (8–79) months. A response rate of 50% and median

progression- free and median overall survival of 10 and 27 months,

respectively, was reported after platinum re- challenge.

399

Several anti PD-1 and anti PD- L1 checkpoint inhibitors have

been shown to have activity in endometrial carcinoma and thus far

pembrolizumab has been approved by the Food and Drug Admin-

istration (FDA) based on the results of a phase 2 single arm trial

for the treatment of MSI- high (MSI- H)/MMRd solid tumors that

have progressed on conventional therapy.

400 401

The combination of

intravenous pembrolizumab and lenvatinib, an oral multi- receptor

tyrosine kinase inhibitor, received FDA approval in October 2019

for the second- line systemic therapy of microsatellite- stable (ie,

non- MSI- H/MMRd) endometrial carcinoma based on the results

of a phase 2 single- arm trial reporting 36% response rate in this

population, including signicant activity in those with serous carci-

noma.

402 403

No phase 3 randomized data are yet available.

Approximately 30% of uterine serous carcinomas show HER2/

neu over- expression. A small randomized phase 2 trial of paclitaxel

and carboplatin with or without trastuzumab in HER2/neu positive

disease showed a 4.6 month increase in median progression- free

survival.

404

Anti- angiogenic agents and PI3kinase/mTor and MEK

inhibitors also have demonstrated activity but secure evidence of

benet is inconclusive due to the limited sample size of the trials,

inconsistency of results, and the low therapeutic index of the drugs,

suggesting further investigations in well- designed and properly

powered molecularly driven randomized trials are warranted.

405–416

Recommendations

► Hormone therapy is the preferred front- line systemic therapy

for patients with low- grade carcinomas without rapidly

progressive disease (II, A).

► Progestogens (medroxyprogesterone acetate 200 (–300) mg

and megestrol acetate 160 mg) are recommended (III, A).

► Alternative options for hormonal therapies include aromatases

inhibitors, tamoxifen, fulvestrant (III, C).

► The standard chemotherapy treatment is carboplatin AUC 5–6

+ paclitaxel 175 mg/m

every 21 days for six cycles (I, A).

► There is no standard of care for second- line chemotherapy.

Doxorubicin and paclitaxel are considered the most active ther-

apies (IV, C).

► In patients with a long platinum- free interval, re- introduction of

platinum can be considered (IV, C).

► Anti- PD1- based immune therapy with pembrolizumab could be

considered for second- line therapy of MSI/MMRd carcinomas.

The combination of pembrolizumab and the multi- tyrosine-

kinase inhibitor lenvatinib could be considered for second- line

treatment of microsatellite- stable carcinomas (III, B). However,

its use may be limited due to regulatory approvals or reim-

bursement in different countries. Clinical trial participation

should be offered to all patients with relapse disease (V, B).

Palliative radiotherapy

Historically, radiotherapy has been an efcient treatment to palliate

bleeding and pain from pelvic disease or systemic metastases. This

results in rapid pain relief and temporary cessation of bleeding in

the majority of patients.

417

Recommendations

► Radiotherapy is indicated for palliation of symptoms related to

pelvic or systemic disease (IV, A).

► Hypofractionated small volume EBRT can be used for treating

primary disease in patients not t for radical treatment (IV, B).

PRINCIPLES OF RADIOTHERAPY

The following sections present the general principles, the princi-

ples of adjuvant radiotherapy, of denitive treatment, and of radio-

therapy for recurrent disease.

258–261 307 362 372 377 418–423

General principles

State- of- art techniques and radiotherapy dose are chosen based on

clinical ndings, pathology, and patient factors including co- mor-

bidities. For complex treatments or rare cases, referral to a special-

ized center is recommended. Prospective assessment of toxicity is

recommended. Patients should have counseling on pelvic care and

general and sexual rehabilitation whenever appropriate.

Adjuvant radiotherapy

Radiotherapy should preferably commence within 6 (–8) weeks of

surgery or be scheduled in relation to chemotherapy.

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Joint statement

EBRT

IMRT/VMAT techniques are recommended because the more

conformal dose distribution increases normal tissue- sparing

compared with a four- eld conventional or 3D- conformal plan.

424

The clinical target volume (CTV) includes the pelvic nodes (external

iliac, internal iliac, obturator, distal common iliac), parametria, and

upper vagina. The upper common iliac and sub- aortic pre- sacral

lymph nodes are included when there is cervical stromal involve-

ment and/or pelvic lymph node involvement. The lymph node

target volume may be extended to include the aortic bifurcation or

para- aortic nodes, up to or just above the level of the renal vessels,

depending on the location and number of positive lymph nodes, site

of sentinel lymph nodes, and whether there is extrauterine primary

tumor involvement. The CTV should be individualized when there

is a positive resection margin, pelvic peritoneal disease, or vaginal

involvement. Treatment with a comfortably full bladder reduces

the volume of irradiated small bowel and bladder. The planning

target volume (PTV) should account for potential internal motion,

depending on the method of verication used during the course

of treatment. Image- guided radiotherapy by repeated volumetric

imaging with cone beam CT (and use of so- called library of plans

or plan of the day techniques) may enable the use of smaller CTV-

PTV margins to reduce normal tissue toxicity. The prescription

dose is commonly 45–50.4 Gy in 25–28 fractions over 5–6 weeks.

An integrated or sequential EBRT boost is given to residual lymph

node disease, sites of extracapsular nodal spread, and positive

lateral resection margins with a total dose of 55–60 Gy EQD2

for microscopic residual disease, or up to 66 Gy for macroscopic/

bulky disease. Concurrent and adjuvant chemotherapy may be

considered for stage III disease, serous histology and/or recurrent

disease.

Vaginal brachytherapy

Vaginal examination is undertaken to ensure the vaginal cuff is

healed and to assess the size and shape of the vagina to guide

applicator selection. Usually a vaginal cylinder is used but other

applicators can be used, depending on patient anatomy. The target

volume is individually determined and is usually the upper third of

the vagina to a depth of 5 mm (both superiorly and halfway along

the active length). The high- dose rate brachytherapy dose is most

commonly 21–24 Gy in 3–4 fractions to 0.5 cm from the applicator

surface, or 8–11 Gy in 2–3 fractions when given as a boost following

EBRT. A higher dose is required for treatment of residual disease

or positive margins. Pulsed- dose rate brachytherapy can be used

following EBRT to boost macroscopic residual disease witha dose

of 15–25 Gy. The treatment planning options are to use a standard

library plan for each applicator size and treatment length or to use

image- guided adaptive brachytherapy. In institutions where image-

guided adaptive brachytherapy is applied, imaging of the applicator

with CT scan or MRI evaluates whether the applicator is in close

apposition to the vaginal mucosa and close to organs at risk. This

allows verication and calculation of cumulative doses, especially if

vaginal brachytherapy is used as a boost after EBRT. Image- guided

adaptive brachytherapy is strongly recommended when there is

residual vaginal disease following surgery using similar principles

to treatment for recurrent disease.

Denitive treatment

Denitive radiotherapy with EBRT, brachytherapy, or a combination

of both is indicated for primary tumors where surgery is contra-

indicated for medical reasons. If patients are medically unt for

surgery, consider whether a long course of EBRT would be toler-

ated or, if not, a more hypofractionated approach could be used.

Intrauterine brachytherapy as a sole treatment modality is used for

low- grade early stage disease whereas the combination of EBRT

and intra- cavitary brachytherapy is recommended for high- grade

tumors and/or deep myometrial invasion. Specialist anesthetic

review may be required to assess suitability for brachytherapy or

whether brachytherapy could be applied with local anesthesia only.

More advanced inoperable disease is treated with a combination of

pelvic EBRT and intrauterine brachytherapy with or without concur-

rent platinum- based chemotherapy. EBRT is planned with at least

three- dimensional (3D) conformal radiotherapy to ensure inclusion

of the whole uterus. The preferred technique is intensity- modulated

radiotherapy with adaptive image guidance to verify target volume

coverage and to maximize normal tissue sparing. A highly conformal

EBRT boost (with IMRT or stereotactic body radiotherapy) can be

used to escalate the total dose to the tumor site in the uterus to at

least 65 Gy if brachytherapy is not feasible.

Image- guided adaptive brachytherapy is recommended, prefer-

ably using MRI at the time of brachytherapy, in order to optimize

tumor coverage and organ at risk doses. The brachytherapy appli-

cator should consist of an intrauterine applicator (preferably a

dedicated applicator with multiple channels for the larger uterus)

and a vaginal component depending on the extent of any extra-

uterine disease. Interstitial applications may be required to achieve

adequate coverage. In view of the rarity of denitive treatment for

endometrial carcinoma, referral to a dedicated center is recom-

mended. The tumor- related target volumes include the (residual)

gross tumor volume on MRI (GTV- res) and the CTV is the whole

uterus and any extrauterine sites of extension before EBRT. The

treatment plan aims include a total dose (EQD2

) of at least 80 Gy

to GTV- res, CTV D90 of about 48 Gy with brachytherapy alone, and

60–65 Gy with the combination of EBRT and brachytherapy.

Recurrent disease

Radiotherapy treatment for recurrent endometrial carcinoma

depends on the site of disease and any previous treatment. It

involves EBRT, brachytherapy, or a combination of both modalities.

Concurrent or sequential chemotherapy may also be considered.

Radiation-naïve or previous brachytherapy only

Pelvic EBRT is used according to the guidelines above. Brachytherapy

is used to boost recurrent disease in the vagina; in selected cases

with supercial tumors brachytherapy alone can be considered. The

brachytherapy applicator options include a vaginal cylinder or mold

for supercial lesions whereas interstitial applicators can be used

for bulkier tumors.

Image- guided adaptive brachytherapy is recommended, prefer-

ably using MRI at the time of brachytherapy, in order to optimize

tumor coverage and organ at risk doses. When image- guided adap-

tive brachytherapy is used, the target volumes should be contoured

according to the recent GEC- ESTRO recommendation for primary

vaginal cancer, aiming for a total dose (EQD2

) of 80–85 Gy

to CTV D90 with the combination of EBRT and image- guided

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Joint statement

brachytherapy.

422

If brachytherapy is not feasible due to tumor

location or topography, a sequential EBRT boost with conformal

radiotherapy, IMRT, or stereotactic body radiotherapy is used to

deliver a total GTV dose of at least 65 Gy EQD2

Re-irradiation

Re- irradiation is individualized according to the extent of disease,

previous radiation elds, and time elapsed from the previous treat-

ment. In general, recurrences with a longer disease- free interval

as well as recurrences less than 2–4 cm tend to have improved

outcomes. Ideally, this should be done in specialist centers with

prospective collection of dosimetric and clinical data. The most

common re- irradiation technique is intracavitary- interstitial

brachytherapy, preferably image- guided with CT scan or MRI.

421

However, in selected cases EBRT, stereotactic body radiotherapy,

proton or carbon ion therapy is an option, particularly for pelvic side-

wall or lymph node disease. Organ at risk dose constraints should

take into account prior radiotherapy treatment to derive cumulative

doses. Some low- dose rate data suggest improved outcomes with

doses more than 50 Gy. The high- dose rate data are more varied

with some studies suggesting improved local control with doses

more than 40 Gy EQD2

PRINCIPLES OF PATHOLOGIC EVALUATION

The following sections present the requirements for specimens

submitted for pathologic evaluation including specimen grossing

and sampling, for the pathology report, and the molecular classi-

cation.

19 21 23 26 425 426

The sections are proposed in agreement with

the recently published recommendations from the ISGyP and Inter-

national Collaboration on Cancer Reporting, and WHO Classication

of Tumors (5th edition).

9 33 427–429

Requirements for specimens submitted for pathologic

evaluation

Patient information, previous cytology, histologic specimens, clinical

and radiological data need to be included on the specimen request

form, particularly if there is no electronic patient le. This needs to

provide itemised details of biopsy and surgical specimen (type of

hysterectomy, presence of ovaries and fallopian tubes, presence of

lymph nodes, and designation of lymph node sites). Biopsies should

be sent to the pathology department in a container with liquid xa-

tive (10% neutral formalin is preferred). Surgical specimens should

be either sent in a xative or preferably fresh if there is a specic

workow for it and if the microbiological risk is controlled. This

allows proper opening of the uterus and sampling a fresh tissue for

research purposes.

Specimen grossing and sampling

All pathology reports should include a detailed section, code/block

key on which the origin/designation of all tissue blocks should be

recorded.

The specimen needs to be oriented, which means that the ante-

rior and posterior walls of the uterus are identied using anatomic

landmarks such as the peritoneal reection and the round ligament/

ovaries. All organs/structures received should be documented and

their measurements and gross appearance recorded.

The uterus should be opened immediately on receipt in the

pathology laboratory and placed in formalin within an hour of

opening whenever possible. If the uterus is not immediately sent

to a pathology laboratory, the uterine cavity needs to be opened

technically correctly to guarantee proper xation. The uterus is

preferably opened along the lateral uterine walls (3 and 9 o’clock),

although 12 and 6 o’clock sectioning may be acceptable.

The pathology laboratory personnel and/or pathologists should

manage the requests for fresh tissue for banking and/or investiga-

tional protocols and this task should be completed as soon as the

specimen is received in the pathology laboratory.

Inking of peritoneal and/or non- peritoneal surfaces is recom-

mended in hysterectomy specimens and is mandatory in radical

hysterectomy specimens in which the parametrium and vaginal

cuff are present.

At least the largest dimension of the tumor must be provided,

although providing three dimensions is recommended. Horizontal/

transverse sectioning is recommended. Sampling one section per

centimeter of the largest tumor dimension is recommended.

In case of pre- operative endometrial sampling with a malignant

diagnosis and no visible lesion on gross examination or a history

of atypical endometrial hyperplasia/EIN, the entire endometrium

and adjacent inner myometrium should be submitted for micro-

scopic examination. The same applies to hysterectomy specimens

that have been obtained for other reasons (leiomyomas, adeno-

myosis, etc) when the endometrium is grossly inconspicuous but

endometrial carcinoma or atypical endometrial hyperplasia/EIN are

detected on the initial histological sections.

At least one full- thickness section of the uterine wall including

serosa is required to show the deepest point of myometrial invasion.

The number of sections submitted should not be altered in the

context of adenomyosis. However, in cases where the assess-

ment of myometrial invasion is difcult because of tumor involving

adenomyosis, taking additional sections of the uterine wall may be

useful.

Whenever possible, the interface between the tumor and its

surroundings should be submitted for microscopic examination.

This facilitates the measurement of the depth of myometrial inva-

sion and the identication of precursor lesions.

At least one representative section of non- neoplastic endome-

trium should be submitted for microscopic examination. In addition,

any grossly identied endometrial lesions separate from the tumor

should be submitted.

All gross endometrial abnormalities need to be submitted for

microscopic examination in the hysterectomy specimen from

patients with Lynch syndrome. In the absence of a gross lesion,

the endometrium should be submitted in toto, including the lower

uterine segment.

A minimum of two sections (one anterior, one posterior) should

be submitted from the lower uterine segment.

Parametrial tissue/parametrium should be sampled before

opening the uterus as this approach minimizes the chance of

nding carryovers. All of the parametrial tissue/parametrium should

be submitted for histologic examination. If macroscopic tumor is

seen in the parametrial tissue/parametrium, the most proximal

parametrial section should include the adjacent outer portion of the

cervical wall.

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Joint statement

The cervix should be left attached to the corpus during the gross

examination of a hysterectomy specimen obtained for endometrial

carcinoma. At least two full thickness sections (one anterior and

one posterior) should be submitted from a grossly unremarkable

cervix. At least two representative sections of tumor involving the

cervix should be submitted when the cervix is grossly involved by

endometrial carcinoma. These sections must include the full thick-

ness of the cervical wall and the ectocervical or vaginal cuff margin.

Gross examination of a morcellated hysterectomy specimen

requires special attention to identify any endometrial abnormality,

although this may be extremely difcult to see in some cases. If

such an abnormality is detected, the entire endometrial lesion

and the adjacent myometrium should be submitted for micro-

scopic examination. In addition, sampling of myometrial tissue

containing any serosal surface should be undertaken. If the endo-

metrium appears grossly unremarkable and the initial represen-

tative sections demonstrate the presence of atypical endometrial

hyperplasia/EIN or endometrial carcinoma, careful re- grossing is

required with the submission of all the visible endometrial lining

and adjacent myometrium. If the morcellated specimen contains

the uterine cervix, this should be sampled representatively.

Gross examination of the fallopian tube must be carefully under-

taken and any areas with macroscopic abnormalities should be

submitted for microscopic examination. If the fallopian tube is

unremarkable, the entire tube should be submitted for microscopic

examination using the sectioning and extensively examining the

mbriated end (according to the SEE- FIM protocol), particularly for

serous carcinoma and carcinosarcoma, while only the mbrial end

should be submitted in toto in other scenarios using the guidelines

of the SEE- FIM protocol, along representative cross- sections of the

remainder of the fallopian tube.

Gross examination of the ovary must be carefully performed. In

case of endometrial serous, clear cell carcinoma or carcinosar-

coma, the entire ovary should be submitted after slicing it perpen-

dicularly to its long axis at 2–3 mm intervals. If possible, the same

protocol should be used for oophorectomy specimens accompa-

nying hysterectomies for other endometrial carcinoma histotypes.

Should the latter not be possible, at least two sections of each ovary

should be submitted.

Omentectomy is part of the staging procedure of endometrial

serous carcinoma, undifferentiated carcinoma, and carcinosar-

coma. The gross appearance and measurement of the omentum

should be provided. Omental tissue should be sliced at 0.5 cm

intervals to detect small abnormalities. If the omentum is grossly

positive, one or two representative sections are enough for micro-

scopic evaluation, but if it is grossly negative, one representative

section per 2 or 3 cm of maximal omental dimension or at least a

total of four blocks of tissue should be submitted.

Lymph nodes from different anatomic sites should be sent in

separate appropriately labeled specimen containers and handled

separately. They should be carefully dissected from the adipose

tissue. This can be done with a thorough visual examination and

palpation. A small amount of adipose tissue should be left around

larger lymph nodes to evaluate the presence or absence of extra-

nodal extension. Lymph nodes up to 2 mm are totally embedded. If

larger than 2 mm, parallel slices at 2–3 mm intervals perpendicular

to the long axis of the node should be performed. All grossly unre-

markable lymph node tissue should be submitted for microscopic

examination. The number of lymph nodes submitted per cassette

and the way they have been submitted—for example, in toto if

very small or sectioned—should be specied in the section code.

With grossly positive lymph nodes, representative sections to

demonstrate the largest size of tumor involvement as well as the

surrounding adipose tissue should be submitted for microscopic

examination and noted in the section code.

The description of the sentinel lymph node should include gross

measurement and description of gross appearance including the

presence of dye. The lymph node is sliced at 2–3 mm intervals

perpendicular to its long axis. A small rim of adipose tissue should

be left around the lymph node. The entire lymph node is submitted

for microscopic examination in properly coded cassettes. Ultrast-

aging is encouraged (ie, additional recuts and/or IHC for keratin). At

the present time there is no universal ultrastaging protocol.

Frozen section for intra- operative assessment is not encouraged

for myometrial invasion assessment because of poor reproducibility

and because it interferes with pre- analytical issues and the possi-

bility of carryovers.

Report of pathology results (required items)

► Description of the specimen(s) submitted for histologic

evaluation

► Attached anatomic structures

► Accompanying specimens

► Tumor type (WHO Classication of Tumors (5th edition))

► Tumor grade (FIGO and WHO Classication of Tumors (5th

edition)). Endometrioid endometrial carcinoma is graded using

FIGO grading criteria: grades 1, 2, and 3 tumors exhibit ≤5%,

6–50%, and >50% solid non- glandular (including cribriform),

non- squamous growth. The presence of severe cytologic

atypia in the majority of cells (>50%) increases the grade by

one level, but serous carcinoma should be excluded in cases

with nuclear atypia that is out of proportion to the architecture.

Binary grading is recommended by the WHO Classication of

Tumors (5th Edition) whereby grades 1–2 tumors are classied

as low- grade and grade 3 tumors as high- grade.

► Absence or presence and depth of myometrial invasion should

be reported in all endometrial carcinoma as 'none or less than

half' OR 'half or more'. The measurement should be performed

from the adjacent endometrial–myometrial interface.

► If myometrial invasion occurs from carcinoma within adeno-

myosis, the deepest myoinvasive point should be reported

according to where this is located in the myometrium, and

regardless of whether or not it arises from adenomyosis. In

case of an exophytic tumor, the depth of myometrial invasion,

and not tumor thickness, should be measured by identifying the

adjacent endo–myometrial junction and by correlating with the

macroscopic appearance. For tumors involving polyps, meas-

urement of invasion is performed only if the tumor invades the

underlying myometrium.

► LVSI should be unequivocal and reported as focal and exten-

sive/substantial (ve vessels or more). LVSI should not be

included in assessment of myometrial invasion depth.

► Cervical stromal invasion: for the purposes of standard

reporting, the uppermost endocervical mucinous gland iden-

tied in the section should be taken as the upper limit of the

endocervix.

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Joint statement

► Vaginal involvement.

► Uterine serosal involvement. Tumor inltrating the full myome-

trial thickness and reaching sub- mesothelial bro- connective

tissue or the mesothelial layer should be reported as serosal

involvement; tumor may or may not be present on the surface

of the uterus; a desmoplastic response may or may not be

present.

► Parametrial involvement.

► Adnexal involvement. Care should be taken to determine

whether the ovarian involvement is considered to be meta-

static or 'synchronous'. Synchronous low- grade endometrioid

carcinomas of the endometrium and the ovary have been

demonstrated mostly to be clonally related in the vast majority

of cases. Their reported indolent behavior supports conserva-

tive management when the following criteria are met: (a) both

tumors are low grade; (b) <50% myometrial invasion; (c) no

involvement of any other site; (d) absence of extensive LVSI

at any location. These parameters should be reported and

included in a specic comment.

In cases of serous endometrial carcinoma with co- existing

tubal intra- epithelial (mucosal) carcinoma, with or without

stromal invasion, ancillary techniques should be undertaken

to help dene whether the Fallopian lesion is independent or

metastatic. In cases of endometrioid endometrial carcinoma, a

comment may be included on the unknown prognostic signi-

cance of this nding.

► Omental involvement.

► Peritoneal involvement.

► Lymph node status including sentinel lymph node status

reports the total number of nodes found and the number of

positive lymph nodes, and the presence of extranodal extension

(list for all separates sites). Micrometastasis (>0.2 mm and up

to 2 mm) are reported as pN1(mi). ITCs no greater than 0.2 mm

in regional nodes should be reported as pN0 (i+).

► Pathologically proven distant metastases.

► Required ancillary techniques (IHC for p53, MSH-6 and PMS-2,

complemented with MLH-1 and MSH-2, MLH-1 promoter

methylation analysis in cases of MLH-1/PMS-2 decrease

expression). Additional immunohistochemical markers may be

important for pathologic diagnosis (PTEN, p16, ER, Napsin A,

Racemase, Pax8, E- Cadherin) or prognosis (L1CAM).

► Provisional pathologic staging pre- tumor board/multi-

disciplinary team meeting. The TNM staging system (Union for

International Cancer Control and American Joint Committee

on Cancer versions) for endometrioid carcinoma is largely

concordant with the widely used FIGO system.

Report of pathology results (recommended items unrelated to

stage and with limited supporting evidence)

► Tumor site.

► Tumor size.

► Percentages of different components of mixed carcinoma and

in carcinosarcoma.

► Measurement of absolute depth of myometrial invasion,

percentage of myometrium inltrated by tumor, invasion of

inner, middle, or outer one third of the myometrium, distance of

myo- invasive tumor to serosal surface.

► Microcystic, elongated, fragmented pattern of invasion.

► Peritoneal cytology (if available).

Recommended ancillary investigations.

Molecular classication

The decision to use molecular classication in all endometrial

carcinoma cases in the subset of high- grade or high- risk tumors

or in none of the cases depends on the availability of resources

and decision by the multi- disciplinary team of each center.

Molecular classication is recommended to be performed

by the TCGA surrogate using the diagnostic algorithm provided

by Vermij et al.

This diagnostic algorithm requires testing of

three immunohistochemical markers (p53, MSH-6, PMS-2) and

somatic mutation analysis of POLE (exons 9, 11, 13, 14). Guid-

ance on the interpretation of pathogenicity of POLE variants is

provided by Leon- Castillo et al.

Five categories of tumors are recognized: (1) ultramutated/with

pathogenic POLE mutations; (2) hypermutated with MSI/MMRd

(loss of MMR protein immunoreactivity); (3) high copy number/

p53abn (p53 mutant immunoreactive pattern); (4) low copy

number/NSMP (retained MMR protein immunoreactivity, and p53

wild- type immunoreactive pattern); (5) multiple classier (any

combination of markers included in the previous categories).

If available, molecular classication data should be integrated into

conventional pathologic diagnosis. The report should include informa-

tion regarding the methods used for IHC as well as for POLE mutation

analysis. It should include information from the literature regarding the

pathogenicity of each POLE mutation detected.

PSYCHO-ONCOLOGICAL SUPPORT FOR WOMEN WITH

ENDOMETRIAL CARCINOMA

Endometrial carcinoma, even as a cancer with a relatively good prog-

nosis, is a life- threatening disease. Treatment may produce signicant

toxicities which cause substantial short- and long- term side effects,

functional loss in various behavioral and life domains as well as psycho-

social distress. The patient and her caregivers may face major chal-

lenges in terms of coping and adjustment.

Therefore, continuous evaluation for psychological distress, sexual

dysfunction, and psychiatric co- morbidity as well as identication of

psychosocial needs are of major importance.

430

The rst step includes

an early assessment and identication of the patient’s distress.

431

There

are several standardized and validated screening instruments available

such as the Hospital Anxiety and Depression Scale or the easy to use

Distress Thermometer.

432

Depending on the result of the diagnostic

process, various interventions should be offered such as counseling,

individual or group psychotherapy, psychoeducational interventions,

art therapies, or relaxation techniques. For patients with a disease

involving genital organs, cancer itself, surgical treatment and subse-

quent hormonal loss may impair sexual function. Therefore, discussion

and treatment of sexual problems should be integrated as part of a

holistic approach.

In order to empower patients to cope with physical and

psychosocial long- term side effects of disease, treatment, and to

preserve quality of life, they should receive a personalized survi-

vorship care plan including information and education life style

and prevention of secondary malignancies and other diseases.

Contact with advocacy groups should be offered to all patients.

on August 30, 2024 by guest. Protected by copyright.http://ijgc.bmj.com/Int J Gynecol Cancer: first published as 10.1136/ijgc-2020-002230 on 18 December 2020. Downloaded from

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Joint statement

Author afliations

Department of Gynecology and Obstetrics, Innsbruck Medical University,

Innsbruck, Austria

Evangelische Kliniken Essen- Mitte, Essen, Germany

Department of Pathology, Hospital Universitari Arnau de Vilanova, University of

Lleida, CIBERONC, Irblleida, Spain

Department of Pathology, Hospital Universitari de Bellvitge, University of

Barcelona, Idibell, Spain

Department of Gynecology and Obstetrics, Gynecologic Oncology, Leuven Cancer

Institute, Catholic University Leuven, Leuven, Belgium

Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles

University, General University Hospital in Prague, Prague, Czech Republic

Department of Oncology, Rigshospitalet, Copenhagen University Hospital,

Copenhagen, Denmark

Department of Radiation Oncology, Medical Faculty of the University of Cologne,

Cologne, Germany

UCL Cancer Institute, University College, London, UK

Department of Pathology, Leids Universitair Medisch Centrum, Leiden,

Netherlands

Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France

Division of Gynecologic Oncology, Fondazione Policlinico Universitario A Gemelli

IRCCS, Rome, Italy

Department of Gynaecologic Oncology, Imperial College London Faculty of

Medicine, London, UK

Department of Medical Oncology, Clinica Universidad de Navarra, Madrid, Spain

Department of Pathology, Hospital Graz II, Graz, Austria

School of Medicine, Johannes Kepler University Linz, Linz, Austria

Department of Obstetrics and Gynecology, Innsbruck Medical University,

Innsbruck, Austria

Department of Surgery, Institut Gustave Roussy, Villejuif, France

Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam,

Netherlands

Department of Medical Oncology, St James Hospital, Dublin, Ireland

Department of Obstetrics and Gynecologic Oncology, University Hospital,

Strasbourg, France

Histopathology and Molecular Diagnostics, Azienda Ospedaliero Universitaria

Careggi, Florence, Italy

Department of Gynecology with Center for Oncological Surgery, Campus

Virchow Klinikum, Charité–Universitätsmedizin Berlin, Corporate Member of Freie

Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health,

Berlin, Germany

Department of Radiation Oncology, Comprehensive Cancer Center, Christian

Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical

University of Vienna, Vienna, Austria

Department of Gynaecology, Royal Marsden Hospital, London, UK

Department of Medical Oncology, Amsterdam University Medical Centres,

Amsterdam, Noord- Holland, Netherlands

Department of Gynecology and Obstetrics, TU Dresden Medizinische Fakultat Carl

Gustav Carus, Dresden, Germany

Gynecologic Oncology Program, European Institute of Oncology, IRCCS, Milan and

University of Milan- Bicocca, Milan, Italy

Clinical Research Unit, Institut Bergonie, Bordeaux, France

Department of Radiation Oncology, Leiden University Medical Center, Leiden,

Netherlands

Presented at

These guidelines statements were developed by ESGO, ESTRO and ESP and are

published in the International Journal of Gynaecological Cancer, Radiotherapy &

Oncology and the Virchows Archiv.

Acknowledgements The authors thank ESGO, ESTRO, and ESP for their

support. ESGO ofce, especially Kamila Macku, provided invaluable logistical

and administrative support throughout the process. The authors also thank the

191 international reviewers (physicians and patient representatives, Appendix 2)

for their valuable comments and suggestions. The European Society for Medical

Oncology, Professor Cristiana Sessa and the ESMO- ESGO- ESTRO consensus

conference working group are gratefully acknowledged for the previous 2014

Endometrial Consensus Conference. The authors wish to express sincere gratitude

to Annette Hasenburg and Joachim Weis for describing the psycho- oncological

aspects in this article.

Contributors The development group (including all authors) is collectively

responsible for the decision to submit for publication. NCon (chair), CLC (co-

chair), XM- G (co- chair) and FP (methodologist) have written the rst draft of the

manuscript. All other contributors have actively given personal input, reviewed the

manuscript, and have given nal approval before submission.

Funding All costs relating to the development process were covered from ESGO,

ESTRO, and ESP funds.

Competing interests NCon: advisory boards for Seattle Genetics, AstraZeneca

and Mersana, education fees from Medscape Oncology, and grants for travelling

from Roche, Genmab and Amgen. IV: advisory boards for Amgen, AstraZeneca,

Clovis Oncology, Carrick Therapeutics, Debiopharm International, F Hoffmann- La

Roche, Genmab, GSK, Immunogen, Millenium Pharmaceuticals, MSD Belgium,

Octimet Oncology, Oncoinvent, Pharmamar- Doctaforum Servicios, Roche,

Sotio, Tesaro, Deciphera Pharmaceuticals and Verastem Oncology (fees for

consulting to his university), contracted research (KU Leuven) for Oncoinvent AS

and Genmab, corporate sponsored research for Amgen and Roche, and grants

for travelling from Amgen, MSD/Merck, Roche, AstraZeneca and Tesaro. DC:

advisory boards for AstraZeneca, Roche, Sotio and Novocure. MRM: personal

nancial interests for AstraZeneca, Biocard, Clovis Oncology, Geneos, Genmab,

Karyopharm Therapeutics, Merck, Mersana, MSD, Oncology Venture, Pzer, Roche,

SeatleGenetics, SeraPrognostics, Sotio, Tesaro- GSK, ZaiLab; leadership role for

Karyopharm Therapeutics, Sera Prognostics; institutional nancial interests (study

grants) for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pzer, Tesaro-

GSK, Ultimovacs. JL: advisory boards for AstraZeneca, Pzer, GSK, Eisai, MSD/

Merck, Artios Pharma, Regeneron, Amgen and Clovis Oncology, and grants for

travelling from Clovis Oncology. CC: advisory boards for MSD, Takeda and GSK,

conducting research for TherAguiX and Roche, and grants for travelling from

Takeda. AF: advisory boards for GSK and Johnson & Johnson SpA, and grants for

travelling from Pharmmar and MSD Italia. CF: advisory boards for AstraZeneca,

Clovis, Ethicon, Roche, MSD, GSK and Tesaro, and grants for travelling from

Sequana. AGM: speakers’ bureau activities for AstraZeneca, Pharmamar, Roche

and GSK, advisory boards for Amgen, AstraZeneca, Clovis Oncology, Genmab,

GSK, Immunogen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pzer/Merck,

Pharmamar, Roche and Sotio, and grants for travelling from AstraZeneca,

Pharmamar Roche and Tesaro. DL: advisory boards for Roche, Amgen, MSD, GSK,

Clovis, AstraZeneca, Immunogen, Genmab, Pharmamar and Merck, and grants

for travelling from Pharmamar, GSK, Roche and AstraZeneca. CM: consulting/

advisory boards for Roche, Novartis, Amgen, MSD, AstraZeneca, Pzer, Pharmamar,

Cerulean, Vertex and Tesaro, funded research from EU, FWF, AstraZeneca and

Roche, and honoraria/expenses from Roche, Novartis, Amgen, MSD, Pharmamar,

AstraZeneca and Tesaro. JS: advisory boards for Roche, Eisei, MSD, AstraZeneca,

Clovis, GSK and Tesaro. AT: advisory boards for Genmab; PW: advisory boards

for Amgen, AstraZeneca, MSD, Novartis, Pzer, Pharmamar, Lilly, Roche Pharma

GmbH, TEVA, Eisai, Clovis and Tesaro, and grants for travelling from Roche Pharma

GmbH, AstraZeneca, MSD, Amgen and Pzer. NC: consulting and advisory services,

speaking or writing engagements, public presentations for Roche, AstraZeneca,

MSD, Pharmamar, Tesaro, GSK, Clovis, Advaxis, Pzer, Takeda, Immunogen, Biocad,

Amgen, Novartis and Ellipses, institutional nancial interests for Roche, Pharmamar

and AstraZeneca, and non- nancial interests for ESMO clinical Guidelines (subject

editor for gynecological cancer). XMG, SM, TB, SL, PM, RN, DOD, DQ, MRR, AS, AW,

FP, and CLC: no conicts of interest.

Patient consent for publication Not required.

Provenance and peer review Commissioned; internally peer reviewed.

Data availability statement All data relevant to the study are included in the

article or uploaded as supplementary information.

ORCID iDs

NicoleConcin http:// orcid. org/ 0000- 0002- 9795- 2643

JonathanLedermann http:// orcid. org/ 0000- 0003- 3799- 3539

ChristinaFotopoulou http:// orcid. org/ 0000- 0001- 6375- 9645

DenisQuerleu http:// orcid. org/ 0000- 0002- 3984- 4812

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