ESMO-ESGO-ESTRO Consensus guidelines
ESMO–ESGO–ESTRO consensus con e ence on endome ial cance :
Diagnosis, ea men and ollow-up
q
Nicole a Colombo
a,
⇑
, Ca ien C eu zbe g
b
, F ede ic Aman
c,d
, Tjalling Bosse
e
, An onio González-Ma ín
,g
,
Jona han Lede mann
h
, Ch is ian Ma h
i
, Remi Nou
j
, Denis Que leu
k,l
, Mansoo Raza Mi za
m
,
C is iana Sessa
n
, The ESMO–ESGO–ESTRO Endome ial Consensus Con e ence Wo king G oup
1
a
Di ision o Medical Gynecologic Oncology, Eu opean Ins i u e o Oncology and Uni e si y o Milan-Bicocca, Milan, I aly;
b
Depa men o Radia ion Oncology, Leiden Uni e si y Medical
Cen e , Leiden, The Ne he lands;
c
Depa men o Gynecological Oncology, Uni e si y Hospi al Leu en, Leu en, Belgium;
d
Cen e o Gynecological Oncology Ams e dam (CGOA), An oni
an Leeuwenhoek, Ams e dam, The Ne he lands;
e
Depa men o Pa hology, Leiden Uni e si y Medical Cen e , Leiden, The Ne he lands;
Medical Oncology Depa men , GEICO, Mad id,
Spain;
g
MD Ande son Cance Cen e , Mad id, Spain;
h
Depa men o Oncology and Cance T ials, UCL Cance Ins i u e, London, Uni ed Kingdom;
i
Depa men o Obs e ics and
Gynecology, Innsb uck Medical Uni e si y, Innsb uck, Aus ia;
j
Depa men o Radio he apy, Leiden Uni e si y Medical Cen e , Leiden, The Ne he lands;
k
Depa men o Su ge y,
Ins i u Be gonié, Bo deaux, F ance;
l
Gynecology and Obs e ics Depa men , McGill Uni e si y Heal h Cen e, Mon eal, Canada;
m
Depa men o Oncology, Rigshospi ale , Copenhagen
Uni e si y Hospi al, Copenhagen, Denma k; and
n
Depa men o Medical Oncology, Oncology Ins i u e o Sou he n Swi ze land, Ospedale San Gio anni, Bellinzona, Swi ze land
a icle in o
A icle his o y:
Recei ed 16 Oc obe 2015
Accep ed 18 No embe 2015
A ailable online 9 Decembe 2015
Keywo ds:
Endome ial neoplasms
P ac ice guideline
Consensus
T ea men
Adju an
Su ge y
abs ac
The i s join Eu opean Socie y o Medical Oncology (ESMO), Eu opean SocieTy o Radio he apy &
Oncology (ESTRO) and Eu opean Socie y o Gynaecological Oncology (ESGO) consensus con e ence on
endome ial cance was held on 11–13 Decembe 2014 in Milan, I aly, and comp ised a mul idisciplina y
panel o 40 leading expe s in he managemen o endome ial cance . Be o e he con e ence, he expe
panel p epa ed h ee clinically- ele an ques ions abou endome ial cance ela ing o he ollowing ou
a eas: P e en ion and sc eening, su ge y, adju an ea men and ad anced and ecu en disease. All el-
e an scien i ic li e a u e, as iden i ied by he expe s, was e iewed in ad ance. Du ing he consensus
con e ence, he panel de eloped ecommenda ions o each speci ic ques ion and a consensus was
eached. Resul s o his consensus con e ence, oge he wi h a summa y o e idence suppo ing each ec-
ommenda ion, a e de ailed in his a icle. All pa icipan s ha e app o ed his inal a icle.
Ó2015 The Au ho s. Published by Else ie I eland L d. Radio he apy and Oncology 117 (2015) 559–581
This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-
nd/4.0/).
Key message
This ESMO–ESGO–ESTRO consensus con e ence manusc ip was
compiled by a mul idisciplina y panel o 40 expe s.
I add esses clinically- ele an ques ions ega ding p e en ion,
sc eening, su ge y, adju an he apy and managemen o
ad anced/ ecu en endome ial cance , and complemen s he
ESMO clinical p ac ice guidelines.
Recommenda ions p o ided a e accompanied by ele an
suppo ing e idence.
In oduc ion
Endome ial cance is he mos common gynaecological cance
in de eloped coun ies. The numbe o newly diagnosed cases in
Eu ope was nea ly 100,000 in 2012, wi h an age s anda dised inci-
dence o 13.6 pe 100,000 women. Cumula i e isk o a diagnosis o
endome ial cance is 1.71% [1].
Mo e han 90% o cases o endome ial cance occu in women
>50 yea s o age, wi h a median age a diagnosis o 63 yea s. How-
e e , 4% o women wi h endome ial cance a e younge han
40 yea s old [2], many o whom s ill wish o e ain hei e ili y.
The majo i y o endome ial cance s a e diagnosed ea ly (80% in
s age I), wi h i e-yea su i al a es o o e 95%. Howe e , i e-
yea su i al a es a e much lowe i he e is egional sp ead o
dis an disease (68% and 17%, espec i ely) [3].
His o ically, endome ial ca cinoma has been classi ied in o wo
main clinicopa hological and molecula ypes: Type I is he much
h p://dx.doi.o g/10.1016/j. adonc.2015.11.013
0167-8140/Ó2015 The Au ho s. Published by Else ie I eland L d.
This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
q
These Guidelines we e de eloped by he Eu opean Socie y o Medical Oncology
(ESMO), he Eu opean Socie y o Gynaecological Oncology (ESGO), and he
Eu opean SocieTy o Radio he apy and Oncology (ESTRO), and a e published join ly
in he Annals o Oncology, he In e na ional Jou nal o Gynecological Cance and
Radio he apy & Oncology. The h ee socie ies nomina ed pa icipan s who a ended
he consensus con e ence and co-au ho ed he inal manusc ip .
⇑
Co espondence o: P o . Nicole a Colombo, ESMO Guidelines Commi ee,
ESMO Head O ice, Via L. Taddei 4, CH-6962 Viganello-Lugano, Swi ze land.
E-mail add ess: [email p o ec ed].
1
See Appendix o membe s o he ESMO–ESGO–ESTRO Endome ial Consensus
Con e ence Wo king G oup.
Radio he apy and Oncology 117 (2015) 559–581
Con en s lis s a ailable a ScienceDi ec
Radio he apy and Oncology
jou nal homepage: www. heg eenjou nal.com
mo e common endome ioid adenoca cinoma (80–90%) and Type
II comp ises non-endome ioid sub ypes such as se ous, clea cell
and undi e en ia ed ca cinomas, as well as ca cinosa coma/
malignan -mixed Mülle ian umou (10–20%) [4]. Molecula da a
in suppo o his dicho omous classi ica ion ha e become an in e-
g al componen o pa hologic e alua ion, as ype I ca cinomas a e
p e e en ially associa ed wi h gene ic al e a ions in PTEN, KRAS,
CTNNB1 and PIK3CA and MLH1 p omo e hype me hyla ion,
whe eas se ous ca cinomas p o o ypically ha bou TP53 mu a-
ions. Howe e , his dualis ic model has limi a ions as conside able
molecula he e ogenei y exis s; o example, 25% o high g ade
endome ioid ca cinomas exp ess mu a ed TP53 and beha e like
se ous ca cinomas [5]. Ex ensi e wo k pe o med by The Cance
Genome A las (TCGA) Resea ch Ne wo k has signi ican ly
imp o ed ou unde s anding o he molecula landscape o
endome ial cance , in oducing no 2, bu 4 molecula sub ypes
including: (1) POLE (ul amu a ed) umou s, (2) mic osa elli e
uns able umou s, (3) copy-numbe high umou s wi h mos ly
TP53 mu a ions and (4) emaining g oup wi hou hese al e a ions
[6]. He edi a y endome ial adenoca cinomas a e mos ly seen in
amilies wi h he edi a y non-polyposis colon cance (HNPCC,
Lynch synd ome [LS]). Al hough he majo i y o endome ial ca ci-
nomas ela ed o LS a e Type I cance s, he p opo ion o Type II
cance s seems o be highe han in he case o spo adic endome-
ial ca cinoma [7].
Al hough he majo i y o cases o endome ial cance a e diag-
nosed a an ea ly s age, di e ences in pa ien cha ac e is ics and
his opa hological ea u es o he disease impac bo h on pa ien
p ognosis and he ecommended ea men app oach. Gi en he
la ge body o li e a u e a ailable ha add esses he managemen
o endome ial cance , he aim o his consensus con e ence was
o p oduce mul idisciplina y e idence-based guidelines on
selec ed clinically- ele an ques ions in o de o complemen he
al eady-a ailable Eu opean Socie y o Medical Oncology (ESMO)
Clinical P ac ice Guidelines (CPG) o he diagnosis, ea men
and ollow-up o pa ien s wi h endome ial cance [8].
Me hods
In 2014, ESMO decided o upda e he clinical ecommenda ions
o endome ial cance using a consensus con e ence app oach.
The consensus panel comp ised 40 expe s in he managemen o
endome ial cance , and included ep esen a ion om he Eu o-
pean SocieTy o Radio he apy & Oncology (ESTRO), he Eu opean
Socie y o Gynaecological Oncology (ESGO) and ESMO. Each panel
membe was assigned o one o ou wo king g oups, wi h a wo k-
ing g oup chai and co-chai appoin ed o each g oup. Th ee con-
sensus con e ence chai s (N. Colombo, C. C eu zbe g, C. Sessa) we e
also appoin ed.
Each wo king g oup was assigned a subjec a ea as ollows:
1. P e en ion and sc eening o endome ial cance (Chai : F.
Aman ; Co-Chai : T. Bosse).
2. Su ge y (Chai : C Ma h; Co-Chai : D. Que leu).
3. Adju an ea men (Chai : R. Nou ; Co-Chai : M.R. Mi za).
4. Ad anced and ecu en disease (Chai : J. Lede mann; Co-Chai :
A. González-Ma ín).
The consensus con e ence was held on 11–13 Decembe 2014
in Milan, I aly. Be o e his consensus con e ence, h ee clinically-
ele an ques ions we e iden i ied o each subjec a ea/wo king
g oup, gi ing a o al o 12 clinically- ele an ques ions as ollows:
1. Which su eillance should be used o asymp oma ic
women?
2. Wha wo k-up and managemen scheme should be unde -
aken o e ili y p ese ing he apy in pa ien s wi h a ypi-
cal hype plasia (AH)/endome ial in aepi helial neoplasia
(EIN) and g ade 1 endome ioid endome ial cance (EEC)?
3. Which (molecula ) ma ke s can help dis inguish (p e)-
cance ous lesions om benign mimics?
4. How does he medical condi ion in luence su gical
ea men ?
5. Wha a e he indica ions o and o wha ex en is lym-
phadenec omy indica ed in he su gical managemen o
endome ial cance ?
6. How adical should he su ge y be in di e en s ages and
pa hological sub ypes o endome ial cance ?
7. Wha is he cu en bes de ini ion o isk g oups o adju-
an he apy?
8. Wha a e he bes e idence-based adju an ea men
s a egies o pa ien s wi h low- and in e media e- isk
endome ial cance ?
9. Wha a e he bes e idence-based adju an ea men
s a egies o pa ien s wi h high- isk endome ial cance ?
10. Does su ge y o adio he apy (RT) ha e a ole in ad anced o
ecu en endome ial cance ?
11. Wha a e he op imal sys emic he apies o ad anced/
ecu en disease?
12. Wha a e he mos p omising a ge ed agen s and which
s udy designs should be used o e alua e hei clinical
bene i ?
Each wo king g oup was esponsible o e iewing he ele an
li e a u e in o de o d a p elimina y ecommenda ions ela ing
o each o hei assigned ques ions. No sys ema ic li e a u e sea ch
was unde aken. Du ing he con e ence, in pa allel sessions, he
ou wo king g oups discussed and eached ag eemen on ecom-
menda ions ela ing o each o hei assigned ques ions. Recom-
menda ions om each g oup we e hen p esen ed o he en i e
panel o expe s, whe e hey we e discussed and modi ied as
equi ed. An adap ed e sion o he ‘In ec ious Diseases Socie y
o Ame ica-Uni ed S a es Public Heal h Se ice G ading Sys em’
was used (Table 1 [9]) o de ine he le el o e idence and s eng h
o each ecommenda ion p oposed by he g oup. Finally, a o e was
conduc ed o de e mine he le el o ag eemen among he expe
panel o each o he ecommenda ions. Panel membe s we e
allowed o abs ain om o ing in cases whe e hey ei he had
insu icien expe ise o ag ee/disag ee wi h he ecommenda ion
o i hey had a con lic o in e es ha could be conside ed as
in luencing hei o e.
Resul s o his consensus con e ence, oge he wi h a summa y
o e idence suppo ing each ecommenda ion, a e de ailed in his
a icle, and a summa y o all ecommenda ions is included in sup-
plemen a y Table S1. Howe e , hese addi ional ecommenda ions
o speci ic clinical si ua ions should be ead in conjunc ion wi h
he ESMO CPG o he diagnosis, ea men and ollow-up o
pa ien s wi h endome ial cance [8].
Resul s
P e en ion and sc eening o endome ial cance
Risk ac o s o endome ial cance
Mos pa ien s wi h endome ial cance ha e an iden i iable
sou ce o excess oes ogen and ypically display a cha ac e is ic
clinical p o ile comp ising a high body mass index (BMI) ha is
conside ed as o e weigh (BMI 25–30) o obese (BMI 30), o en
wi h o he componen s o me abolic synd ome (e.g. hype ension,
diabe es). The e idence ha g ea e body a ness ( e lec ed by BMI,
560 Endome ial cance consensus con e ence guidelines
measu es o abdominal gi h and adul weigh gain) is a cause o
endome ial cance is con incing. Glycaemic load is p obably a
cause o endome ial cance , while he e idence sugges ing ha
seden a y habi s (ma ked by si ing ime) and adul a ained
heigh a e causes o endome ial cance is limi ed [10].
High BMI co ela es wi h good p ognos ic ea u es o endome-
ial cance , including low umou g ade, endome ioid his ology
and p esen a ion a ea ly s age. In a small subse o pa ien s, he
pa hogenesis is ela ed o misma ch epai abno mali y and LS.
Tumou s associa ed wi h misma ch epai abno mali ies and LS
appea o be dis inc , wi h wo se p ognos ic ac o s and wo se clin-
ical ou come [11].
Acco ding o a ecen me a-analysis in ol ing six s udies and
3132 cance cases, ela i e isk (RR) o de eloping endome ial
cance in women wi h me abolic synd ome is 1.89 (95% con idence
in e al [CI] 1.34–2.67, P= <0.001). Acco ding o indi idual compo-
nen s o me abolic synd ome, obesi y is associa ed wi h he g ea -
es inc ease in RR o 2.21 (P= <0.001) [12]. The s eng h o
associa ion be ween obesi y and cance isk inc eases wi h
inc easing BMI: RR o o e weigh is 1.32 (95% CI 1.16–1.50) and
o obesi y is 2.54 (95% CI 2.11–3.06) [13]. O he componen s o
he me abolic synd ome linked o endome ial cance include
hype ension, wi h a RR o 1.81 (P= 0.024) [12] o an odds a io
(OR) o 1.77 (1.34–2.34) [14]. Hype iglyce idaemia has a weake
bu s ill signi ican associa ion (RR 1.17, P< 0.001) [12].
Diabe es melli us, in pa icula ype II, has long been held as an
independen isk ac o o endome ial cance , wi h an app oxi-
ma e doubling o isk (OR 2.1; 95% CI 1.40–3.41), [14]. Howe e ,
he ac ha people wi h ype II diabe es melli us (T2DM) end
o be obese is a con ounding ac o , and a ecen epidemiological
s udy om he Uni ed S a es ques ioned he independen ole o
T2DM as a isk ac o o endome ial cance [15].
Nullipa i y and in e ili y a e also classical isk ac o s o
endome ial cance . Among he causes o in e ili y, polycys ic
o a ian synd ome (PCOS) seems o be he mos impo an , wi h
an almos 3- old inc ease in isk (OR 2.79–2.89) [16]. Howe e ,
as wi h diabe es, obesi y seems o be a con ounding ac o , and
he BMI-adjus ed OR is lowe (2.2; 95% CI 0.9–5.7) [17].
O he isk ac o s o endome ial cance include unopposed
oes ogen he apy, oes ogen-p oducing umou s and ea ly mena -
che/la e menopause. Unopposed oes ogen he apy inc eases he
isk o endome ial cance 10- o 30- old i ea men con inues
5 yea s o mo e [18]. Oes ogen-p oducing umou s, o o a ian
g anulosa, and heca cell umou s ca y an inc eased isk o
endome ial cance , wi h up o 20% o women wi h hese umou s
epo ed as ha ing a simul aneous endome ial cance [19]. Bo h
ea ly mena che and la e menopause a e associa ed wi h a 2- old
inc eased isk o endome ial cance . The RR is 2.4 o women
<12 s P15 yea s [20] and is 1.8 o women P55 s <50 yea s [21].
S udies o women wi h b eas cance aking amoxi en wi h
he apeu ic o p e en i e in en ha e shown ha he RR o de el-
oping endome ial cance is 2.53 imes highe han ha o an age
ma ched popula ion. This isk di e s depending on menopausal
s a us. P emenopausal women ea ed wi h amoxi en ha e no
known inc eased isk o endome ial cance , while his isk in pos -
menopausal women is 4.0 (95% CI 1.70–10.90) [22]. The le el o
isk o endome ial cance is also dose and ime dependen .
LS o HNPCC is an au osomal dominan inhe i ed diso de
caused by ge mline mu a ions in DNA misma ch epai genes.
Women wi h mu a ions in MLH1, MSH2, MSH6 o PMS2 ha e up
o a 40–60% li e ime isk o de eloping bo h endome ial and col-
o ec al cance s, as well as a 9–12% li e ime isk o de eloping o a -
ian cance [23].
Sc eening and p e en ion o endome ial cance
Mos cases o endome ial cance canno be p e en ed, bu
educing he isk ac o s and in oducing p o ec i e ac o s in o
he li es yle whene e possible, may lowe he isk o de eloping
his disease.
All women should be old abou he isks and symp oms o
endome ial cance and be s ongly encou aged o engage in egu-
la physical ac i i y (exe cise) and adop an ac i e li es yle which
can help o a ain and main ain a heal hy weigh as well as lowe -
ing he isk o o he isk ac o s o endome ial cance such as high
blood p essu e and diabe es. The use o combined o al con acep-
i es is signi ican ly associa ed wi h dec ease in endome ial can-
ce in e e use s, a bene i ha is g ea e wi h inc easing
du a ion o use.
1. Which su eillance should be used o asymp oma ic
women?
Women wi h a e age isk o endome ial cance
The e is no indica ion ha popula ion-based sc eening has a ole
in he ea ly de ec ion o endome ial cance among women who a e
a a e age endome ial cance isk and ha e no symp oms. The e is
also no s anda d o ou ine sc eening es o endome ial cance .
Sc eening o asymp oma ic women o endome ial ca cinoma
has in gene al been ecommended only o hose wi h LS [24,25].
The e is no e idence ha sc eening by ul asonog aphy (e.g.
endo aginal o ans aginal ul asound) educes mo ali y om
endome ial cance . Mo eo e , coho s udies indica e ha sc eening
asymp oma ic women will esul in unnecessa y addi ional biopsies
because o alse-posi i e es esul s. Risks associa ed wi h alse-
posi i e es s include anxie y and complica ions om biopsies [26].
A he ime o menopause, women should be s ongly encou -
aged o epo any aginal bleeding, discha ge o spo ing o hei
doc o o ensu e hey ecei e app op ia e ea men o any p ecan-
ce ous diso de s o he endome ium.
Recommenda ion 1.1. The e is no e idence o endome ial
cance sc eening in he gene al popula ion
Le el o e idence: II
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Table 1
Le els o e idence and g ades o ecommenda ion.
Le els o e idence
I E idence om a leas one la ge andomised, con olled ial o good
me hodological quali y (low po en ial o bias) o me a-analyses o well-
conduc ed andomised ials wi hou he e ogenei y
II Small andomised ials o la ge andomised ials wi h a suspicion o
bias (lowe me hodological quali y) o me a-analyses o such ials o o
ials wi h demons a ed he e ogenei y
III P ospec i e coho s udies
IV Re ospec i e coho s udies o case–con ol s udies
V S udies wi hou con ol g oup, case epo s, expe s opinions
G ades o ecommenda ion
A S ong e idence o e icacy wi h a subs an ial clinical bene i , s ongly
ecommended
B S ong o mode a e e idence o e icacy bu wi h a limi ed clinical
bene i , gene ally ecommended
C Insu icien e idence o e icacy o bene i does no ou weigh he isk o
he disad an ages (ad e se e en s, cos s, ...), op ional
D Mode a e e idence agains e icacy o o ad e se ou come, gene ally no
ecommended
E S ong e idence agains e icacy o o ad e se ou come, ne e
ecommended
By pe mission o he In ec ious Diseases Socie y o Ame ica-Uni ed S a es Public
Heal h Se ice G ading Sys em [9].
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 561
Women a inc eased isk o endome ial cance
Women a inc eased isk o endome ial cance due o a his-
o y o unopposed oes ogen he apy, la e menopause, amox-
i en he apy, nullipa i y, in e ili y o ailu e o o ula e,
obesi y, diabe es o hype ension should be in o med o he
isks and symp oms o endome ial cance and s ongly encou -
aged o epo any unexpec ed bleeding o spo ing o hei
physicians.
Asymp oma ic women wi h isk ac o s o endome ial cance
who ha e endome ial hickening and o he posi i e indings on
ul asound, such as inc eased ascula i y, inhomogenei y o he
endome ium, pa icula e luid o hickened endome ium o e
11 mm should be managed on a case-by-case basis. The po en ial
bene i s, isks and limi a ions o es ing o ea ly endome ial can-
ce should be explained in o de o ensu e in o med decision-
making abou es ing.
P emenopausal women ea ed wi h amoxi en do no equi e
addi ional moni o ing beyond ou ine gynaecological ca e. Pos -
menopausal women aking amoxi en should be in o med abou
symp oms o endome ial hype plasia o cance [27].
Al hough indings om a ecen ly published me a-analysis ha e
e i ied he e icacy o he le ono ges el in au e ine de ice (LNG-
IUD) in p e en ing de no o polyps in b eas cance pa ien s ea ed
wi h amoxi en, he e was insu icien e idence o asce ain
whe he he LNG-IUD was associa ed wi h any bene i in educing
he incidence o p ecance ous o cance ous lesions [28].
Recommenda ion 1.2. Unopposed oes ogen ea men should
no be s a ed o should be discon inued in women wi h a u e us
in si u
Le el o e idence: III
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 1.3. Rou ine su eillance in asymp oma ic
women wi h obesi y, PCOS, diabe es melli us, in e ili y, nullipa -
i y o la e menopause is no ecommended
Le el o e idence: III
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 1.4. Fo women wi h adul g anulosa cell
umou , i hys e ec omy has no been pe o med, endome ial
sampling is ecommended. I his shows no e idence o (p e)malig-
nancy, no u he sc eening o endome ial malignancies is
equi ed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 1.5. In pa ien s wi h epi helial o a ian cance
unde going e ili y spa ing ea men , endome ial sampling is
ecommended a he ime o diagnosis
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 1.6. Rou ine sc eening o endome ial cance
in asymp oma ic amoxi en use s is no ecommended
Le el o e idence: III
S eng h o ecommenda ion: B
Consensus: 94.6% (35) yes, 5.4% (2) abs ain (37 o e s)
Women wi h high isk o endome ial cance
Women wi h a high isk o endome ial cance include
known ca ie s o HNPCC-associa ed gene ic mu a ions, hose
who ha e a subs an ial likelihood o being a mu a ion ca ie
(i.e. a mu a ion is known o be p esen in he amily), and
women wi hou gene ic es ing esul s bu who a e om
amilies wi h a suspec ed au osomal dominan p edisposi ion
o colon cance .
Findings om a p ospec i e obse a ional coho s udy o
women wi h LS op ing o endome ial cance sc eening and who
unde wen annual ou pa ien hys e oscopy and endome ial
sampling (OHES) sugges ha in women wi h LS, annual OHES is
accep able and has high diagnos ic accu acy in sc eening
o endome ial cance and a ypical endome ial hype plasia
(AEH) [29]. Howe e , la ge in e na ional s udies a e needed o
con i ma ion.
Women wi h an HNPCC-associa ed mu a ion o wi h a subs an-
ial likelihood o ha ing an HNPCC-associa ed mu a ion should be
in o med o he po en ial bene i s, isks and limi a ions o es ing
o ea ly endome ial cance ; hey should also be in o med ha
he ecommenda ion o sc eening is based on expe opinion in
he absence o de ini i e scien i ic e idence.
Al hough he e is insu icien e idence o endo se annual
sc eening o endome ial cance in his g oup, annual sc eening
beginning a age 35 is ecommended due o he high isk o
endome ial cance and he po en ially li e- h ea ening na u e o
his disease. As sc eening will be o limi ed e icacy in gynaecolog-
ical cance s (endome ial and o a ian), once he amily is com-
ple ed, pa icula ly by age 35–40 yea s, ca e ul conside a ion
mus be gi en o he op ion o p ophylac ic hys e ec omy and
bila e al salpingo-oopho ec omy [30].
In women wi h LS, he ollowing op ions a e a ailable:
Annual sc eening beginning a age 35 ( ecommended).
Regula hys e oscopy and endome ial biopsies o hys e ec-
omy (cu en op ions).
The applica ion o local p oges e one using he LNG-IUD.
T ea men o p emalignan disease (AEH, EIN).
Hys e ec omy and bila e al oopho ec omy.
E alua ing he likelihood o a pa ien ha ing a gynaecological
cance p edisposi ion synd ome enables he physician o p o ide
indi idualised assessmen s o cance isk, as well as he oppo uni y
o o e ailo ed sc eening and p e en ion s a egies such as su eil-
lance, chemop e en ion and p ophylac ic su ge y ha may educe
he mo bidi y and mo ali y associa ed wi h hese synd omes.
Recommenda ion 1.7. Su eillance o he endome ium by
gynaecological examina ion, ans aginal ul asound and aspi a-
ion biopsy s a ing om he age o 35 yea s (annually un il
hys e ec omy) should be o e ed o all LS mu a ion ca ie s
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 97.3% (36) yes, 2.7% (1) abs ain (37 o e s)
Recommenda ion 1.8. P ophylac ic su ge y (hys e ec omy and
bila e al salpingo-oopho ec omy), p e e ably using a minimally
in asi e app oach, should be discussed a he age o 40 as an
op ion o LS mu a ion ca ie s o p e en endome ial and o a ian
cance . All p os and cons o p ophylac ic su ge y mus be discussed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
562 Endome ial cance consensus con e ence guidelines
2. Wha wo k-up and managemen scheme should be
unde aken o e ili y p ese ing he apy in pa ien s wi h AH/
EIN and g ade 1 EEC?
Wo k-up o e ili y p ese ing he apy
The diagnosis o endome ial ca cinoma in young women o
childbea ing age is a e. Indeed, only 4% o pa ien s wi h endome-
ial ca cinoma a e less han 40 yea s o age [2]. Younge and p e-
menopausal women wi h endome ial ca cinoma seem o ha e a
be e p ognosis han olde pa ien s, wi h inc eased a es o ea ly
s age and low g ade disease epo ed [2,31,32].
The s anda d app oach o he managemen o endome ial can-
ce in young women o childbea ing age is hys e ec omy and bila -
e al salpingo-oopho ec omy wi h o wi hou lymphadenec omy.
Al hough his is a highly e ec i e app oach, ca ying a 5-yea su -
i al a e o 93%, i also esul s in a pe manen loss o ep oduc i e
po en ial. Conse a i e managemen o endome ial ca cinoma is
based on medical ea men wi h o al p oges ins. The mos impo -
an issues when conside ing a conse a i e managemen
app oach a e he assessmen o clinical and pa hological cha ac e -
is ics o he umou and selec ion o he app op ia e medical
in e en ion.
A conse a i e managemen app oach could be conside ed in
pa ien s wi h a his ological diagnosis o g ade 1 endome ial ca ci-
noma (o p emalignan disease such as AH) [31]. The op imal
me hod o ob ain hese his ologic cha ac e is ics is dila a ion and
cu e age (D&C) [33]; his p ocedu e is supe io o pipelle biopsy
in e ms o accu acy o he umou g ade [34].
The his ological diagnosis should be e iewed by an expe
pa hologis o imp o e he accu acy o his ological assessmen
(endome ial ca cinoma o AH) and he eliabili y o umou g ad-
ing [35], whe eas he ini ial s age should be con i med by
enhanced pel ic magne ic esonance imaging (MRI) o exclude
o e myome ial in asion, as well as adnexal o pel ic node
in ol emen [36]. Pa ien s should be in o med ha his is a non-
s anda d app oach and hey should be willing o accep close
ollow-up du ing and a e he ea men . They should also be
in o med o he need o u u e hys e ec omy in case o ailu e o
he ea men and/o a e p egnancies.
Recommenda ion 2.1. Pa ien s wi h AH/EIN o g ade 1
endome ioid endome ial cance eques ing e ili y p ese ing
he apy mus be e e ed o specialised cen es
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 2.2. In hese pa ien s, D&C wi h o wi hou
hys e oscopy mus be pe o med
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 97.3% (36) yes, 2.7% (1) abs ain (37 o e s)
Recommenda ion 2.3. AH/EIN o g ade 1 EEC mus be con-
i med/diagnosed by a specialis gynaecopa hologis
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 2.4. Pel ic MRI should be pe o med o exclude
o e myome ial in asion and adnexal in ol emen . Expe
ul asound can be conside ed as an al e na i e
Le el o e idence: III
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 2.5. Pa ien s mus be in o med ha e ili y-
spa ing ea men is a non-s anda d ea men and he p os and
cons mus be discussed. Pa ien s should be willing o accep close
ollow-up and be in o med o he need o u u e hys e ec omy
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 97.3% (36) yes, 2.7% (1) abs ain (37 o e s)
Managemen schemes o e ili y-p ese ing he apy
Conse a i e medical ea men o endome ial cance is based
on p oges ins wi h med oxyp oges e one ace a e (MPA; 400–
600 mg/day) o meges ol ace a e (MA; 160–320 mg/day) [33].
Few pape s ha e add essed he use o LNG-IUD bu p elimina y da a
using such ea men (added o gonado opin- eleasing ho mone
[GnRH] analogues) seem o demons a e simila emission and
ecu ence a es as o al p oges ins [37]. Assessmen o esponse
mus be pe o med a 6 mon hs wi h a new D&C and imaging [38].
Response a es associa ed wi h he conse a i e managemen
o endome ial ca cinoma a e a ound 75% [39,40], bu ecu ence
a es a e 30–40% [39,41,42]. S anda d su ge y wi h hys e ec omy
should be p oposed o non- esponde s while main enance ea -
men o a u he 6 mon hs can be conside ed in esponde s
who wish o delay p egnancy [33].
Al hough p oges e one ecep o (PgR) s a us is a eliable
p edic i e ac o o disease emission, a ou ine check is no
ecommended since 50% o PgR nega i e pa ien s will espond o
ea men [43].
P egnancy is associa ed wi h a educed isk o endome ial
cance ecu ence [40]. Findings om ecen me a-analyses
showed ha he pooled li e bi h a e among women ecei ing
e ili y-p ese ing ea men o endome ial cance was 28%,
and eached 39% when assis ed ep oduc ion echnology was used
[39,44]. Thus, o pa ien s achie ing a comple e esponse a
6 mon hs, concep ion mus be encou aged and hese pa ien s
should be e e ed o a e ili y clinic.
Fo pa ien s wi h disease ecu ence a e an ini ial esponse,
hys e ec omy should be p oposed as he i s op ion. Mo eo e ,
gi en he high a e o ecu ence, a e comple ion o childbea ing
(o a e he age o po en ial p egnancy), s anda d ea men wi h
hys e ec omy and salpingo-oopho ec omy is ecommended.
P ese a ion o he o a ies can be conside ed in selec ed cases,
depending on he pa ien ’s age and gene ic isk ac o s.
Recommenda ion 2.6. Fo pa ien s unde going e ili y-
p ese ing he apy, MPA (400–600 mg/day) o MA (160–320 mg/-
day) is he ecommended ea men . Howe e , ea men wi h
LNG-IUD wi h o wi hou GnRH-analogues can also be conside ed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 2.7. In o de o assess esponse, D&C, hys-
e oscopy and imaging a 6 mon hs mus be pe o med. I no
esponse is achie ed a e 6 mon hs, s anda d su gical ea men
should be pe o med
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 2.8. In case o comple e esponse, concep ion
mus be encou aged and e e al o a e ili y clinic is ecommended
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 563

Recommenda ion 2.9. Main enance ea men should be consid-
e ed in esponde s who wish o delay p egnancy
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 2.10. Pa ien s no unde going hys e ec omy
should be e-e alua ed clinically e e y 6 mon hs
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 97.3% (36) yes, 2.7% (1) abs ain (37 o e s)
Recommenda ion 2.11. A e comple ion o childbea ing, a hys-
e ec omy and salpingo-oopho ec omy should be ecommended.
The p ese a ion o he o a ies can be conside ed depending on
age and gene ic isk ac o s
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
3. Which (molecula ) ma ke s can help dis inguish
(p e)cance ous lesions om benign mimics?
Di e en ial diagnosis be ween benign u e ine lesions and
endome ial (p e)ca cinomas is based mainly on mo phological
c i e ia bu may be suppo ed by addi ional immunohis ochemical
(IHC) ma ke s and molecula al e a ions in p oblema ic cases [45].
Cu en ly, AH/EIN is he p e e ed e minology o he p ecu so
lesion o he mos common ype o endome ial ca cinoma,
endome ioid ca cinoma, including i s a ian s.
Recommenda ion 3.1. In case o unce ain y low h eshold e e -
al o a specialised gynaecopa hologis is ecommended
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
The di e en ial diagnosis o AH/EIN includes, in pa icula ,
endome ial hype plasia wi hou a ypia, bu also includes o he
mimics, such as glandula and s omal b eakdown, ocal glandula
c owding and epi helial me aplasias (e.g. hype sec e o y changes).
Loss o PTEN exp ession, mos ly by mu a ion, and loss o PAX-2 by
down egula ion [46–48], a e he only immunohis ochemical
ma ke s ha ha e been su icien ly s udied and can be used on
cu e age ma e ial. Loss o PTEN occu s in 40–50% o AH/EIN cases,
whe eas loss o PAX-2 occu s in 70% o AH/EIN, and a join loss o
PTEN and PAX-2 occu s in a ound 30% o AH/EIN [49–51].
Recommenda ion 3.2. PTEN and PAX-2 IHC is ecommended o
dis inguish AH/EIN om benign mimics. O he ma ke s ha can be
used in his con ex a e MLH1 and ARID1a by IHC
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Ano he his ological en i y ha may a ise in he di e en ial
diagnosis o AH/EIN is he a e a ypical polypoid adenomyoma
(APA), o which he e a e no IHC s ains wi h p ac ical alue.
Recommenda ion 3.3. IHC is no ecommended o dis inguish
APA om AH/EIN
Le el o e idence: V
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
The pu a i e p ecu so o se ous ca cinoma, se ous endome ial
in aepi helial ca cinoma (SEIC), is conside ed a non-in asi e cance
a he han a p ecance since i may be associa ed wi h ex ensi e
ex au e ine disease [9]. Molecula al e a ions o se ous ca cinoma
a e al eady p esen in SEIC, which is especially ue o p53 exp es-
sion [52–54]. A comple ely nega i e immuno eac i e pa e n o
p53 (‘all o null’) is conside ed a su oga e o p53 mu a ion, and is
p esen in almos all SEIC and in asi e se ous ca cinomas [55].
Recommenda ion 3.4. p53 by IHC is ecommended o dis inguish
SEIC om i s mimics
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
In selec ed cases o endome ial cance , clinical and adiological
wo k-up may no be conclusi e abou he endome ial o igin o he
u e ine umou . In addi ion, endoce ical, o a ian and endome ial
adenoca cinomas may show his opa hological o e lap. Se e al IHC
ma ke s ha e been p oposed o hese di e en ial diagnoses, bu
hese ma ke s lack sensi i i y o speci ici y o be used as single
ma ke s. When endoce ical o igin is conside ed, he use o a panel
o ma ke s, including ca cinoemb yonic an igen (CEA), imen in,
oes ogen ecep o (ER) and p16 (as su oga e o human papilloma
i us [HPV]), is ecommended [56]. In case o p16 posi i i y, he
s aining pa e n should be aken in o accoun . Di use p16 s aining
is equen ly seen in se ous, clea cell and mucinous ca cinoma
endome ial cance s [57,58]. In cases o scan y issue wi h se ous
ca cinoma, an o a ian o igin o he se ous ca cinoma should be con-
side ed. The mos disc imina o y ma ke o his di e en ial diag-
nosis is Wilms umou 1 gene (WT-1) [59], which is exp essed in
80–100% o high-g ade se ous ca cinomas o he o a y [60,61] com-
pa ed wi h 7–20% in se ous endome ial ca cinomas [62,63]. In gen-
e al, he exp ession p o ile should be in e p e ed in he con ex o
he mo phological sub ype. An indi idual app oach, wi h close co -
ela ion be ween clinical p esen a ion and mo phological sub ype,
is he e o e ecommended.
Recommenda ion 3.5. A panel o ma ke s mus be used in cases
whe e endoce ical cance is suspec ed. This panel should include
a leas ER, imen in, CEA and p16 by IHC, and needs o be assessed
in he his ologic and clinical con ex . In addi ion, HPV analysis can
be conside ed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 3.6. WT-1 by IHC is he ecommended ma ke
o de e mine he o igin o se ous cance
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 3.7. Mo phology (and no IHC) should be used
o dis inguish AH/EIN om EEC
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Su ge y
4. How does he medical condi ion in luence su gical
ea men ?
Manda o y p e-ope a i e wo k-up
The consensus is based on cu en clinical p ac ice. Family his-
o y is usually aken o iden i y isk ac o s associa ed wi h LS,
564 Endome ial cance consensus con e ence guidelines
including endome ial cance , colon cance and o he cance s
belonging o he Lynch spec um. Gene al assessmen and, i
app op ia e, ge ia ic assessmen a e equi ed in pa ien s wi h
como bidi ies and elde ly pa ien s, espec i ely, in o de o adap
he su gical s a egy. Indeed, endome ial cance is equen ly
associa ed wi h obesi y, hype ension and diabe es and, in some
pa ien s, he ex en o su ge y o s aging ha is heo e ically
equi ed may no be easible. In such cases, a bene i - isk assess-
men o su ge y may lead o an indi idualised decision o pe o m
a ‘non-s anda d’ su ge y o a limi ed s aging p ocedu e.
Pel ic examina ion and pel ic ul asonog aphy a e manda o y
componen s o clinical s aging o endome ial cance in o de o
es ablish a en a i e In e na ional Fede a ion o Gynecology and
Obs e ics (FIGO) s aging be o e de ini i e pa hology. In addi ion
o being he i s imaging echnique used o e alua e abno mal
u e ine bleeding, ul asonog aphy, p e e ably specialised ul a-
sonog aphy [64], o e s he possibili y o e alua ing he size o
he umou , uling ou o a ian disease, and assessing myome ial
in asion and ce ical s omal in ol emen [65].
P e-ope a i e pa hological in o ma ion is c ucial o es ablish-
ing he su gical plan. Fi s , all pa ien s wi h a isk o cance ,
pa icula ly pa ien s wi h pos menopausal bleeding and a hype -
plas ic endome ium a ul asound, should be in es iga ed wi h
endome ial biopsy o cu e age in o de o (1) a oid u e ine
mo cella ion, which poses a isk o sp eading unsuspec ed cance -
ous issue, no ably endome ial ca cinomas o sa comas, beyond
he u e us and may make he pa hological assessmen o myome-
ial in asion ex emely di icul ; and (2) p e en he disco e y o
an unexpec ed malignancy a e inadequa e su ge y (sub o al
hys e ec omy and/o p ese a ion o he o a ies in a pos -
menopausal pa ien , incomple e s aging). Second, as g ading o
EEC has a signi ican p ognos ic impac [66] and a ious his o ypes
o endome ial cance ha bou di e en na u al his o ies, he
p ima y he apeu ic s a egy mus be adap ed o he in o ma ion
p o ided by a p e-ope a i e pa hological examina ion, despi e
he ac ha disc epancies be ween p e-ope a i e e alua ion and
inal pa hology exis [67].
The inal he apeu ic s a egy should be adap ed acco ding o
he in o ma ion a ailable be o e su ge y, aking in o accoun he
en a i e s age (appa en s age I o mo e ad anced s age), g ade
(o endome ioid umou s; g ade 1–3 o a bina y sys em) and
his o ype (endome ioid e sus non-endome ioid umou ).
Recommenda ion 4.1. Manda o y wo k-up mus include: Family
his o y; gene al assessmen and in en o y o como bidi ies;
ge ia ic assessmen , i app op ia e; clinical examina ion, includ-
ing pel ic examina ion; ans aginal o ans ec al ul asound; and
comple e pa hology assessmen (his o ype and g ade) o an
endome ial biopsy o cu e age specimen
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 4.2. Ex en o su ge y should be adap ed o he
medical condi ion o he pa ien
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Op ional p e-ope a i e wo k-up
Imaging
Addi ional imaging is conside ed acco ding o he clinical si u-
a ion. Compu ed omog aphy (CT) scan and/o posi on emission
omog aphy (PET)-CT a e op ions in clinically ad anced endome-
ial cance . In appa en s age I endome ial cance , MRI may be
use ul o comple e in o ma ion ega ding myome ial in asion
[65]. Howe e , his applies only in ins i u ions whe e he indica-
ion o lymph node dissec ion (LND) is ailo ed acco ding o he
s a i ica ion o pa ien s in o low-, in e media e- and high- isk
g oups. In his se ing, specialised ul asonog aphy and/o
in a-ope a i e pa hological examina ion o he u e us may also
be conside ed [68].
Recommenda ion 4.3. In clinical s age I, g ade 1 and 2: A leas
one o he h ee ollowing ools should be used o assess
myome ial in asion i LND is conside ed: Expe ul asound
and/o MRI and/o in a-ope a i e pa hological examina ion
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 4.4. O he imaging me hods ( ho acic, abdom-
inal and pel ic CT scan, MRI, PET scan o ul asound) should be
conside ed o assess o a ian, nodal, pe i oneal o me as a ic disease
Le el o e idence: IV
S eng h o ecommenda ion: C
Consensus: 94.6% (35) yes, 2.7% (1) abs ain, 2.7% (1) no (37
o e s)
Se um umou ma ke s
The e is e idence ha he se um umou ma ke s cance an i-
gen 125 (CA-125) and, mo e ecen ly, human epididymis p o ein
4, a e signi ican ly co ela ed wi h his ological g ade, s age, lymph
node me as ases, myome ial in asion and ce ical in ol emen
[69–71]. Howe e , he app op ia e cu -o has no been es ab-
lished and e idence ha se um ma ke assessmen is clinically
use ul is lacking.
Recommenda ion 4.5. The e is no e idence o he clinical
use ulness o se um umou ma ke s, including CA-125
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 91.9% (34) yes, 5.4% (2) abs ain, 2.7% (1) no (37
o e s)
Su gical managemen o appa en s age I endome ial cance
Wi h he excep ion o pa ien s managed conse a i ely,
ex a ascial o al hys e ec omy wi hou colpec omy is he main-
s ay o managemen o pa ien s wi h endome ial cance . The
a ionale o he addi ional emo al o he adnexae is o p e en
o a ian cance and ule ou o a ian me as ases. In p emenopausal
pa ien s, howe e , o a ian p ese a ion may be discussed in
selec ed cases. Younge pa ien s wi h endome ial cance o en
ha e ea ly s age, low g ade umou s. Thus, o a oid he sho -
e m and long- e m consequences o su gical menopause, he e
is a a ionale o o a ian p ese a ion in young women. Se e al
e ospec i e s udies ha e ecen ly p o ided e idence ha o a ian
p ese a ion has no s a is ically signi ican impac on he o e all
su i al (OS) o young pa ien s wi h ea ly-s age endome ial
cance [72]. Howe e , ex eme ca e mus be aken o ule ou
synch onous concomi an o a ian malignancy.
Recommenda ion 4.6. S anda d su ge y is o al hys e ec omy
wi h bila e al salpingo-oopho ec omy wi hou aginal cu
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Recommenda ion 4.7. O a ian p ese a ion can be conside ed in
pa ien s younge han 45 yea s old wi h g ade 1 EEC wi h myome-
ial in asion <50% and no ob ious o a ian o o he ex au e ine
disease
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 565
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 4.8. In cases o o a ian p ese a ion, salpingec-
omy is ecommended
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Recommenda ion 4.9. O a ian p ese a ion is no ecommended
o pa ien s wi h cance amily his o y in ol ing o a ian cance
isk (e.g. BRCA mu a ion, LS, e c.). Gene ic counselling/ es ing
should be o e ed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (37 o e s)
Minimally in asi e su gical echniques
Hys e ec omy and bila e al salpingo-oopho ec omy can be ca -
ied ou using he open, lapa oscopic o aginal app oach.
The la ges andomised ial compa ing lapa oscopy o lapa o-
omy is he LAP2 s udy [73], which was designed o compa e
lapa oscopy e sus lapa o omy o comp ehensi e su gical
s aging and managemen o s age I–IIA u e ine cance , including
hys e ec omy, salpingo-oopho ec omy, pel ic cy ology and pel ic
and pa a-ao ic lymphadenec omy. In his ial, pa ien s we e
andomly assigned o lapa oscopy (n= 1696) o open lapa o omy
(n= 920). A signi ican ly longe ope a i e ime was epo ed o
he lapa oscopy g oup compa ed wi h he lapa o omy g oup
(204 s 130 minu es, espec i ely). In a-ope a i e complica ion
a es we e simila be ween g oups. Howe e , lapa oscopy was
associa ed wi h signi ican ly ewe mode a e o se e e pos -
ope a i e ad e se e en s (14% s 21%) and a lowe equency o
hospi alisa ions o mo e han 2 days (52% s 94%) han lapa o-
omy. Al hough pel ic and pa a-ao ic lymph nodes we e no
emo ed in 8% and 4% o pa ien s in he lapa oscopy and lapa o-
omy g oups, espec i ely (P< 0.0001), he e was no di e ence in
he o e all de ec ion o ad anced s age disease be ween he wo
g oups. The majo sho coming o his ial is he high con e sion
a e ela ed o i s mul icen ic design. Indeed, 25.8% o pa ien s
assigned o he lapa oscopic g oup we e con e ed o lapa o-
omy, wi h a s a emen o ‘poo isibili y’ epo ed in 14.6% o
cases, e lec ing he lea ning cu e o some in es iga o s, pa ic-
ula ly o LND. In con as , a con e sion a e o 10.8%, wi h poo
isibili y eco ded as he main ac o in 4.9% o cases, was
epo ed in a Du ch andomised ial in which no lymphadenec-
omy was pe o med [74]. Howe e , as u he aining o he use
o obo ic assis ance would likely ha e esul ed in e en be e
esul s wi h lapa oscopic su ge y, his high con e sion a e
epo ed in LAP2 does no weaken he au ho s’ conclusions, and
his ial p o ides e idence ha lapa oscopic su gical s aging
o u e ine cance esul s in ewe complica ions and sho e
hospi al s ay.
Acco ding o a me a-analysis o da a om eigh andomised
con olled ials (RCTs) conduc ed by Zullo e al. [75], in a-
ope a i e complica ion a es we e no di e en be ween
lapa oscopy and lapa o omy (RR 1.25; 95% CI 0.99–1.56) wi h
no signi ican he e ogenei y ac oss he s udies. Es ima ed blood
loss and haemoglobin o haema oc i changes we e consis en ly
less a e lapa oscopy in he six s udies whe e his was epo ed.
Ope a i e ime was highe by 34–74 min in he lapa oscopy
g oup. The au ho s also ound a signi ican ad an age o lapa o-
scopy o e lapa o omy in e ms o pos -ope a i e complica ions
(RR 0.71; 95% CI 0.63–0.79) wi h signi ican he e ogenei y ac oss
he s udies.
Ao ic dissec ion can also be achie ed in obese pa ien s using an
ex ape i oneal lapa oscopic app oach [76].
Taken oge he , hese indings p o ide de ini i e e idence o he
sho - e m bene i and cos -e ec i eness o lapa oscopic hys e ec-
omy in pa ien s wi h gynaecological cance . This includes pa ien s
wi h como bidi ies, obesi y o ad anced age. Rega ding como bid-
i y, Tozzi e al. [77] ound ha he su gical echnique is he only
signi ican pa ame e associa ed wi h complica ion a e, ega dless
o isk g oup, s essing he ac ha pa ien s wi h se ious como -
bidi ies bene i mos om lapa oscopy. The issue o ad anced
age has also been add essed in he gynaecological oncology li e a-
u e. Sies o e al. [78] epo ed ou comes om a se ies o 48
pa ien s aged >65 yea s who had unde gone lapa oscopic su ge y
o endome ial cance . Ou comes om his g oup we e compa a-
ble o younge pa ien s in e ms o ope a i e ime, blood loss, need
o blood ans usions, nodal coun and in a-ope a i e and pos -
ope a i e complica ions. The au ho s conclude ha in he absence
o absolu e anaes hesia con aindica ions, lapa oscopy is easible
and sa e in olde women wi h endome ial cance . Howe e , as
cance in olde women was mo e equen ly ups aged han in
younge women, hey s a e ha comp ehensi e su gical s aging
should be o e ed, ega dless o age, o a oid unde s aging and o
op imise ea men s a egies.
Six andomised ials compa ing ou comes a e lapa o omy e -
sus lapa oscopy a e cu en ly a ailable, ou o which ha e been
includedina published me analysis [79].Howe e ,only wo o hese
ou ials epo ed da a o OS, disease- ee su i al and cance -
ela ed su i al. Based on he a ailabili y o new da a, his me a-
analysis was subsequen ly upda ed by Palomba e al. in 2009 [80]
o include a hi d ial epo ing hese long- e mou comes, esul ing
in a sample o 359 pa ien s. No signi ican he e ogenei y was
obse ed among hese ials and he e was no signi ican ad e se
e ec o a lapa oscopic app oach on he OS, disease- ee su i al
o cance - ela ed su i al (OR 0.96, 0.95 and 0.91, espec i ely).
Long- e m ou comes o he andomised con olled LAP2 ial
we e published in 2012 [81]. The p ima y endpoin was non-
in e io i y o he ecu ence- ee in e al. Non-in e io i y was
de ined as no mo e han a 40% inc ease in he isk o ecu ence
wi h lapa oscopy compa ed wi h lapa o omy. The es ima ed haza d
a io (HR) o ecu ence- ee su i al wi h lapa oscopy e sus
lapa o omy was 1.14 (90% CI 0.92–1.46).Ac ual ecu ence a es
we e subs an ially lowe han an icipa ed; he es ima ed 3-yea
ecu ence a e was 11.4% wi h lapa oscopy and 10.2% wi h lapa o-
omy, and he es ima ed 5-yea OS was almos iden ical in bo h
a ms (89.8%).
Recommenda ion 4.10. Minimally in asi e su ge y is ecom-
mended in he su gical managemen o low-and in e media e-
isk endome ial cance
Le el o e idence: I
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
In a e ospec i e, mul i-ins i u ional ial o pa ien s wi h high
g ade endome ial cance , ou comes o 191 pa ien s who unde -
wen lapa o omy we e compa ed wi h 192 pa ien s who unde -
wen minimal in asi e su ge y. In his ial, women wi h high
g ade endome ial cance s aged by minimally in asi e echniques
expe ienced ewe complica ions and simila su i al ou comes
compa ed wi h hose s aged by lapa o omy [82].
Recommenda ion 4.11. Minimally in asi e su ge y can be con-
side ed in he managemen o high- isk endome ial cance
Le el o e idence: IV
S eng h o ecommenda ion: C
Consensus: 100% yes (37 o e s)
566 Endome ial cance consensus con e ence guidelines
Al e na i e app oaches o pa ien s unsui able o s anda d su gical
he apy
Al hough ad ances in su gical echniques, anaes hesiology and
pe i-ope a i e managemen mean ha he as majo i y o
pa ien s wi h endome ial cance a e amenable o s anda d su gi-
cal he apy, a small p opo ion o pa ien s a e s ill medically un i
o lapa oscopic su ge y o lapa o omy. Howe e , hese pa ien s
can s ill be managed ei he su gically by aginal hys e ec omy,
whene e possible, wi h bila e al salpingo-oopho ec omy, o by
de ini i e RT, combining ex e nal beam adia ion he apy (EBRT)
and b achy he apy, o by ho monal ea men . In addi ion,
aginal hys e ec omy is an accep able minimally in asi e su gical
op ion in some low- isk pa ien s who do no need LND (see
Sec ion 4).
Recommenda ion 4.12. Vaginal hys e ec omy wi h salpingo-
oopho ec omy can be conside ed in pa ien s un i o he ecom-
mended su ge y and in selec ed pa ien s wi h low- isk endome-
ial cance
Le el o e idence: IV
S eng h o ecommenda ion: C
Consensus: 100% yes (37 o e s)
Recommenda ion 4.13. In medically un i pa ien s, RT o
ho mone ea men can be conside ed
Le el o e idence: IV
S eng h o ecommenda ion: C
Consensus: 100% yes (37 o e s)
5. Wha a e he indica ions o and o wha ex en is
lymphadenec omy indica ed in he su gical managemen o
endome ial cance ?
Su gical s aging in appa en s age I EEC
Collec ion o pe i oneal cy ology was included as a s aging p o-
cedu e in ea lie ecommenda ions, bu i is no longe conside ed
manda o y. Howe e , since e ospec i e s udies indica e ha pos-
i i e pe i oneal cy ology has p ognos ic alue, collec ion o his
in o ma ion could be conside ed, especially in pa ien s wi h
umou s o non-endome ioid his ology [83,84].
Recommenda ion 5.1. Pe i oneal cy ology is no longe conside ed
manda o y o s aging
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (37 o e s)
Lymphadenec omy
Lymphadenec omy is an in eg al pa o he comp ehensi e su -
gical s aging o endome ial cance . Howe e , he ole o lym-
phadenec omy in ea ly endome ial cance is unclea and
con o e sy emains ega ding he indica ions o , he ana omic
ex en o , and he he apeu ic alue o lymphadenec omy in he
managemen o he disease.
The de ini ion o an adequa e lymphadenec omy has no been
s anda dised: Cu en app oaches include pel ic lymphadenec-
omy, pa a-ao ic lymphadenec omy o he in e io mesen e ic
a e y (IMA) and pa a-ao ic lymphadenec omy up o he enal
essels. Lymph node coun s ha e become a ma ke o adequacy
o lymph node e alua ion in a a ie y o solid umou disease si es.
In endome ial cance , wo e ospec i e e iews ha e shown ha
pa ien s had imp o ed su i al when a leas 10 o 12 lymph nodes
we e emo ed du ing lymphadenec omy [85,86]. Lymph node
coun s he e o e p o ide a su oga e way o measu ing he ade-
quacy o a LND and, as such, mo e han 10 nodes should be
emo ed [87,88].
Sampling o lymph nodes has a low sensi i i y in endome ial
cance [89]. Indeed, i has been shown ha pa a-ao ic nodes
may be posi i e in he absence o posi i e pel ic nodes [90,91],
sugges ing ha pa a-ao ic lymph nodes should be emo ed in
cases whe e a lymphadenec omy is indica ed. In he Mayo Clinic
expe ience o 281 pa ien s wi h endome ial cance who unde -
wen lymphadenec omy, 22% o pa ien s wi h high- isk disease
had lymph node me as ases: 51% had bo h posi i e pel ic and
pa a-ao ic nodes, 33% had posi i e pel ic lymph nodes only, and
16% had isola ed pa a-ao ic lymphadenopa hy [92]. As he majo -
i y (77%) o pa ien s wi h pa a-ao ic lymph node in ol emen had
me as ases abo e he IMA, pa a-ao ic lymphadenec omy up o he
enal essels is ecommended.
The concep o sen inel lymph node (SLN) dissec ion (SLND) was
i s de eloped in ce ical cance as a ool o selec pa ien s mos
sui able o su gical managemen . In low- and in e media e- isk
endome ial cance , he a ionale is di e en as he need o SLND
is con o e sial. Howe e , SLND could ep esen a comp omise
be ween no dissec ion (lea ing a small p opo ion o node posi i e
pa ien s) and ull dissec ion (adding a useless p ocedu e o he
majo i y o node-nega i e pa ien s). In addi ion, ul as aging o
he SLNs de ec s mic ome as ases o he wise undiagnosed by con-
en ional his ology, e en in pa ien s conside ed a low isk, on he
basis o g ade and dep h myome ial in asion [93]. Howe e , hese
la ge se ies only use he ce ix as he injec ion si e. The ques ion o
al e na i e injec ion si es in he endome ium o u e ine undus,
which a e ana omically mo e logical, is s ill a opic o in es iga ion.
Injec ion unde hys e oscopic, ul asound, lapa oscopic o open
guidance in pa ien s wi h endome ial cance has been add essed,
wi hou e idence o bene i o he mo e demanding and less
p ac ical modali ies.Ne e heless, e idence is accumula ing ha
he SLND may be use ul in he managemen o endome ial
cance s [94].
Recommenda ion 5.2. I a lymphadenec omy is pe o med, sys-
ema ic emo al o pel ic and pa a-ao ic nodes up o he le el o
he enal eins should be conside ed
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 91.9% (34) yes, 2.7% (1) abs ain, 5.4% (2) no (37
o e s)
Recommenda ion 5.3. SLND is s ill expe imen al, bu la ge se ies
sugges ha i is easible. SLND inc eases he de ec ion o lymph
nodes wi h small me as ases and isola ed umou cells; howe e ,
he impo ance o hese indings is unclea
Le el o e idence: IV
S eng h o ecommenda ion: D
Consensus: 100% yes (37 o e s)
Indica ions o lymphadenec omy
Al hough he he apeu ic e ec o lymphadenec omy is unclea ,
i is an in eg al pa o comp ehensi e s aging. The ad an ages o
comp ehensi e su gical s aging a e a be e de ini ion o p ognosis
and app op ia e iage o pa ien s o adju an he apy.
Da a om wo RCTs do no suppo he he apeu ic bene i o
lymphadenec omy in ea ly s age endome ial cance . Benede i-
Panici e al. andomised 514 women wi h clinical s age I endome-
ial cance o ei he sys ema ic pel ic lymphadenec omy o no
LND and ound no imp o emen in disease- ee su i al o OS
be ween he wo g oups [95]. Simila ly, he ASTEC ial, which
included 1408 pa ien s wi h s age I endome ial cance who we e
andomised o ecei e su gical s aging wi h o wi hou pel ic
lymphadenec omy, ailed o show a bene icial e ec o
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 567
dis an si es. The e is cu en ly no e idence o sugges ha mode n
echniques o image-guided b achy he apy and in ensi y-
modula ed RT (IMRT) a e supe io o con en ional app oaches,
al hough a single ins i u ion e ospec i e s udy o RT (EBRT p e-
dominan ly using an IMRT echnique ollowed by image-guided
high dose a e [HDR] b achy he apy) o aginal ecu ence has
also epo ed high umou con ol a es [172].
Recommenda ion 10.5. RT wi h cu a i e in en is indica ed in
pa ien s wi h isola ed aginal elapse a e su ge y
Le el o e idence: III
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
Chemo he apy wi h RT o ecu ence
RT can be conside ed o pa ien s wi h aginal o pel ic nodal
ecu ence. Imp o emen s in RT echniques allow o be e means
o localised ea men , o possibly e ea men o pa ien s who
ha e p e iously ecei ed RT. Whe he chemo he apy has an addi-
ional bene i is unclea . The ongoing andomised phase II
GOG0238 (NCT00492778) ial is compa ing pel ic i adia ion o
45 Gy in 25 ac ions plus ei he b achy he apy o ex e nal beam
boos wi h he same schedule plus concomi an cispla in (40 mg/
m
2
weekly) in women wi h aginal/pel ic elapse who ha e no
ecei ed p io RT.
Recommenda ion 10.6. Fo aginal o pel ic nodal ecu ence,
chemo he apy wi h RT could be conside ed in pa ien s wi h high-
isk ea u es o sys emic elapse
Le el o e idence: IV
S eng h o ecommenda ion: C
Consensus: 97.1% (33) yes, 2.9% (1) abs ain (34 o e s)
Combined app oaches o ecu ence and e-i adia ion
The use o sys emic he apy o su ge y p io o RT o aginal
o pel ic node ecu ence could be conside ed in ce ain pa ien s
wi h mo e bulky disease. As he echniques o image-guided
RT ha e imp o ed, he e a e si ua ions whe e e-i adia ion
can be conside ed, al hough e idence om clinical ials is
lacking.
Recommenda ion 10.7. Use o sys emic he apy o su ge y p io
o RT o aginal o pel ic node ecu ence could be conside ed in
ce ain pa ien s
Le el o e idence: V
S eng h o ecommenda ion: C
Consensus: 100% yes (34 o e s)
Recommenda ion 10.8. Re-i adia ion could be conside ed in
highly selec ed pa ien s using specialised echniques
Le el o e idence: V
S eng h o ecommenda ion: C
Consensus: 100% yes (34 o e s)
Pallia i e RT
RT can be e ec i ely used o pallia e symp oms such as bleed-
ing, bone me as ases o pain ul nodal ecu ence. No andomised
ials ha e been conduc ed compa ing RT wi h pallia i e
chemo he apy.
Recommenda ion 10.9. RT is indica ed o pallia ion o symp oms
ela ed o local ecu ence o sys emic disease
Le el o e idence: IV
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
Radical RT o p ima y endome ial cance
RT can be used as a p ima y ea men in pa ien s wi h un e-
sec able disease, o whe e he e a e medical con aindica ions o
su ge y [173,174]. T ea men in ol es in au e ine b achy he apy
alone o in combina ion wi h EBRT. Image guided b achy he apy
may imp o e ou comes [175]. Two yea local con ol a es o mo e
han 90% can be achie ed o medically inope able s age I disease.
Recommenda ion 10.10. RT may be indica ed o p ima y
umou s ha a e un esec able, o whe e su ge y canno be
pe o med o is con aindica ed o medical easons
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (34 o e s)
11. Wha a e he op imal sys emic he apies o ad anced/
ecu en disease?
The majo i y o pa ien s wi h ad anced o ecu en disease will
be candida es o sys emic pallia i e he apy. The choice be ween
ho monal ea men and chemo he apy elies on se e al ac o s,
including his opa hological and clinical ea u es o he indi idual
pa ien .
Ho monal he apy: Which pa ien and when?
Ho monal he apy is indica ed o pa ien s wi h ad anced o
ecu en endome ial cance and endome ioid his ology. This
s a emen is based on se e al clinical ials ha ha e shown clini-
cal ac i i y wi h a a ou able oxici y p o ile [176,177].
Recommenda ion 11.1. Ho mone he apy is indica ed in
ad anced o ecu en EEC
Le el o e idence: II
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
Response o ho monal he apy is qui e a iable, and a numbe
o pa hological ac o s con ibu ing o his a ia ion ha e been
iden i ied. Fo example, ho monal he apy is mo e likely o be
e ec i e in g ade 1 o 2 endome ioid umou s. In a la ge clinical
ial o MPA, he esponse a e was 37% o g ade 1, 23% o g ade
2 and 9% o g ade 3 umou s [176]. O he s ha e epo ed simila
indings [177]. Pa ien s wi h ho mone ecep o posi i e disease
ha e also been shown o ha e a highe chance o esponding o
endoc ine he apy. In a andomised ial, he esponse a e
obse ed in pa ien s wi h ER and PgR posi i e disease was a ound
25% and 37%, espec i ely, bu was only 7–8% in pa ien s wi h ER/
PgR nega i e disease [176,177]. Based on hese esul s, i seems
ha posi i i y o ER and/o PgR could be a p edic i e ac o o
esponse o endoc ine he apy and so should be de e mined be o e
ini ia ing ho monal he apy.
Recommenda ion 11.2. Ho mone he apy is mo e likely o be
e ec i e in g ade 1 o 2 endome ioid umou s
Le el o e idence: IV
S eng h o ecommenda ion: B
Consensus: 100% yes (34 o e s)
Recommenda ion 11.3. Ho mone ecep o s a us should be
de e mined be o e ho mone he apy is ini ia ed, as i is mo e
likely o be e ec i e in pa ien s wi h posi i e PgR and ER s a us
Le el o e idence: III
S eng h o ecommenda ion: B
Consensus: 97.1% (33) yes, 2.9% (1) abs ain (34 o e s)
574 Endome ial cance consensus con e ence guidelines

Biopsy o ecu en disease can be conside ed, since he e may
be di e ences in ho mone ecep o s a us in he p ima y and
me as a ic umou . In a p ospec i e collec ion o 686 p ima y
endome ial umou s and 171 me as a ic lesions, loss o PgR
exp ession inc eased wi h disease p og ession, wi h 23% o p i-
ma y umou s and 76% o me as a ic lesions demons a ing PgR
loss [178].
Recommenda ion 11.4. Biopsy o ecu en disease could be
conside ed as he e may be di e ences in ho mone ecep o s a us
in he p ima y and me as a ic umou
Le el o e idence: III
S eng h o ecommenda ion: C
Consensus: 100% yes (34 o e s)
Ho mone he apy is he p e e ed on -line sys emic he apy
o pa ien s wi h ho mone ecep o posi i e g ade 1 o 2 umou s
in he absence o apidly p og essi e disease, as i p o ides an
excellen bene i / isk a io and con enien oxici y p o ile. How-
e e , pa ien s wi h isce al in ol emen and apidly p og essi e
disease a e no candida es o ho mone he apy as i is no usually
associa ed wi h a apid esponse.
Recommenda ion 11.5. Ho mone he apy is he p e e ed on -
line sys emic he apy o pa ien s wi h ho mone ecep o posi i e
umou s – g ade 1 o 2 and wi hou apidly p og essi e disease
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
The p oges ogens, MPA 200 mg o MA 160 mg, a e gene ally
ecommended. They ha e shown clea ac i i y o he on -line
ea men o non-selec ed pa ien s wi h ecu en o pe sis en
endome ioid umou s no sui able o su ge y o RT, wi h
esponse a es o a ound 25% and PFS imes o 3 mon hs
[176,179]. Da a om a andomised ial compa ing low (200 mg/-
day) e sus high (1000 mg/day) dose MPA in 299 pa ien s wi h
ad anced o ecu en endome ial ca cinoma showed ha low-
dose MPA was mo e ac i e han he high dose in e ms o esponse
a e (25% s 15%, espec i ely) and OS (11.0 s 7.0 mon hs, espec-
i ely) [176].
Recommenda ion 11.6. P oges ogens (e.g. MPA 200 mg o MA
160 mg) a e gene ally ecommended
Le el o e idence: III
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
O he endoc ine he apies ha e also demons a ed ac i i y in
phase II ials among pa ien s wi h ad anced o ecu en endome-
ial cance , wi h amoxi en, anas ozole and ul es an all associ-
a ed wi h esponse a es o app oxima ely 10% [180–182].
In e es ingly, pa ien s included in he anas ozole ial had no
ecei ed p io p oges in he apy [182]. The combina ion o amox-
i en and MPA is associa ed wi h esponse a es and PFS simila o
MPA alone [183,184].
Recommenda ion 11.7. O he ho monal agen s o conside a e
p oges ins include amoxi en, ul es an and a oma ase inhibi o s
Le el o e idence: III
S eng h o ecommenda ion: C
Consensus: 100% yes (34 o e s)
Chemo he apy: Is he e any s anda d o ca e?
Endome ial cance is a ela i ely chemo-sensi i e disease, wi h
an h acyclines, pla inum-based d ugs and axanes shown o be he
mos ac i e agen s. Two clinical ials showed ha he combina-
ion o cispla in and doxo ubicin was mo e ac i e han doxo ubicin
alone in e ms o esponse a e (43–41% s 17–25%) bu wi h no
bene i in e ms o OS [185,186]. The combina ion also esul ed
in a highe incidence o g ade 3–4 myelo oxici y and nausea/
omi ing.
In ano he GOG ial, conduc ed in pa ien s wi h measu able
FIGO III–IV endome ial cance , he addi ion o pacli axel o cis-
pla in and doxo ubicin was associa ed wi h a highe esponse a e
and PFS han cispla in and doxo ubicin alone (objec i e esponse
a e [ORR]: 57% s 34%, espec i ely, P< 0.01; median PFS: 8.3 s
5.3 mon hs, espec i ely, P< 0.01), and a small bu signi ican
imp o emen in OS (median 15.3 s 12.3 mon hs, espec i ely,
P= 0.037) [187]. Howe e , oxici y, especially pe iphe al neu opa-
hy, was signi ican ly highe (g ade 2–3: 39% s 5%, espec i ely).
Fo his eason, i has no been widely adop ed as a s anda d o ca e.
Finally, GOG209 was a andomised, non-in e io i y ial ha
compa ed he combina ion o pacli axel 160 mg/m
2
, cispla in
60 mg/m
2
and doxo ubicin 50 mg/m
2
(TAP) wi h pacli axel
175 mg/m
2
and ca bopla in AUC 6 (TC), bo h adminis e ed e e y
3 weeks. A o al o 1305 pa ien s we e included in his ial, and
p elimina y da a (no ye ully published) indica e a simila
esponse a e (51.3% s 51.2%) and PFS (median 13.5 s
13.3 mon hs) [188]. The median OS (p ima y s udy endpoin )
was 40.3 mon hs o TAP and 36.5 mon hs o TC, which me he
c i e ia o non-in e io i y. TC had a mo e a ou able oxici y p o ile
han TAP in his ial, wi h ewe pa ien s discon inuing he apy
due o oxici y (12% s 18%). In addi ion, TC can be adminis e ed
in he ou pa ien se ing whe eas TAP is gi en in he inpa ien
se ing in mos coun ies. This aspec may be impo an in e ms
o logis ical, inancial and quali y o li e conside a ions in he
pallia i e se ing.
Recommenda ion 11.8. The s anda d o ca e is 6 cycles o h ee-
weekly ca bopla in and pacli axel. This is based on he p elimina y
communica ion o a andomised ial showing simila e icacy and
less oxici y compa ed o cispla in/doxo ubicin/pacli axel
Le el o e idence: I
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
E idence suppo ing he use o second line chemo he apy a e
pla inum-con aining he apy in pa ien s wi h endome ial cance
is limi ed, especially in cases whe e he ea men - ee in e al ol-
lowing i s line chemo he apy is less han 6–12 mon hs. Al hough
a ious egimens ha e been e alua ed in his se ing [189–192],no
andomised ials ha e been published. The e o e, no speci ic eg-
imen can be ecommended as a s anda d o ca e o second line
chemo he apy.
Recommenda ion 11.9. The e is no s anda d o ca e o second
line chemo he apy
Le el o e idence: V
S eng h o ecommenda ion: C
Consensus: 100% yes (34 o e s)
12. Wha a e he mos p omising a ge ed agen s and which
s udy designs should be used o e alua e hei clinical bene i ?
Po en ially ‘d uggable’ molecula al e a ions in endome ial cance
Acco ding o he WHO classi ica ion o endome ial ca cinoma,
he e a e se en di e en ypes o umou s; howe e , endome ioid
ca cinoma, g ade 3 and se ous ca cinomas accoun o he as
majo i y o agg essi e umou s. Molecula gene ic al e a ions
in ol ed in he de elopmen o endome ioid cance s di e om
hose o se ous umou s and his mus be aken in o accoun when
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 575
designing clinical ials o e alua e he e icacy o molecula a -
ge ed agen s.
O e he las i een yea s, i has been demons a ed ha
endome ial cance shows mic osa elli e ins abili y (MSI) and
mu a ions in PTEN, PIK3CA and KRAS, and ha be a-ca enin genes
a e he mos common molecula abno mali ies in endome ioid
ca cinomas, whe eas se ous umou s ha e al e a ions o p53 and
loss o he e ozygosi y on se e al ch omosomes, as well as o he
molecula al e a ions (STK15, p16, E-cadhe in, and C-e bB2)
[193]. Recen ly, he TCGA Resea ch Ne wo k pe o med an in e-
g a ed genomic cha ac e isa ion o endome ial ca cinoma [5].
The PI3K/AKT pa hway is one o he mos equen ly al e ed sig-
nalling pa hways in endome ioid umou s, o en esul ing om
mu a ions in PTEN, PIK3CA and PIK3RI [194]. O pa icula in e es
is he downs eam e ec o , mammalian a ge o apamycin
(mTOR), and inhibi o s o mTOR a e now unde going e alua ion
in clinical ials. The RAS-RAF-MEK-ERK signalling pa hway also
plays an impo an ole in hese umou s, wi h equen mu a ions
in KRAS, bu also inac i a ion o umou supp esso s such as
RASF1A [195,196]. Fib oblas g ow h ac o -2 (FGFR2) is mu a ed
in 10–14% o endome ioid umou s and is a a ge o ecep o y -
osine kinase inhibi o s [197]. Angiogenesis also plays a ole in
endome ial umou igenesis [198]. In addi ion, umou homolo-
gous ecombina ion and misma ch epai de iciencies a e seen in
endome ioid umou s, he la e o which is pa icula ly associ-
a ed wi h LS, and hese pa hways could be in e es ing a ge s.
Al hough he e a e a la ge numbe o speci ic gene abno mali-
ies and abe an signalling pa hways ha appea o be p omising
a ge s, he equency o each abno mali y is small and his p e-
sen s a challenge o e alua ing he apies in clinical ials [199].
Examples include known umou ma ke s such L1CAM, Anexin 2,
o he y osine kinase ecep o s (insulin-like g ow h ac o ecep o
[IGFR], epide mal g ow h ac o ecep o [EGFR]), and signalling
pa hways in ol ed in epi helial o mesenchymal ansi ion ( ans-
o ming g ow h ac o -be a [TGF-b], wn ) o s em cell-ness
(No ch). PI3K/PTEN/AKT/mTOR pa hway, PTEN, MAPK-KRAS,
angiogenesis (especially FGFR2 and ascula endo helial g ow h
ac o [VEGF]/VEGF ecep o [VEGFR]), ER/PR and homologous
ecombina ion de iciency (HRD)/MSI a e al e ed in endome ial
cance , and he ele ance o hese po en ial a ge s should be s ud-
ied in clinical ials wi h a ge ed agen s.
Recommenda ion 12.1. PI3K/PTEN/AKT/mTOR pa hway, PTEN,
RAS-MAPK, angiogenesis (especially FGFR2 and VEGF/VEGFR),
ER/PgR and HRD/MSI a e al e ed in endome ial cance and
hei ele ance should be s udied in clinical ials wi h a ge ed
agen s
Le el o e idence: III
S eng h o ecommenda ion: B
Consensus: 100% yes (34 o e s)
New agen s in ecu en o me as a ic endome ial cance
The bene i o s anda d chemo he apy and ho monal he apies
is usually modes and o sho du a ion. Cu en ly, se e al di e en
a ge ed he apies a e unde going clinical e alua ion bu none a e
cu en ly licensed o use. EGFR, human epide mal g ow h ac o
ecep o -2 (HER2), mTOR and VEGFR inhibi o s ha e been es ed
in phase I and II ials, wi h modes esponse a es [200–203]. How-
e e , since his consensus con e ence was held, indings om wo
andomised phase II ials e alua ing he addi ion o be acizumab
o TC in ad anced o ecu en endome ial cance sugges ha his
migh be a p omising app oach wo hy o u he e alua ion in
phase III clinical ials [204,205]. GOG-86P was a 3-a m ial e alu-
a ing he addi ion o be acizumab, emsi olimus o ixabepilone o
i s line TC in 349 pa ien s wi h ad anced o ecu en endome ial
cance [204]. No di e ences in PFS we e seen when he h ee a ms
we e compa ed wi h his o ical da a o TC om GOG 209 [188].
Howe e , be acizumab appea ed supe io when he median OS
esul s we e compa ed wi h hese his o ical con ol da a (34.0 s
22.7 mon hs, P< 0.039). In he MITO END-2 ial, which included
108 pa ien s wi h ad anced o ecu en endome ial cance who
had ecei ed 0 o 1 p io lines o chemo he apy, be acizumab
was added o 6–8 cycles o TC and hen con inued as main enance
he apy. This app oach esul ed in a signi ican imp o emen in
median PFS (13 s 8.7 mon hs, P= 0.036) and a nume ical inc ease
in median OS (23.5 s 18 mon hs, P= 0.24), al hough hese OS da a
a e no ye ma u e [205].
Despi e hese p omising esul s, ew clinical ials o new a -
ge ed he apies a e molecula ly d i en [206] and he p e alence
o po en ial a ge s in me as a ic lesions has been s udied less han
in p ima y umou s [178].
Taken oge he , hese indings sugges ha PI3 Kinase, mTOR
and angiogenesis inhibi o s a e he mos p omising classes o
d ugs o in es iga e in endome ial cance [207], and p og ess in
his a ea is likely o be as e i s udies a e bioma ke d i en wi h
biopsy a en y.
Recommenda ion 12.2. D ugs a ge ing PI3K/mTOR pa hway
signalling and angiogenesis ha e shown modes ac i i y bu no
agen has been app o ed o clinical use, and u he bioma ke
d i en s udies a e wa an ed
Le el o e idence: III
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
Clinical ial design
While clinical ial endpoin s such as OS and PFS a e desi able, i
may no be possible o make p og ess unless no el ial design and
endpoin s a e used. The e should be be e selec ion o pa ien s,
using a mo e sys ema ic app oach o in eg a ion o bioma ke s as
well as ea lie cha ac e isa ion and s anda disa ion o diagnos ic
imaging and bioma ke assessmen s. Tumou esponse o biologi-
cal agen s may no occu o he same deg ee as wi h chemo he apy
and al e na i e ea ly endpoin s, such as he pe cen age o pa ien s
ee om p og ession a 18 weeks [208], ha e been used. T ial
designs ha include di e en gynaecological cance s o he same
his o ype should also be conside ed, an app oach ha is being
aken in in he ongoing phase III GOG0261 ial o pacli axel plus
ca bopla in e sus pacli axel plus i os amide in pa ien s wi h di -
e en ypes o gynaecological ca cinosa comas (NCT00954174),
and a andomised phase II ial o nin edanib e sus chemo he apy
in pa ien s wi h ecu en clea cell ca cinoma o he o a y o
endome ium (Eud aCT 2013-002109-73). The e is also an
a gumen o no being oo selec i e, as he p esence o a speci ic
bioma ke a ge may no be e lec i e o he p obabili y o
esponse. In a ecen analysis o phase II s udies o mTOR
inhibi o s, he e was no co ela ion be ween esponse and he
p esence o mu a ions in he PI3K-AKT pa hway [209], a esul ha
could be explained by a a ie y o easons, including he p esence
o mul iple mu a ions, c oss- alk in he signalling pa hways
in ol ed, and he lack o e-biopsy samples o discoun
disco dance be ween he umou mu a ion p o ile a diagnosis e -
sus ecu ence.
Se ing up indi idual ials is bo h cos ly and ime-
consuming, al hough adap i e phase II/III ials may o e some
ad an ages [210]. Al e na i e s a egies such as he ‘baske ’
app oach, which includes all pa ien s subdi ided by speci ic his-
ological o molecula coho s unde he umb ella o a single
ial, may be he mos e icien way o wa d [211]. Such ials
should also inco po a e no el endpoin s and he design would
be s eng hened by he inclusion o sequen ial and epea ed
assessmen s o bioma ke s.
576 Endome ial cance consensus con e ence guidelines
Recommenda ion 12.3. Clinical ial designs o new, a ge ed
he apy:
1: Baske s udies wi h mul iple coho s ela ed o his ological
sub ypes and/o molecula al e a ions a e conside ed a
p io i y
2: Bioma ke d i en clinical ials wi h biopsy a en y and
sequen ial biopsies in ials wi h molecula endpoin s a e
ecommended
3: PFS o PFS a a de ined ime-poin a e he p e e ed p ima y
endpoin s o ea ly phase ials
4: OS is he p e e ed p ima y endpoin in phase III ials,
unless c osso e is planned o expec ed
Le el o e idence: V
S eng h o ecommenda ion: A
Consensus: 100% yes (34 o e s)
Funding
All cos s ela ing o he consensus con e ence we e co e ed
om he Eu opean Socie y o Medical Oncology cen al unds.
The e was no ex e nal unding o he e en o manusc ip
p oduc ion.
Disclosu es
F ede ic Aman (senio in es iga o o he Resea ch Fund Flan-
de s [FWO]), Nicole a Colombo (consul ancy – Roche, As a
Zeneca), Luis Chi a de Agus ín (speake o Roche and Takeda),
Gün e Emons ( esea ch g an s om Ae e na Zen a is and As a
Zeneca), Ch is ian Ku zede ( esea ch unding om Roche, speake
o Roche), Fab ice Lécu u ( esea ch g an s om In ui i e Su gicals,
ad iso y boa d o Roche), Jona han Lede mann (ad iso y boa ds
o As aZeneca, Clo is Oncology, Me ck/MSD, Baye , Oxigene),
Helga Sal esen (pending in ellec ual p ope y igh s o some
aspec s ela ing o STMN/pSTMN1 as a p ognos ic ma ke o
endome ial cance [US 127962,946(HS) and US 147155,412
(HS)]). All emaining au ho s ha e decla ed no con lic s o in e es .
Acknowledgemen s
The au ho s hank Jenni e Lama e, Clai e B amley, Ma hew
Wallace, Aude Galli and all ESMO s a o hei suppo h oughou
he whole consensus p ocess.
Angela Co s o phine o Ks o in Medical Communica ions L d
p o ided medical w i ing suppo wi h he p epa a ion o his
manusc ip . This suppo was unded by ESMO.
Appendix
ESMO–ESGO–ESTRO Endome ial Consensus Con e ence Wo king
G oup
Miguel Abal, T ansla ional Medical Oncology (IDIS), Complexo
Hospi ala io Uni e si a io de San iago de Compos ela (SERGAS),
San iago de Compos ela, Spain; Ozden Al undag, Depa men o
Medical Oncology, Basßken Uni e si y Hospi al, Anka a, Tu key;
F ede ic Aman , Depa men o Gynecological Oncology, Uni e si y
Hospi al Leu en, Leu en, Belgium and Cen e o Gynecological
Oncology Ams e dam (CGOA), An oni an Leeuwenhoek, Ams e -
dam, The Ne he lands; Susana Bane jee, Gynaecology Uni , The
Royal Ma sden NHS Founda ion T us , London, Uni ed Kingdom;
Tjalling Bosse, Depa men o Pa hology, Leiden Uni e si y Medical
Cen e , Leiden, The Ne he lands; An onio Casado, EORTC Gyneco-
logical umo g oup, Hospi al Uni e si a io San Ca los, Mad id,
Spain; Luis Chi a de Agus ín, MD Ande son Cance Cen e , Mad id,
Spain and Uni e si y o Texas, USA; Da id Cibula, Depa men o
Obs e ics and Gynecology, Cha les Uni e si y, P ague, Czech
Republic; Nicole a Colombo, Di ision o Medical Gynecologic
Oncology, Eu opean Ins i u e o Oncology and Uni e si y o
Milan-Bicocca, Milan, I aly; Ca ien C eu zbe g, Depa men o
Radia ion Oncology, Leiden Uni e si y Medical Cen e , Leiden,
The Ne he lands; Josep-Ma ía del Campo, Di ision o Medical
Oncology, Vall d’Heb on Ins i u e o Oncology, Ba celona, Spain;
Gün e Emons, Depa men o Obs e ics & Gynecology, Geo g-
Augus -Uni e si ä Gö ingen, F auenklinik, Gö ingen, Ge many;
F édé ic Go in, Depa men o Gynecologic Oncology, CHU Liège,
Si e Hôpi al de la Ci adelle, Liège, Belgium; An onio González-
Ma ín, Medical Oncology Depa men , GEICO and MD Ande son
Cance Cen e , Mad id, Spain; S e ano G eggi, Depa men o Gyne-
cologic Oncology, Na ional Cance Ins i u e o Naples, Naples, I aly;
Ch is ine Haie-Mede , Radia ion Oncology Depa men ,
B achy he apy Se ice, Gus a e Roussy Hospi al, Villejui , F ance;
Dionyssios Ka sa os, Depa men o Gynecologic Oncology,
Azienda Ospedalie o-Uni e si a ia Ci à della Salu e, San ’Anna
Hospi al and Uni e si y o Tu in, Tu in, I aly; Vesna Kesic, Medical
Facul y, Uni e si y o Belg ade and Depa men o Obs e ics and
Gynecology, Clinical Cen e o Se bia, Belg ade, Se bia; Ch is ian
Ku zede , Depa men o Gynaecology and Gynaecologic Oncology,
Kliniken Essen-Mi e, Essen, Ge many; Sigu d Lax, Depa men o
Pa hology, Hospi al G az Wes , G az, Aus ia; Fab ice Lécu u, Se -
ice de Chi u gie Gynécologique e Cancé ologique, Hôpi al Eu -
opéen Geo ges Pompidou, Pa is, F ance; Jona han Lede mann,
Depa men o Oncology and Cance T ials, UCL Cance Ins i u e,
London, Uni ed Kingdom; Tally Le y, Di ision o Gynecologic
Oncology, Wol son Medical Cen e , Tel-A i Uni e si y, Holon,
Is ael; Domenica Lo usso, Depa men o Gynecologic Oncology,
Fondazione ‘‘IRCCS” Na ional Cance Ins i u e o Milan, Milan,
I aly; Johanna Mäenpää, Depa men o Obs e ics and Gynecology,
Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e,
Finland; Ch is ian Ma h, Depa men o Obs e ics and Gynecol-
ogy, Innsb uck Medical Uni e si y, Innsb uck, Aus ia; Xa ie
Ma ias-Guiu, Depa men o Pa hology and Molecula Gene ics
and Resea ch Labo a o y, Hospi al Uni e si a i A nau de Vilano a,
Uni e si y o Lleida, Lleida, Spain; Philippe Mo ice, Gynaecological
Su ge y Depa men , Ins i u Gus a e Roussy, Villejui , F ance;
Hans W. Nijman, Depa men o Gynaecologic Oncology, Uni e si y
Medical Cen e G oningen, Uni e si y o G oningen, G oningen,
The Ne he lands; Remi Nou , Depa men o Radio he apy, Leiden
Uni e si y Medical Cen e , Leiden, The Ne he lands; Melanie Pow-
ell, Depa men o Clinical Oncology, Ba s Heal h NHS T us , S
Ba holomew’s Hospi al, Wes Smi h ield, London, Uni ed King-
dom; Denis Que leu, Depa men o Su ge y, Ins i u Be gonié, Bo -
deaux, F ance and Gynecology and Obs e ics Depa men , McGill
Uni e si y Heal h Cen e, Mon eal, Quebec, Canada; Mansoo R.
Mi za, Depa men o Oncology, Rigshospi ale , Copenhagen
Uni e si y Hospi al, Copenhagen, Denma k; Nick Reed, Depa -
men o Clinical Oncology, Bea son Oncology Cen e, Ga na el
Gene al Hospi al, Glasgow, Uni ed Kingdom; Alexand os Rodolakis,
Fi s Depa men o Obs e ics and Gynecology, A hens Uni e si y,
Alexand a Hospi al, A hens, G eece; Helga Sal esen, Depa men o
Clinical Science, Haukeland Uni e si y Hospi al, Be gen, No way;
Jalid Sehouli, Depa men o Gynecology, Cha i é Uni e -
si ä smedizin Be lin, Be lin, Ge many; C is iana Sessa, Depa men
o Medical Oncology, Oncology Ins i u e o Sou he n Swi ze land,
Ospedale San Gio anni, Bellinzona, Swi ze land; Alexand a Taylo ,
Gynaecology Uni and Radio he apy Depa men , The Royal Ma s-
den NHS Founda ion T us , London, Uni ed Kingdom; Anneke
Wes e mann, Depa men o Medical Oncology, Academic Medical
Cen e , Ams e dam, The Ne he lands; Alain G. Zeime , Depa men
o Obs e ics and Gynecology, Innsb uck Medical Uni e si y,
Innsb uck, Aus ia.
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 577
Appendix A. Supplemen a y da a
Supplemen a y da a associa ed wi h his a icle can be ound, in
he online e sion, a h p://dx.doi.o g/10.1016/j. adonc.2015.11.
013.
Re e ences
[1] WHO. GLOBOCAN 2012: Es ima ed cance incidence, mo ali y and
p e alence wo ldwide in 2012. 2012; h p://globocan.ia c. /Pages/ ac _
shee s_popula ion.aspx (3 Ap il 2015, da e las accessed).
[2] Lee NK, Cheung MK, Shin JY, e al. P ognos ic ac o s o u e ine cance in
ep oduc i e-aged women. Obs e Gynecol 2007;109:655–62.
[3] Na ional Cance Ins i u e. Endome ial cance ea men Physician Da a
Que y (PDQ). 2015; h p://www.cance .go /cance opics/pdq/ ea men /
endome ial/heal hp o essional (1 Ap il 2015, da e las accessed).
[4] ACOG. ACOG p ac ice bulle in, clinical managemen guidelines o
obs e ician-gynecologis s, numbe 65, Augus 2005: managemen o
endome ial cance . Obs e Gynecol 2005;106:413–25.
[5] Kando h C, Schul z N, Che niack AD, e al. In eg a ed genomic
cha ac e iza ion o endome ial ca cinoma. Na u e 2013;497:67–73.
[6] Reid-Nicholson M, Iyenga P, Humme AJ, e al. Immunopheno ypic di e si y
o endome ial adenoca cinomas: implica ions o di e en ial diagnosis. Mod
Pa hol 2006;19:1091–100.
[7] B oaddus RR, Lynch HT, Chen LM, e al. Pa hologic ea u es o endome ial
ca cinoma associa ed wi h HNPCC: a compa ison wi h spo adic endome ial
ca cinoma. Cance 2006;106:87–94.
[8] Colombo N, P e i E, Landoni F. Endome ial cance : ESMO Clinical P ac ice
Guidelines o diagnosis, ea men and ollow-up. Ann Oncol 2013;24:
i33–8.
[9] Dykewicz CA. Summa y o he guidelines o p e en ing oppo unis ic
in ec ions among hema opoie ic s em cell ansplan ecipien s. Clin In ec
Dis 2001;33:139–44.
[10] Wo ld Cance Resea ch Fund/Ame ican Ins i u e o Cance Resea ch.
Con inuous Upda e P ojec Repo . Food, Nu i ion, Physical Ac i i y, and
he P e en ion o Endome ial Cance . 2013; h p://www.
die andcance epo .o g (2 Ap il 2015, da e las accessed).
[11] Ga g K, Soslow RA. Endome ial ca cinoma in women aged 40 yea s and
younge . A ch Pa hol Lab Med 2014;138:335–42.
[12] Esposi o K, Chiodini P, Capuano A, e al. Me abolic synd ome and endome ial
cance : a me a-analysis. Endoc ine 2014;45:28–36.
[13] Zhang Y, Liu H, Yang S, e al. O e weigh , obesi y and endome ial cance isk:
esul s om a sys ema ic e iew and me a-analysis. In J Biol Ma ke s
2014;29:e21–9.
[14] Rosa o V, Zucche o A, Bose i C, e al. Me abolic synd ome and endome ial
cance isk. Ann Oncol 2011;22:884–9.
[15] Luo J, Be es o d S, Chen C, e al. Associa ion be ween diabe es, diabe es
ea men and isk o de eloping endome ial cance . B J Cance
2014;111:1432–9.
[16] Ba y JA, Azizia MM, Ha diman PJ. Risk o endome ial, o a ian and b eas
cance in women wi h polycys ic o a y synd ome: a sys ema ic e iew and
me a-analysis. Hum Rep od Upda e 2014;20:748–58.
[17] Fade AN, A iba LN, F asu e HE, on G uenigen VE. Endome ial cance and
obesi y: epidemiology, bioma ke s, p e en ion and su i o ship. Gynecol
Oncol 2009;114:121–7.
[18] Ali AT. Rep oduc i e ac o s and he isk o endome ial cance . In J Gynecol
Cance 2014;24:384–93.
[19] Pei e i M, Colombo N. Sex co d-s omal umo s o he o a y. Tex book o
Gynaecological Oncology. Anka a and Is anbul: Günes Publishing; 2012. pp.
453-456.
[20] B in on LA, Be man ML, Mo el R, e al. Rep oduc i e, mens ual, and medical
isk ac o s o endome ial cance : esul s om a case-con ol s udy. Am J
Obs e Gynecol 1992;167:1317–25.
[21] Zucche o A, Se aino D, Polesel J, e al. Ho mone- ela ed ac o s and
gynecological condi ions in ela ion o endome ial cance isk. Eu J Cance
P e 2009;18:316–21.
[22] Fishe B, Cos an ino JP, Wicke ham DL, e al. Tamoxi en o p e en ion o
b eas cance : epo o he Na ional Su gical Adju an B eas and Bowel
P ojec P-1 S udy. J Na l Cance Ins 1998;90:1371–88.
[23] Lancas e JM, Powell CB, Chen LM, Richa dson DL. Socie y o Gynecologic
Oncology s a emen on isk assessmen o inhe i ed gynecologic cance
p edisposi ions. Gynecol Oncol 2015;136:3–7.
[24] Smi h RA, Cokkinides V, B awley OW. Cance sc eening in he Uni ed S a es,
2009: a e iew o cu en Ame ican Cance Socie y guidelines and issues in
cance sc eening. CA Cance J Clin 2009;59:27–41.
[25] Jacobs I, Gen y-Maha aj A, Bu nell M, e al. Sensi i i y o ans aginal
ul asound sc eening o endome ial cance in pos menopausal women: a
case-con ol s udy wi hin he UKCTOCS coho . Lance Oncol 2011;12:
38–48.
[26] Na ional Cance Ins i u e. Endome ial Cance Sc eening Physician Da a
Que y (PDQ). 2015; www.cance .go /cance opics/pdq/sc eening/
endome ial/Heal hP o essional/ (2 Ap il 2015, da e las accessed).
[27] ACOG. Commi ee Opinion No. 601: amoxi en and u e ine cance . Obs e
Gynecol 2014;123:1394–7.
[28] Fu Y, Zhuang Z. Long- e m e ec s o le ono ges el- eleasing in au e ine
sys em on amoxi en- ea ed b eas cance pa ien s: a me a-analysis. In J
Clin Exp Pa hol 2014;7:6419–29.
[29] Manchanda R, Sa idogan E, Abdel aheim A, e al. Annual ou pa ien
hys e oscopy and endome ial sampling (OHES) in HNPCC/Lynch synd ome
(LS). A ch Gynecol Obs e 2012;286:1555–62.
[30] Vasen HF, Blanco I, Ak an-Collan K, e al. Re ised guidelines o he clinical
managemen o Lynch synd ome (HNPCC): ecommenda ions by a g oup o
Eu opean expe s. Gu 2013;62:812–23.
[31] Duska LR, Ga e A, Rueda BR, e al. Endome ial cance in women 40 yea s
old o younge . Gynecol Oncol 2001;83:388–93.
[32] E ans-Me cal ER, B ooks SE, Reale FR, Bake SP. P o ile o women 45 yea s o
age and younge wi h endome ial cance . Obs e Gynecol 1998;91:349–54.
[33] Rodolakis A, Bilia is I, Mo ice P, e al. Eu opean Socie y o Gynecological
Oncology Task Fo ce o Fe ili y P ese a ion: clinical ecommenda ions o
Fe ili y-Spa ing Managemen in Young Endome ial Cance Pa ien s. In J
Gynecol Cance 2015;25:1258–65.
[34] Lei ao J MM, Kehoe S, Ba aka RR, e al. Compa ison o D&C and o ice
endome ial biopsy accu acy in pa ien s wi h FIGO g ade 1 endome ial
adenoca cinoma. Gynecol Oncol 2009;113:105–8.
[35] Ushijima K, Yaha a H, Yoshikawa H, e al. Mul icen e phase II s udy o
e ili y-spa ing ea men wi h med oxyp oges e one ace a e o
endome ial ca cinoma and a ypical hype plasia in young women. J Clin
Oncol 2007;25:2798–803.
[36] Kinkel K, Kaji Y, Yu KK, e al. Radiologic s aging in pa ien s wi h endome ial
cance : a me a-analysis. Radiology 1999;212:711–8.
[37] Minig L, F anchi D, Bo e i S, e al. P oges in in au e ine de ice and GnRH
analogue o u e us-spa ing ea men o endome ial p ecance s and well-
di e en ia ed ea ly endome ial ca cinoma in young women. Ann Oncol
2011;22:643–9.
[38] Kim MK, Seong SJ, Song T, e al. Compa ison o dila a ion & cu e age and
endome ial aspi a ion biopsy accu acy in pa ien s ea ed wi h high-dose
o al p oges in plus le ono ges el in au e ine sys em o ea ly-s age
endome ial cance . Gynecol Oncol 2013;130:470–3.
[39] Gallos ID, Yap J, Rajkhowa M. Reg ession, elapse, and li e bi h a es wi h
e ili y-spa ing he apy o endome ial cance and a ypical complex
endome ial hype plasia: a sys ema ic e iew and me aanalysis. Am J
Obs e Gynecol 2012;207:266.e1–266.e12.
[40] Pa k JY, Kim DY, Kim JH, e al. Long- e m oncologic ou comes a e e ili y-
spa ing managemen using o al p oges in o young women wi h
endome ial cance (KGOG 2002). Eu J Cance 2013;49:868–74.
[41] Tangji gamol S, Manusi i i haya S, Hanp ase pong J. Fe ili y-spa ing in
endome ial cance . Gynecol Obs e In es 2009;67:250–68.
[42] E kanli S, Ayhan A. Fe ili y-spa ing he apy in young women wi h
endome ial cance : 2010 upda e. In J Gynecol Cance 2010;20:1170–87.
[43] Yamazawa K, Hi ai M, Fuji o A, e al. Fe ili y-p ese ing ea men wi h
p oges in, and pa hological c i e ia o p edic esponses, in young women
wi h endome ial cance . Hum Rep od 2007;22:1953–8.
[44] Koskas M, Uzan J, Lu on D, e al. P ognos ic ac o s o oncologic and
ep oduc i e ou comes in e ili y-spa ing managemen o endome ial
a ypical hype plasia and adenoca cinoma: sys ema ic e iew and me a-
analysis. Fe il S e il 2014;101:785–94.
[45] Mi al K, Soslow R, McCluggage WG. Applica ion o immunohis ochemis y o
gynecologic pa hology. A ch Pa hol Lab Med 2008;132:402–23.
[46] Sun H, Enomo o T, Fuji a M, e al. Mu a ional analysis o he PTEN gene in
endome ial ca cinoma and hype plasia. Am J Clin Pa hol 2001;115:32–8.
[47] O bo A, Nilsen MN, A nes MS, e al. Loss o exp ession o MLH1, MSH2, MSH6,
and PTEN ela ed o endome ial cance in 68 pa ien s wi h endome ial
hype plasia. In J Gynecol Pa hol 2003;22:141–8.
[48] Hech JL, Pinkus JL, Pinkus GS. Enhanced de ec ion o a ypical hype plasia in
endome ial polyps by PTEN exp ession. Appl Immunohis ochem Mol
Mo phol 2004;12:36–9.
[49] Mon e NM, Webs e KA, Neube g D, e al. Join loss o PAX2 and PTEN
exp ession in endome ial p ecance s and cance . Cance Res
2010;70:6225–32.
[50] Allison KH, Upson K, Reed SD, e al. PAX2 loss by immunohis ochemis y occu s
ea ly and o en in endome ial hype plasia. In J Gynecol Pa hol 2012;31:151–9.
[51] Quick CM, Lau y AR, Mon e NM, Mu e GL. U ili y o PAX2 as a ma ke o
diagnosis o endome ial in aepi helial neoplasia. Am J Clin Pa hol
2012;138:678–84.
[52] Tashi o H, Isacson C, Le ine R, e al. P53 gene mu a ions a e common in
u e ine se ous ca cinoma and occu ea ly in hei pa hogenesis. Am J Pa hol
1997;150:177–85.
[53] Zheng W, Khu ana R, Fa ahmand S, e al. P53 immunos aining as a signi ican
adjunc diagnos ic me hod o u e ine su ace ca cinoma: p ecu so o
u e ine papilla y se ous ca cinoma. Am J Su g Pa hol 1998;22:1463–73.
[54] Jia L, Liu Y, Yi X, e al. Endome ial glandula dysplasia wi h equen p53 gene
mu a ion: a gene ic e idence suppo ing i s p ecance na u e o endome ial
se ous ca cinoma. Clin Cance Res 2008;14:2263–9.
[55] Lax SF, Kendall B, Tashi o H, e al. The equency o p53, K- as mu a ions, and
mic osa elli e ins abili y di e s in u e ine endome ioid and se ous
ca cinoma: e idence o dis inc molecula gene ic pa hways. Cance
2000;88:814–24.
[56] Cas illon DH, Lee KR, Nucci MR. Dis inc ion be ween endome ial and
endoce ical adenoca cinoma: an immunohis ochemical s udy. In J Gynecol
Pa hol 2002;21:4–10.
578 Endome ial cance consensus con e ence guidelines
[57] Saad RS, Mashhou M, No ech-Mozes S, e al. P16INK4a exp ession in
undi e en ia ed ca cinoma o he u e us does no exclude i s endome ial
o igin. In J Gynecol Pa hol 2012;31:57–65.
[58] Ne ze IM, Ke ne H, Li win L, e al. Diagnos ic implica ions o p16
exp ession in se ous papilla y endome ial cance . In J Gynecol Cance
2011;21:1441–5.
[59] Bagby C, Ronne BM, Yemelyano a A, e al. Clinically occul ubal and o a ian
high-g ade se ous ca cinomas p esen ing in u e ine samples: diagnos ic
pi alls and clues o imp o e ecogni ion o umo o igin. In J Gynecol Pa hol
2013;32:433–43.
[60] Hashi A, Yuminamochi T, Mu a a S, e al. Wilms umo gene
immuno eac i i y in p ima y se ous ca cinomas o he allopian ube,
o a y, endome ium, and pe i oneum. In J Gynecol Pa hol 2003;22:
374–7.
[61] Köbel M, Kalloge SE, Ca ick J, e al. A limi ed panel o immunoma ke s can
eliably dis inguish be ween clea cell and high-g ade se ous ca cinoma o
he o a y. Am J Su g Pa hol 2009;33:14–21.
[62] Al-Hussaini M, S ockman A, Fos e H, McCluggage WG. WT-1 assis s in
dis inguishing o a ian om u e ine se ous ca cinoma and in dis inguishing
be ween se ous and endome ioid o a ian ca cinoma. His opa hology
2004;44:109–15.
[63] Egan JA, Ionescu MC, Eapen E, e al. Di e en ial exp ession o WT1 and p53 in
se ous and endome ioid ca cinomas o he endome ium. In J Gynecol
Pa hol 2004;23:119–22.
[64] E iksson LS, Lindq is PG, Flö e Rådes ad A, e al. T ans aginal ul asound
assessmen o myome ial and ce ical s omal in asion in women wi h
endome ial cance : in e obse e ep oducibili y among ul asound expe s
and gynecologis s. Ul asound Obs e Gynecol 2015;45:476–82.
[65] Eps ein E, Blomq is L. Imaging in endome ial cance . Bes P ac Res Clin
Obs e Gynaecol 2014;28:721–39.
[66] Schol en AN, Smi VT, Bee man H, e al. P ognos ic signi icance and
in e obse e a iabili y o his ologic g ading sys ems o endome ial
ca cinoma. Cance 2004;100:764–72.
[67] Helpman L, Kupe s R, Co ens A, e al. Assessmen o endome ial sampling as
a p edic o o inal su gical pa hology in endome ial cance . B J Cance
2014;110:609–15.
[68] S ephan JM, Hansen J, Samuelson M, e al. In a-ope a i e ozen sec ion
esul s eliably p edic inal pa hology in endome ial cance . Gynecol Oncol
2014;133:499–505.
[69] An onsen SL, Høgdall E, Ch is ensen IJ, e al. HE4 and CA125 le els in he
p eope a i e assessmen o endome ial cance pa ien s: a p ospec i e
mul icen e s udy (ENDOMET). Ac a Obs e Gynecol Scand 2013;92:1313–22.
[70] Yildiz A, Ye imala H, Kasap B, e al. P eope a i e se um CA 125 le el in he
p edic ion o he s age o disease in endome ial ca cinoma. Eu J Obs e
Gynecol Rep od Biol 2012;164:191–5.
[71] Mu z-Dehbalaie I, Egle D, Fessle S, e al. HE4 is an independen p ognos ic
ma ke in endome ial cance pa ien s. Gynecol Oncol 2012;126:186–91.
[72] Sun C, Chen G, Yang Z, e al. Sa e y o o a ian p ese a ion in young pa ien s
wi h ea ly-s age endome ial cance : a e ospec i e s udy and me a-
analysis. Fe il S e il 2013;100:782–7.
[73] Walke JL, Piedmon e MR, Spi os NM, e al. Lapa oscopy compa ed wi h
lapa o omy o comp ehensi e su gical s aging o u e ine cance :
Gynecologic Oncology G oup S udy LAP2. J Clin Oncol 2009;27:5331–6.
[74] Mou i s MJ, Bijen CB, A s HJ, e al. Sa e y o lapa oscopy e sus lapa o omy in
ea ly-s age endome ial cance : a andomised ial. Lance Oncol
2010;11:763–71.
[75] Zullo F, Falbo A, Palomba S. Sa e y o lapa oscopy s lapa o omy in he
su gical s aging o endome ial cance : a sys ema ic e iew and me aanalysis
o andomized con olled ials. Am J Obs e Gynecol 2012;207:94–100.
[76] Pakish J, Soliman PT, F umo i z M, e al. A compa ison o ex ape i oneal
e sus anspe i oneal lapa oscopic o obo ic pa a-ao ic lymphadenec omy
o s aging o endome ial ca cinoma. Gynecol Oncol 2014;132:366–71.
[77] Tozzi R, Malu S, Koehle C, Schneide A. Analysis o mo bidi y in pa ien s
wi h endome ial cance : is he e a commi men o o e lapa oscopy?
Gynecol Oncol 2005;97:4–9.
[78] Sies o G, Uccella S, Ghezzi F, e al. Su gical and su i al ou comes in olde
women wi h endome ial cance ea ed by lapa oscopy. Menopause
2010;17:539–44.
[79] Palomba S, Falbo A, Moccia o R, e al. Lapa oscopic ea men o endome ial
cance : a me a-analysis o andomized con olled ials (RCTs). Gynecol Oncol
2009;112:415–21.
[80] Palomba S, Falbo A, Russo T, Zullo F. Upda ing o a ecen me a-analysis o
andomized con olled ials o assess he sa e y and he e icacy o he
lapa oscopic su ge y o ea ing ea ly s age endome ial cance . Gynecol
Oncol 2009;114:135–6.
[81] Walke JL, Piedmon e MR, Spi os NM, e al. Recu ence and su i al a e
andom assignmen o lapa oscopy e sus lapa o omy o comp ehensi e
su gical s aging o u e ine cance : Gynecologic Oncology G oup LAP2 S udy. J
Clin Oncol 2012;30:695–700.
[82] Fade AN, Seamon LG, Escoba PF, e al. Minimally in asi e su ge y e sus
lapa o omy in women wi h high g ade endome ial cance : a mul i-si e s udy
pe o med a high olume cance cen e s. Gynecol Oncol 2012;126:180–5.
[83] Han KH, Pa k NH, Kim HS, e al. Pe i oneal cy ology: a isk ac o o ecu ence
o non-endome ioid endome ial cance . Gynecol Oncol 2014;134:293–6.
[84] Ga g G, Gao F, W igh JD, e al. Posi i e pe i oneal cy ology is an independen
isk- ac o in ea ly s age endome ial cance . Gynecol Oncol 2013;128:77–82.
[85] Lu man CV, Ha ilesky LJ, C agun JM, e al. Pel ic lymph node coun is an
impo an p ognos ic a iable o FIGO s age I and II endome ial ca cinoma
wi h high- isk his ology. Gynecol Oncol 2006;102:92–7.
[86] Abu-Rus um NR, Iasonos A, Zhou Q. Is he e a he apeu ic impac o egional
lymphadenec omy in he su gical ea men o endome ial ca cinoma? Am J
Obs e Gynecol 2008;198:457.e1–5; discussion 457.e5–457.e6.
[87] C agun JM, Ha ilesky LJ, Calingae B, e al. Re ospec i e analysis o
selec i e lymphadenec omy in appa en ea ly-s age endome ial cance . J
Clin Oncol 2005;23:3668–75.
[88] Kilgo e LC, Pa idge EE, Al a ez RD, e al. Adenoca cinoma o he
endome ium: su i al compa isons o pa ien s wi h and wi hou pel ic
node sampling. Gynecol Oncol 1995;56:29–33.
[89] C easman WT, Mo ow CP, Bundy BN, e al. Su gical pa hologic sp ead
pa e ns o endome ial cance : a Gynecologic Oncology G oup S udy. Cance
1987;60:2035–41.
[90] Abu-Rus um NR, Gomez JD, Alek ia KM, e al. The incidence o isola ed
pa aao ic nodal me as asis in su gically s aged endome ial cance pa ien s
wi h nega i e pel ic lymph nodes. Gynecol Oncol 2009;115:236–8.
[91] Dowdy SC, Ale i G, Cliby WA, e al. Ex a-pe i oneal lapa oscopic pa a-ao ic
lymphadenec omy–a p ospec i e coho s udy o 293 pa ien s wi h
endome ial cance . Gynecol Oncol 2008;111:418–24.
[92] Ma iani A, Dowdy SC, Cliby WA, e al. P ospec i e assessmen o lympha ic
dissemina ion in endome ial cance : a pa adigm shi in su gical s aging.
Gynecol Oncol 2008;109:11–8.
[93] Balles e M, Dube na d G, Lécu u F, e al. De ec ion a e and diagnos ic
accu acy o sen inel-node biopsy in ea ly s age endome ial cance : a
p ospec i e mul icen e s udy (SENTI-ENDO). Lance Oncol 2011;12:469–76.
[94] Abu-Rus um NR. Sen inel lymph node mapping o endome ial cance : a
mode n app oach o su gical s aging. J Na l Comp Canc Ne w
2014;12:288–97.
[95] Benede i Panici P, Basile S, Maneschi F. Sys ema ic pel ic lymphadenec omy
s. no lymphadenec omy in ea ly-s age endome ial ca cinoma: andomized
clinical ial. J Na l Cance Ins 2008;100:1707–16.
[96] Ki chene H, Swa AM, Qian Q, e al. E icacy o sys ema ic pel ic
lymphadenec omy in endome ial cance (MRC ASTEC ial): a andomised
s udy. Lance 2009;373:125–36.
[97] Naumann RW. The ole o lymphadenec omy in endome ial cance : was he
ASTEC ial doomed by design and a e we des ined o epea ha mis ake?
Gynecol Oncol 2012;126:5–11.
[98] Smi h DC, Macdonald OK, Lee CM, Ga ney DK. Su i al impac o lymph node
dissec ion in endome ial adenoca cinoma: a su eillance, epidemiology, and
end esul s analysis. In J Gynecol Cance 2008;18:255–61.
[99] T imble EL, Kosa y C, Pa k RC. Lymph node sampling and su i al in
endome ial cance . Gynecol Oncol 1998;71:340–3.
[100] Todo Y, Ka o H, Kaneuchi M, e al. Su i al e ec o pa a-ao ic
lymphadenec omy in endome ial cance (SEPAL s udy): a e ospec i e
coho analysis. Lance 2010;375:1165–72.
[101] Chan JK, Cheung MK, Huh WK, e al. The apeu ic ole o lymph node esec ion
in endome ioid co pus cance : a s udy o 12,333 pa ien s. Cance
2006;107:1823–30.
[102] Kim HS, Suh DH, Kim MK, e al. Sys ema ic lymphadenec omy o su i al in
pa ien s wi h endome ial cance : a me a-analysis. Jpn J Clin Oncol
2012;42:405–12.
[103] Va gas R, Rauh-Hain JA, Clemme J, e al. Tumo size, dep h o in asion, and
his ologic g ade as p ognos ic ac o s o lymph node in ol emen in
endome ial cance : a SEER analysis. Gynecol Oncol 2014;133:216–20.
[104] Takano M, Ochi H, Takei Y, e al. Su ge y o endome ial cance s wi h
suspec ed ce ical in ol emen : is adical hys e ec omy needed (a GOTIC
s udy)? B J Cance 2013;109:1760–5.
[105] Wa anabe Y, Sa ou T, Nakai H, e al. E alua ion o pa ame ial sp ead in
endome ial ca cinoma. Obs e Gynecol 2010;116:1027–34.
[106] Que leu D, Mo ow CP. Classi ica ion o adical hys e ec omy. Lance Oncol
2008;9:297–303.
[107] Shih KK, Yun E, Ga dne GJ, e al. Su gical cy o educ ion in s age IV
endome ioid endome ial ca cinoma. Gynecol Oncol 2011;122:608–11.
[108] Vandenpu I, T o ik J, Ve go e I, e al. The ole o adju an chemo he apy in
su gical s ages I-II se ous and clea cell ca cinomas and ca cinosa coma o
he endome ium: a collabo a i e s udy. In J Gynecol Cance 2011;21:332–6.
[109] Gokce ZK, Tu an T, Ka alok A, e al. Clinical ou comes o u e ine
ca cinosa coma: esul s o 94 pa ien s. In J Gynecol Cance 2015;25:279–87.
[110] Aman F, Moe man P, Ne en P, e al. Endome ial cance . Lance
2005;366:491–505.
[111] B ië JM, Hollema H, Reesink N, e al. Lymph ascula space in ol emen : an
independen p ognos ic ac o in endome ial cance . Gynecol Oncol
2005;96:799–804.
[112] Cohn DE, Ho owi z NS, Mu ch DG, e al. Should he p esence o
lymph ascula space in ol emen be used o assign pa ien s o adju an
he apy ollowing hys e ec omy o uns aged endome ial cance ? Gynecol
Oncol 2002;87:243–6.
[113] Gadducci A, Ca azzana A, Cosio S, e al. Lymph- ascula space in ol emen
and ou e one- hi d myome ial in asion a e s ong p edic o s o dis an
haema ogeneous ailu es in pa ien s wi h s age I–II endome ioid- ype
endome ial cance . An icance Res 2009;29:1715–20.
[114] Geme O, A ie AB, Le y T, e al. Lymph ascula space in ol emen
comp omises he su i al o pa ien s wi h s age I endome ial cance :
esul s o a mul icen e s udy. Eu J Su g Oncol 2007;33:644–7.
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 579

[115] Gun upalli SR, Zighelboim I, Kize NT, e al. Lympho ascula space in asion is
an independen isk ac o o nodal disease and poo ou comes in
endome ioid endome ial cance . Gynecol Oncol 2012;124:31–5.
[116] Blake P, Swa AM, O on J, e al. Adju an ex e nal beam adio he apy in he
ea men o endome ial cance (MRC ASTEC and NCIC CTG EN.5 andomised
ials): pooled ial esul s, sys ema ic e iew, and me a-analysis. Lance
2009;373:137–46.
[117] C eu zbe g CL, an Pu en WL, Kope PC, e al. Su ge y and pos ope a i e
adio he apy e sus su ge y alone o pa ien s wi h s age-1 endome ial
ca cinoma: mul icen e andomised ial. PORTEC S udy G oup. Pos
Ope a i e Radia ion The apy in Endome ial Ca cinoma. Lance
2000;355:1404–11.
[118] Keys HM, Robe s JA, B une o VL, e al. A phase III ial o su ge y wi h o
wi hou adjunc i e ex e nal pel ic adia ion he apy in in e media e isk
endome ial adenoca cinoma: a Gynecologic Oncology G oup s udy. Gynecol
Oncol 2004;92:744–51.
[119] Kong A, Johnson N, Ki chene HC, Law ie TA. Adju an adio he apy o s age
I endome ial cance : an upda ed Coch ane sys ema ic e iew and me a-
analysis. J Na l Cance Ins 2012;104:1625–34.
[120] Soong R, Knowles S, Williams KE, e al. O e exp ession o p53 p o ein is an
independen p ognos ic indica o in human endome ial ca cinoma. B J
Cance 1996;74:562–7.
[121] Sal esen HB, I e sen OE, Akslen LA. P ognos ic signi icance o angiogenesis
and Ki-67, p53, and p21 exp ession: a popula ion-based endome ial
ca cinoma s udy. J Clin Oncol 1999;17:1382–90.
[122] AlHilli MM, Ma iani A, Bakkum-Gamez JN, e al. Risk-sco ing models o
indi idualized p edic ion o o e all su i al in low-g ade and high-g ade
endome ial cance . Gynecol Oncol 2014;133:485–93.
[123] Zeime AG, Reime D, Husza M, e al. L1CAM in ea ly-s age ype I
endome ial cance : esul s o a la ge mul icen e e alua ion. J Na l Cance
Ins 2013;105:1142–50.
[124] Bosse T, Nou RA, S elloo E, e al. L1 cell adhesion molecule is a s ong
p edic o o dis an ecu ence and o e all su i al in ea ly s age
endome ial cance : pooled PORTEC ial esul s. Eu J Cance
2014;50:2602–10.
[125] So be B, No ds öm B, Mäenpää J, e al. In a aginal b achy he apy in FIGO
s age I low- isk endome ial cance : a con olled andomized s udy. In J
Gynecol Cance 2009;19:873–8.
[126] Nou RA, Smi VT, Pu e H, e al. Vaginal b achy he apy e sus pel ic
ex e nal beam adio he apy o pa ien s wi h endome ial cance o high-
in e media e isk (PORTEC-2): an open-label, non-in e io i y, andomised
ial. Lance 2010;375:816–23.
[127] So be B, Ho a h G, Ande sson H, e al. Ex e nal pel ic and aginal i adia ion
e sus aginal i adia ion alone as pos ope a i e he apy in medium- isk
endome ial ca cinoma–a p ospec i e andomized s udy. In J Radia Oncol
Biol Phys 2012;82:1249–55.
[128] Bosse T, Pe e s EE, C eu zbe g CL, e al. Subs an ial lymph- ascula space
in asion (LVSI) is a signi ican isk ac o o ecu ence in endome ial cance
- A pooled analysis o PORTEC 1 and 2 ials. Eu J Cance 2015;51:1742–50.
[129] Bendi allah S, Canlo be G, Raimond E, e al. A clue owa ds imp o ing he
Eu opean Socie y o Medical Oncology isk g oup classi ica ion in appa en
ea ly s age endome ial cance ? Impac o lympho ascula space in asion. B
J Cance 2014;110:2640–6.
[130] C eu zbe g CL, an Pu en WL, Kope PC, e al. Su i al a e elapse in
pa ien s wi h endome ial cance : esul s om a andomized ial. Gynecol
Oncol 2003;89:201–9.
[131] McMeekin DS, Filiaci VL, Aghajanian C. A andomized phase III ial o pel ic
adia ion he apy (PXRT) e sus aginal cu b achy he apy ollowed by
pacli axel/ca bopla in chemo he apy (VCB/C) in pa ien s wi h high isk (HR),
ea ly s age endome ial cance (EC): a Gynecologic Oncology G oup ial.
Gynecol Oncol 2014;134 (abs ac LBA 431).
[132] C easman WT, Odicino F, Maisonneu e P, e al. Ca cinoma o he co pus u e i.
FIGO 26 h Annual Repo on he Resul s o T ea men in Gynecological
Cance . In J Gynaecol Obs e 2006;95:S105–43.
[133] G e en KM, Randall M, Fanning J, e al. Pa e ns o ailu e in pa ien s wi h
s age I, g ade 3 ca cinoma o he endome ium. In J Radia Oncol Biol Phys
1990;19:529–34.
[134] S aughn JM, Huh WK, O J JW, e al. S age IC adenoca cinoma o he
endome ium: su i al compa isons o su gically s aged pa ien s wi h and
wi hou adju an adia ion he apy. Gynecol Oncol 2003;89:295–300.
[135] C eu zbe g CL, an Pu en WL, Wá lám-Rodenhuis CC, e al. Ou come o high-
isk s age IC, g ade 3, compa ed wi h s age I endome ial ca cinoma pa ien s:
he Pos ope a i e Radia ion The apy in Endome ial Ca cinoma T ial. J Clin
Oncol 2004;22:1234–41.
[136] Sagae S, Susumu N, Viswana han AN, e al. Gynecologic Cance In e G oup
(GCIG) consensus e iew o u e ine se ous ca cinoma. In J Gynecol Cance
2014;24:S83–9.
[137] Mo ow CP, Bundy BN, Homesley HD, e al. Doxo ubicin as an adju an
ollowing su ge y and adia ion he apy in pa ien s wi h high- isk
endome ial ca cinoma, s age I and occul s age II: a Gynecologic Oncology
G oup S udy. Gynecol Oncol 1990;36:166–71.
[138] Susumu N, Sagae S, Udagawa Y, e al. Randomized phase III ial o pel ic
adio he apy e sus cispla in-based combined chemo he apy in pa ien s
wi h in e media e- and high- isk endome ial cance : a Japanese Gynecologic
Oncology G oup s udy. Gynecol Oncol 2008;108:226–33.
[139] Maggi R, Lissoni A, Spina F, e al. Adju an chemo he apy s adio he apy in
high- isk endome ial ca cinoma: esul s o a andomised ial. B J Cance
2006;95:266–71.
[140] Hogbe g T, Signo elli M, de Oli ei a CF, e al. Sequen ial adju an
chemo he apy and adio he apy in endome ial cance – esul s om wo
andomised s udies. Eu J Cance 2010;46:2422–31.
[141] G e en K, Win e K, Unde hill K, e al. Final analysis o RTOG 9708: adju an
pos ope a i e i adia ion combined wi h cispla in/pacli axel chemo he apy
ollowing su ge y o pa ien s wi h high- isk endome ial cance . Gynecol
Oncol 2006;103:155–9.
[142] Cooke EW, Pappas L, Ga ney DK. Does he e ised In e na ional Fede a ion o
Gynecology and Obs e ics s aging sys em o endome ial cance lead o
inc eased disc imina ion in pa ien ou comes? Cance 2011;117:4231–7.
[143] Page BR, Pappas L, Cooke EW, Ga ney DK. Does he FIGO 2009 endome ial
cance s aging sys em mo e accu a ely co ela e wi h clinical ou come in
di e en his ologies? Re ised s aging, endome ial cance , his ology. In J
Gynecol Cance 2012;22:593–8.
[144] Peco elli S. Re ised FIGO s aging o ca cinoma o he ul a, ce ix, and
endome ium. In J Gynaecol Obs e 2009;105:103–4.
[145] Mo ow CP, Bundy BN, Ku man RJ, e al. Rela ionship be ween su gical-
pa hological isk ac o s and ou come in clinical s age I and II ca cinoma o
he endome ium: a Gynecologic Oncology G oup s udy. Gynecol Oncol
1991;40:55–65.
[146] W igh JD, Fio elli J, Kansle AL. Op imizing he managemen o s age II
endome ial cance : he ole o adical hys e ec omy and adia ion. Am J
Obs e Gynecol 2009;200:419.e1–7.
[147] Klopp A, Smi h BD, Alek ia K, e al. The ole o pos ope a i e adia ion
he apy o endome ial cance : Execu i e summa y o an Ame ican Socie y
o Radia ion Oncology e idence-based guideline. P ac Radia Oncol
2014;4:137–44.
[148] Rossi PJ, Jani AB, Ho owi z IR, Johns one PA. Adju an b achy he apy emo es
su i al disad an age o local disease ex ension in s age IIIC endome ial
cance : a SEER egis y analysis. In J Radia Oncol Biol Phys 2008;70:134–8.
[149] Randall ME, Wilde J, G e en K, Raben M. Role o in aca i a y cu boos a e
adju an ex e nal i adia ion in ea ly endome ial ca cinoma. In J Radia
Oncol Biol Phys 1990;19:49–54.
[150] G e en K, Win e K, Unde hill K, e al. P elimina y analysis o RTOG 9708:
Adju an pos ope a i e adio he apy combined wi h cispla in/pacli axel
chemo he apy a e su ge y o pa ien s wi h high- isk endome ial cance .
In J Radia Oncol Biol Phys 2004;59:168–73.
[151] Sco i V, Bo ghesi S, Mea ini I, e al. Pos ope a i e adio he apy in s age I/II
endome ial cance : e ospec i e analysis o 883 pa ien s ea ed a he
Uni e si y o Flo ence. In J Gynecol Cance 2010;20:1540–8.
[152] Jobsen JJ, Lybee ML, an de S een-Banasik EM, e al. Mul icen e coho
s udy on ea men esul s and isk ac o s in s age II endome ial ca cinoma.
In J Gynecol Cance 2008;18:1071–8.
[153] C osby MA, Twa d JD, Szabo A, e al. Does b achy he apy imp o e su i al in
addi ion o ex e nal beam adia ion he apy in pa ien s wi h high isk s age I
and II endome ial ca cinoma? Am J Clin Oncol 2010;33:364–9.
[154] Seco d AA, Gelle MA, B oadwa e G, e al. A mul icen e e alua ion o
adju an he apy in women wi h op imally esec ed s age IIIC endome ial
cance . Gynecol Oncol 2013;128:65–70.
[155] Klopp AH, Jhing an A, Ramonde a L, e al. Node-posi i e adenoca cinoma o
he endome ium: ou come and pa e ns o ecu ence wi h and wi hou
ex e nal beam i adia ion. Gynecol Oncol 2009;115:6–11.
[156] Randall ME, Filiaci VL, Muss H, e al. Randomized phase III ial o whole-
abdominal i adia ion e sus doxo ubicin and cispla in chemo he apy in
ad anced endome ial ca cinoma: a Gynecologic Oncology G oup S udy. J
Clin Oncol 2006;24:36–44.
[157] Lee LJ, Viswana han AN. Combined chemo he apy and adia ion imp o es
su i al o node-posi i e endome ial cance . Gynecol Oncol
2012;127:32–7.
[158] Mund AJ, McB ide R, Ro mensch J, e al. Signi ican pel ic ecu ence in high-
isk pa hologic s age I–IV endome ial ca cinoma pa ien s a e adju an
chemo he apy alone: implica ions o adju an adia ion he apy. In J Radia
Oncol Biol Phys 2001;50:1145–53.
[159] Viswana han AN, Macklin EA, Be kowi z R, Ma ulonis U. The impo ance o
chemo he apy and adia ion in u e ine papilla y se ous ca cinoma. Gynecol
Oncol 2011;123:542–7.
[160] Hasegawa K, Nagao S, Yasuda M, e al. Gynecologic Cance In e G oup (GCIG)
consensus e iew o clea cell ca cinoma o he u e ine co pus and ce ix. In
J Gynecol Cance 2014;24:S90–5.
[161] Ba ney BM, Pe e sen IA, Ma iani A, e al. The ole o aginal b achy he apy in
he ea men o su gical s age I papilla y se ous o clea cell endome ial
cance . In J Radia Oncol Biol Phys 2013;85:109–15.
[162] Be on-Rigaud D, De ouassoux-Shishebo an M, Lede mann JA, e al.
Gynecologic Cance In e G oup (GCIG) Consensus Re iew o U e ine and
O a ian Ca cinosa coma. In J Gynecol Cance 2014;24:S55–60.
[163] Aman F. The a ionale o comp ehensi e su gical s aging in endome ial
ca cinosa coma. Gynecol Oncol 2005;99:521–2 (au ho eply 522–523).
[164] Reed NS, Mangioni C, Malms om H, e al. Phase III andomised s udy o
e alua e he ole o adju an pel ic adio he apy in he ea men o u e ine
sa comas s ages I and II: an Eu opean O ganisa ion o Resea ch and
T ea men o Cance Gynaecological Cance G oup S udy (p o ocol 55874).
Eu J Cance 2008;44:808–18.
580 Endome ial cance consensus con e ence guidelines
[165] W igh JD, Seshan VE, Shah M. The ole o adia ion in imp o ing su i al o
ea ly-s age ca cinosa coma and leiomyosa coma. Am J Obs e Gynecol
2008;199:536.e1–8.
[166] Clay on Smi h D, Kenne h Macdonald O, Ga ney DK. The impac o adju an
adia ion he apy on su i al in women wi h u e ine ca cinosa coma.
Radio he Oncol 2008;88:227–32.
[167] Nemani D, Mi a N, Guo M, Lin L. Assessing he e ec s o lymphadenec omy
and adia ion he apy in pa ien s wi h u e ine ca cinosa coma: a SEER
analysis. Gynecol Oncol 2008;111:82–8.
[168] Wol son AH, B ady MF, Roce e o T, e al. A gynecologic oncology g oup
andomized phase III ial o whole abdominal i adia ion (WAI) s. cispla in-
i os amide and mesna (CIM) as pos -su gical he apy in s age I–IV
ca cinosa coma (CS) o he u e us. Gynecol Oncol 2007;107:177–85.
[169] Ba lin JN, Pu i I, B is ow RE. Cy o educ i e su ge y o ad anced o ecu en
endome ial cance : a me a-analysis. Gynecol Oncol 2010;118:14–8.
[170] C easman WT, Kohle MF, Odicino F, e al. P ognosis o papilla y se ous, clea
cell, and g ade 3 s age I ca cinoma o he endome ium. Gynecol Oncol
2004;95:593–6.
[171] Jhing an A, Bu ke TW, Ei el PJ. De ini i e adio he apy o pa ien s wi h
isola ed aginal ecu ence o endome ial ca cinoma a e hys e ec omy. In
J Radia Oncol Biol Phys 2003;56:1366–72.
[172] Va go JA, Kim H, House CJ, e al. De ini i e sal age o aginal ecu ence o
endome ial cance : he impac o mode n in ensi y-modula ed-
adio he apy wi h image-based HDR b achy he apy and he in e play o
he PORTEC 1 isk s a i ica ion. Radio he Oncol 2014;113:126–31.
[173] Podzielinski I, Randall ME, B eheny PJ, e al. P ima y adia ion he apy o
medically inope able pa ien s wi h clinical s age I and II endome ial
ca cinoma. Gynecol Oncol 2012;124:36–41.
[174] Fishman DA, Robe s KB, Chambe s JT, e al. Radia ion he apy as exclusi e
ea men o medically inope able pa ien s wi h s age I and II endome ioid
ca cinoma wi h endome ium. Gynecol Oncol 1996;61:189–96.
[175] Gill BS, Kim H, House C, e al. Image-based h ee-dimensional con o mal
b achy he apy o medically inope able endome ial ca cinoma.
B achy he apy 2014;13:542–7.
[176] Thigpen JT, B ady MF, Al a ez RD, e al. O al med oxyp oges e one ace a e in
he ea men o ad anced o ecu en endome ial ca cinoma: a dose-
esponse s udy by he Gynecologic Oncology G oup. J Clin Oncol
1999;17:1736–44.
[177] Dec uze SB, G een JA. Ho mone he apy in ad anced and ecu en
endome ial cance : a sys ema ic e iew. In J Gynecol Cance
2007;17:964–78.
[178] Tangen IL, We ne HM, Be g A, e al. Loss o p oges e one ecep o links o
high p oli e a ion and inc eases om p ima y o me as a ic endome ial
cance lesions. Eu J Cance 2014;50:3003–10.
[179] Len z SS, B ady MF, Majo FJ, e al. High-dose meges ol ace a e in ad anced
o ecu en endome ial ca cinoma: a Gynecologic Oncology G oup S udy. J
Clin Oncol 1996;14:357–61.
[180] Thigpen T, B ady MF, Homesley HD, e al. Tamoxi en in he ea men o
ad anced o ecu en endome ial ca cinoma: a Gynecologic Oncology
G oup s udy. J Clin Oncol 2001;19:364–7.
[181] Ma BB, Oza A, Eisenhaue E, e al. The ac i i y o le ozole in pa ien s wi h
ad anced o ecu en endome ial cance and co ela ion wi h biological
ma ke s–a s udy o he Na ional Cance Ins i u e o Canada Clinical T ials
G oup. In J Gynecol Cance 2004;14:650–8.
[182] Rose PG, B une o VL, VanLe L, e al. A phase II ial o anas ozole in ad anced
ecu en o pe sis en endome ial ca cinoma: a Gynecologic Oncology
G oup s udy. Gynecol Oncol 2000;78:212–6.
[183] Whi ney CW, B une o VL, Zaino RJ, e al. Phase II s udy o
med oxyp oges e one ace a e plus amoxi en in ad anced endome ial
ca cinoma: a Gynecologic Oncology G oup s udy. Gynecol Oncol 2004;92:4–9.
[184] Fio ica JV, B une o VL, Hanjani P, e al. Phase II ial o al e na ing cou ses o
meges ol ace a e and amoxi en in ad anced endome ial ca cinoma: a
Gynecologic Oncology G oup s udy. Gynecol Oncol 2004;92:10–4.
[185] an Wijk FH, Aap o MS, Bolis G, e al. Doxo ubicin e sus doxo ubicin and
cispla in in endome ial ca cinoma: de ini i e esul s o a andomised s udy
(55872) by he EORTC Gynaecological Cance G oup. Ann Oncol
2003;14:441–8.
[186] Thigpen JT, B ady MF, Homesley HD, e al. Phase III ial o doxo ubicin wi h
o wi hou cispla in in ad anced endome ial ca cinoma: a gynecologic
oncology g oup s udy. J Clin Oncol 2004;22:3902–8.
[187] Fleming GF, B une o VL, Cella D, e al. Phase III ial o doxo ubicin plus
cispla in wi h o wi hou pacli axel plus ilg as im in ad anced endome ial
ca cinoma: a Gynecologic Oncology G oup S udy. J Clin Oncol
2004;22:2159–66.
[188] Mille D, Filiaci V, Fleming G, e al. La e-B eaking Abs ac 1: RANDOMIZED
phase III nonin e io i y ial o i s line chemo he apy o me as a ic o
ecu en endome ial ca cinoma: a Gynecologic Oncology G oup s udy.
Gynecol Oncol 2012;125:771.
[189] Makke V, Hensley ML, Zhou Q, e al. T ea men o ad anced o ecu en
endome ial ca cinoma wi h doxo ubicin in pa ien s p og essing a e
pacli axel/ca bopla in: Memo ial Sloan-Ke e ing Cance Cen e expe ience
om 1995 o 2009. In J Gynecol Cance 2013;23:929–34.
[190] G isham RN, Adaniel C, Hyman DM, e al. Gemci abine o ad anced
endome ial cance : a e ospec i e s udy o he Memo ial sloan-Ke e ing
Cance Cen e expe ience. In J Gynecol Cance 2012;22:807–11.
[191] Nagao S, Nishio S, Michimae H, e al. Applicabili y o he concep o ‘‘pla inum
sensi i i y” o ecu en endome ial cance : he SGSG-012/GOTIC-004/
In e g oup s udy. Gynecol Oncol 2013;131:567–73.
[192] Moo e KN, Tian C, McMeekin DS, e al. Does he p og ession- ee in e al
a e p ima y chemo he apy p edic su i al a e sal age chemo he apy in
ad anced and ecu en endome ial cance ?: a Gynecologic Oncology G oup
ancilla y da a analysis. Cance 2010;116:5407–14.
[193] Ma ias-Guiu X, P a J. Molecula pa hology o endome ial ca cinoma.
His opa hology 2013;62:111–23.
[194] Sal esen HB, Ca e SL, Mannelq is M, e al. In eg a ed genomic p o iling o
endome ial ca cinoma associa es agg essi e umo s wi h indica o s o PI3
kinase ac i a ion. P oc Na l Acad Sci USA 2009;106:4834–9.
[195] Mye s AP. New s a egies in endome ial cance : a ge ing he PI3K/mTOR
pa hway– he de il is in he de ails. Clin Cance Res 2013;19:5264–74.
[196] Ye amian A, Mo eno-Bueno G, Dolce X, e al. Endome ial ca cinoma:
molecula al e a ions in ol ed in umo de elopmen and p og ession.
Oncogene 2013;32:403–13.
[197] Du A, Sal esen HB, Chen TH, e al. D ug-sensi i e FGFR2 mu a ions in
endome ial ca cinoma. P oc Na l Acad Sci USA 2008;105:8713–7.
[198] Kama AA, Me i WM, Co ey D, e al. Clinical and biological signi icance o
ascula endo helial g ow h ac o in endome ial cance . Clin Cance Res
2007;13:7487–95.
[199] Sal esen HB, Haldo sen IS, T o ik J. Ma ke s o indi idualised he apy in
endome ial ca cinoma. Lance Oncol 2012;13:e353–61.
[200] Dedes KJ, We e skog D, Ashwo h A, e al. Eme ging he apeu ic a ge s in
endome ial cance . Na Re Clin Oncol 2011;8:261–71.
[201] Aghajanian C, Sill MW, Da cy KM, e al. Phase II ial o be acizumab in
ecu en o pe sis en endome ial cance : a Gynecologic Oncology G oup
s udy. J Clin Oncol 2011;29:2259–65.
[202] Colombo N, McMeekin DS, Schwa z PE, e al. Rida o olimus as a single agen
in ad anced endome ial cance : esul s o a single-a m, phase 2 ial. B J
Cance 2013;108:1021–6.
[203] Tso e D, Welch S, Lau S, e al. Phase II s udy o o al ida o olimus in women
wi h ecu en o me as a ic endome ial cance . Gynecol Oncol
2014;135:184–9.
[204] Aghajanian C, Filiaci VL, Dizon DS. A andomized phase II s udy o
pacli axel/ca bopla in/be acizumab, pacli axel/ca bopla in/ emsi olimus
and ixabepilone/ca bopla in/be acizumab as ini ial he apy o measu able
s age III o IVA, s age IVB o ecu en endome ial cance , GOG86P. J Clin
Oncol 2015;33 (abs ac 5500).
[205] Lo usso D, Fe andina G, Colomb N. Randomized phase II ial o ca bopla in-
pacli axel (CP) compa ed o ca bopla in-pacli axel-be acizumab (CP-B) in
ad anced (s age III–IV) o ecu en endome ial cance : he MITO END-2
ial.. J Clin Oncol 2015;33. abs ac 5502.
[206] We ne HM, Sal esen HB. Cu en s a us o molecula bioma ke s in
endome ial cance . Cu Oncol Rep 2014;16:403.
[207] Weigel B, Bane jee S. Molecula a ge s and a ge ed he apeu ics in
endome ial cance . Cu Opin Oncol 2012;24:554–63.
[208] Konecny GE, Finkle N, Ga cia AA. Phase 2 s udy o second-line do i inib
(TKI258) in pa ien s wi h ib oblas g ow h ac o ecep o 2 (FGFR2)-
mu a ed o -nonmu a ed ad anced and/o me as a ic endome ial cance .
Ann Oncol 2014;25:LBA27.
[209] Mackay HJ, Eisenhaue EA, Kamel-Reid S, e al. Molecula de e minan s o
ou come wi h mammalian a ge o apamycin inhibi ion in endome ial
cance . Cance 2014;120:603–10.
[210] Ko n EL, F eidlin B, Ab ams JS, Halabi S. Design issues in andomized phase II/
III ials. J Clin Oncol 2012;30:667–71.
[211] Redig AJ, Jänne PA. Baske ials and he e olu ion o clinical ial design in an
e a o genomic medicine. J Clin Oncol 2015;33:975–7.
N. Colombo e al. / Radio he apy and Oncology 117 (2015) 559–581 581