2311
Hepa ology, Vol. 73, No. 6, 2021
Li e Me as ases o In ahepa ic
Cholangioca cinoma: Implica ions o an
Upda ed S aging Sys em
Angela Lama ca ,1 Al a o San os- Laso,2 Ki s en U pa el,3 Adelaida La Cas a,2 Simone S ock,3 Alejand o Fo ne ,4,5
Jo ge Ade a ,6 T ine Folse aas,7 Luca Fab is,8 Rocio I.R. Macias ,5,9 Ma cin K awczyk,10,11 Ma ek K awczyk,12
Vincenzo Ca dinale,13 Chia a B aconi,14 Domenico Al a o,13 Ma hias E e ,3 Jesus M. Banales,2,5,15 and Juan W. Valle1,
o he G oup: on behal o he Eu opean Ne wo k o he S udy o Cholangioca cinoma (ENS- CCA)
BaCKgRoUND aND aIMS: In ahepa ic cholangioca -
cinoma (iCCA) wi h li e me as ases is pe cei ed o ha e a
poo p ognosis, bu he Ame ican Join Commi ee on Cance
(AJCC) classi ies hem as ea ly s age in he absence o lymph
nodes o ex ahepa ic sp ead.
appRoaCH aND ReSUl S: Pa ien s wi h iCCA om he
Eu opean Ne wo k o he S udy o Cholangioca cinoma (ENS-
CCA) and Su eillance, Epidemiology, and End Resul s (SEER)
egis ies wi h su i al/s aging (AJCC .7) da a we e eligible.
Modi ied s aging was used (mAJCC .7): g oup A: s ages I- III
(excluding T2bN0); g oup B: s age IVa (excluding T2bN1M0);
g oup C: li e me as ases (T2bN0/1); and g oup D: s age IVb
(ex ahepa ic me as ases). Su i al analysis (Kaplan- Meie and
Cox eg ession) was pe o med in an ENS- CCA aining coho
(TC) and indings in e nally (ENS- CCA iVC) and ex e nally
(SEER) alida ed. The aim was o assess whe he li e me as ases
(g oup C) had a sho e su i al compa ed o o he ea ly s ages
(g oup A) o p opose a modi ied e sion o AJCC .8 (mAJCC
.8). A o al o 574 and 4,171 pa ien s om he ENS- CCA and
SEER egis ies we e included. Following he new classi ica ion,
19.86% and 17.31% o pa ien s om he ENS- CCA and SEER
egis ies we e eclassi ied in o g oup C, espec i ely. In he
ENS- CCA TC, mul i a iable Cox eg ession was adjus ed o
obesi y (p = 0.026) and pe o mance s a us (P < 0.001); pa-
ien s in g oup C (HR, 2.53; 95% CI, 1.18- 5.42; P = 0.017)
had a highe isk o dea h ( s. g oup A). Findings we e ali-
da ed in he ENS- CCA iVC (HR, 2.93; 95% CI, 2.04- 4.19;
P < 0.001) and in he SEER egis y (HR, 1.88; 95% CI, 1.68-
2.09; P < 0.001).
CoNClUSIoNS: iCCA wi h li e me as ases has a wo se
ou come han o he ea ly s ages o iCCA. Gi en ha AJCC
.8 does no ake his in o conside a ion, a modi ica ion o
AJCC .8 (mAJCC .8), including “li e me as ases: mul iple
li e lesions, wi h o wi hou ascula in asion” as an “M1a
s age,” is sugges ed. (Hepa ology 2021;73:2311-2325).
Bilia y ac cance (BTC) includes gallbladde
cance (GBC), cholangioca cinoma (CCA),
and ampulla y umo s (AMPs). CCAs a e
Abb e ia ions: AJCC, Ame ican Join Commi ee on Cance ; CCA, cholangioca cinoma; ECOG- PS, Eas e n Coope a i e Oncology G oup
pe o mance s a us; ENS- CCA, Eu opean Ne wo k o he S udy o Cholangioca cinoma; iCCA, in ahepa ic cholangioca cinoma; IQR, in e qua ile
ange; M, me as asis; mAJCC, modi ied Ame ican Join Commi ee on Cance ; mAJCC .7, modi ied e sion o he AJCC .7 s aging c i e ia;
mAJCC .8, modi ied AJCC .8; N, node; OS, o e all su i al; SEER, Su eillance, Epidemiology, and End Resul s; T, umo .
Recei ed May 5, 2020; accep ed Sep embe 20, 2020.
Addi ional Suppo ing In o ma ion may be ound a onlinelib a y.wiley.com/doi/10.1002/hep.31598/suppin o.
© 2020 The Au ho s. Hepa ology published by Wiley Pe iodicals LLC on behal o Ame ican Associa ion o he S udy o Li e Diseases. This is an
open access a icle unde he e ms o he C ea i e Commons A ibu ion- NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in
any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses.
View his a icle online a wileyonlinelib a y.com.
DOI 10.1002/hep.31598
Po en ial con lic o in e es : D . Lama ca ad ises o and ecei ed g an s om Roche and Ipsen. She is on he speake s’ bu eau o and ecei ed
g an s om AAA and P ize . She ad ises o Eisai and Nu icia. She is on he speake s’ bu eau o Me ck and Incy e. She ecei ed g an s om Baye ,
Si ex, No a is, Mylan, and Delca h. D . Fo ne consul s o , is on he speake s’ bu eau o , and ecei ed g an s om Baye . He consul s o Gue be
and As aZeneca. He is on he speake s’ bu eau o MSD and Gilead. D . B aconi is on he speake s’ bu eau o Baye , Eli Lilly, P ize , Me ck, and
Se ono. D . Valle ad ises o and is on he speake s’ bu eau o Ipsen and No a is. He is on he speake s’ bu eau o and ecei ed g an s om Nucana.
He ad ises o Agios, As aZeneca, Delca h, Keocy , Genoscience, Incy e, Me ck, Mundipha ma, PCT Bio ech, P ize , and Qed. He is on he speake s’
bu eau o AAA. He ecei ed g an s om Celgene. D . LaCas a ecei ed g an s om Roche, Amgen and Pie e- Fab é ou side he scope o his wo k.
D . Banales epo s g an s om INCYTE, pe sonal ees o lec u e om BAYER and INTERCEPT, and consul ing o QED The apeu ics, Albi eo
Pha ma and OWL METABOLOMICS, ou side he submi ed wo k.
Hepa ology, June 2021LAMARCA ET AL.
2312
subdi ided acco ding o loca ion in o in ahepa ic
(iCCA) and ex ahepa ic CCA (eCCA). iCCA ep-
esen s he second- mos common p ima y li e cance
a e HCC.(1) iCCA has ecei ed subs an ial a en-
ion in ecen yea s gi en he p og essi e wo ldwide
inc ease in incidence. P ognosis is poo because o
he ac ha BTCs usually p esen in ad anced s ages
a ibu able o hei asymp oma ic na u e in ea ly
s ages.(2,3) Thus, he e is an u gen need o de elop
be e diagnos ic and he apeu ic s a egies o pa ien s
a ec ed by hese cance s.(4- 6)
Fo many yea s, iCCAs we e joined oge he
wi h o he BTCs, and clinical ials ha e adi ion-
ally ec ui ed all subg oups o BTC. In ac , cu en
s anda d- o - ca e adju an (7,8) and pallia i e(9- 12) che-
mo he apy o BTC does no dis inguish be ween
BTC sub ypes. In con as , he e is inc easing e idence
sugges ing ha iCCA, eCCA, GBC, and AMPs ha e
di e en e iological, clinical, genomic, and molecula
cha ac e is ics.(5)
Among all BTCs, iCCAs a e gaining lo s o a en-
ion o a a ie y o easons. Fi s , pa ien s diagnosed
wi h iCCA a ely p esen wi h bilia y obs uc ion
and jaundice, which may lead o an inc eased pe -
cen age o pa ien s diagnosed wi h ad anced disease,
when no cu a i e op ions a e a ailable.(6) In addi-
ion, ch onic li e diseases (NAFLD, i al hepa i is
[B o C], and ci hosis) a e well- known isk ac o s
o bo h iCCA and HCC, making adiological di -
e en ia ion o iCCA om HCC in pa ien s wi h
unde lying li e disease challenging. Howe e , mos
iCCAs de elop in he absence o unde lying li e dis-
ease, hus making sc eening p og ams challenging.(6)
Second, a p opo ion o iCCAs may de elop mul iple
li e lesions (“li e me as ases”), wi h no e idence o
ex ahepa ic disease; he e o e, li e - di ec ed he a-
pies(13,14) and ex e nal beam adio he apy(15) could
be used as po en ial ea men op ions. Thi d, he e
is e idence sugges ing ha pa ien s diagnosed wi h
iCCA ha e a be e p ognosis compa ed o o he
ad anced BTCs.(16) Finally, he e is s ong e idence
indica ing ha genomic and molecula abe a ions in
iCCA di e om o he BTCs,(17) mainly ep esen ed
by inc eased p esence o ib oblas g ow h ac o
ecep o 2 usion ea angemen s and isoci a e dehy-
d ogenase- 1 and - 2 mu a ions.(18,19) Iden i ica ion o
hese molecula al e a ions has di ec implica ions o
access o a ge ed he apies and p ecision medicine
s a egies, whose success is cu en ly almos limi ed
o iCCA among he BTCs.(20)
aR ICle INFoRMa IoN:
F om he 1 Medical Oncology/Ins i u e o Cance Sciences, The Ch is ie NHS Founda ion T us /Uni e si y o Manches e , Manches e ,
Uni ed Kingdom; 2 Depa men o Li e and Gas oin es inal Diseases, Biodonos ia Heal h Resea ch Ins i u e, Donos ia Uni e si y
Hospi al, Uni e si y o he Basque Coun y (UPV/EHU), San Sebas ian, Spain; 3 Ins i u e o Pa hology, Uni e si y o Regensbu g,
Regensbu g, Ge many; 4 BCLC g oup, Li e Uni , Hospi al Clínic Ba celona, Ba celona, Spain; 5 Na ional Ins i u e o he S udy
o Li e and Gas oin es inal Diseases (CIBERehd), The Na ional Ins i u e o Heal h Ca los III, Mad id, Spain; 6 Depa men o
Medical Oncology, Hospi al Uni e si a io 12 de Oc ub e, Mad id, Spain;
7Sec ion o Gas oen e ology and he No wegian PSC
Resea ch Cen e , Depa men o T ansplan a ion Medicine, Oslo Uni e si y Hospi al, Oslo, No way; 8 Depa men o Molecula
Medicine, Uni e si y o Padua, Padua, I aly; 9 Expe imen al Hepa ology and D ug Ta ge ing (HEVEPHARM) g oup, Uni e si y
o Salamanca, IBSAL, Salamanca, Spain; 10 Depa men o Medicine II, Saa land Uni e si y Medical Cen e, Saa land Uni e si y,
Hombu g, Ge many; 11 Labo a o y o Me abolic Li e Diseases, Cen e o P eclinical Resea ch, Depa men o Gene al, T ansplan
and Li e Su ge y, Medical Uni e si y o Wa saw, Wa saw, Poland; 12 Depa men o Gene al, T ansplan and Li e Su ge y, Medical
Uni e si y o Wa saw, Wa saw, Poland; 13 Gas oen e ology, Sapienza Uni e si y o Rome, Rome, I aly; 14 Medical Oncolog y, The
Uni e si y o Glasgow, Glasgow, Uni ed Kingdom; 15 IKERBASQUE, Basque Founda ion o Science, Bilbao, Spain.
aDDReSS CoRReSpoNDeNCe aND RepRIN ReQUeS S o:
Juan W. Valle, M.B., Ch.B., M.Sc., F.R.C.P.
Di ision o Cance Sciences, Uni e si y o Manches e ;
Depa men o Medical Oncology
The Ch is ie NHS Founda ion T us
Wilmslow Road
Manches e M20 4BX, Uni ed Kingdom
E- mail: [email p o ec ed]
Tel.: +44 161 446 3000
o
Angela Lama ca, M.D., M.Sc., Ph.D.
Depa men o Medical Oncology
The Ch is ie NHS Founda ion T us
Di ision o Cance Sciences, Uni e si y o Manches e
Wilmslow Road
Manches e M20 4BX, Uni ed Kingdom
E- mail: [email p o ec ed]
Tel.: +44 161 446 3000
Hepa ology, Vol. 73, No. 6, 2021 LAMARCA ET AL.
2313
The mos commonly used s aging classi ica ion in
oncology is he one de eloped by he Ame ican Join
Commi ee on Cance (AJCC).(21) S aging c i e ia
o CCA we e no in oduced un il he 2nd Edi ion
(published in 1983 and made e ec i e in 1984).(22)
In addi ion, iCCA was s aged oge he wi h o he
p ima y li e umo s, such as HCC, and i was no
un il he 7 h Edi ion (published in 2009 and e ec-
i e be ween 2010 and 2017; AJCC .7; Table 1)(23)
ha a speci ic s aging sys em o iCCA was p o ided.
The la es upda e was published in 2016 and made
e ec i e in 2018 (8 h Edi ion).(23) Se e al changes
we e applied in his la es e sion, in ol ing, in pa -
icula , he umo (T) s aging (AJCC .8; Table 1).
The T1 ca ego y was subdi ided acco ding o umo
size, whe eas he T3 and T4 de ini ions we e sligh ly
modi ied and assigned o s age III disease (i M0).
Mo eo e , he p e iously de ined T2a (soli a y lesion
wi h ascula in asion) and T2b (mul iple umo s; so-
called li e me as ases o he pu pose o his s udy)
ca ego ies we e me ged.
As s a ed abo e, a signi ican p opo ion o pa ien s
(up o 48%) wi h iCCA may de elop mul iple li e
lesions in he absence o o he ex ahepa ic me as a-
ses.(16) This li e - only pa e n is no unique o iCCA,
bu can also be obse ed in o he p ima y li e cance s,
such as HCC. In HCC, he scena io o mul iple li e
lesions may ep esen mul iple p ima y umo s (mul-
i ocal disease) a ising in he backg ound o ci hosis.
Howe e , his phenomenon is s ill elusi e in iCCA,
especially when de ec ed in he absence o a p eexis -
ing li e disease such as ci hosis, p ima y scle osing
cholangi is, o exposu e o speci ic chemicals.(24- 26) In
he majo i y o pa ien s diagnosed wi h iCCA, p es-
ence o mul iple li e lesions usually e lec s hema-
ogenous in ahepa ic dissemina ion (li e me as ases)
om a p ima y p edominan umo al li e lesion and
is clinically expec ed o ea u e wo se p ognosis, mo e
simila o me as a ic disease han o ea lie s ages. In
ac , hese pa ien s a e usually managed wi h pallia i e
s a egies, simila o condi ions whe e o he dis an
me as ases ha e been iden i ied.(27) In con as , cu -
en s aging sys ems, such as he AJCC, do no ake
accoun o his issue and, in he absence o o he si es
o dis an me as ases, he AJCC s ill classi ies li e
me as ases in iCCA as ea ly s age in he absence o
lymph node o ex ahepa ic sp ead(23,28) (Table 1).
The Eu opean Ne wo k o he S udy o
Cholangioca cinoma (ENS- CCA) ep esen s an
open, mul idisciplina y g oup o clinical, ans-
la ional, and basic esea che s aiming o imp o e
he knowledge on CCA and p omo e ansla ional
ac i i ies; as pa o he ENS- CCA ini ia i es,
a mul icen e pan- Eu opean clinical egis y o
pa ien s wi h CCA has been in de elopmen since
2016, including bo h e ospec i e ( om 2010) and
p ospec i e da a.(4) This s udy aimed o desc ibe he
ou comes o pa ien s wi h iCCA complica ed by
li e me as ases and compa e hem o o he ea lie
s ages, in o de o asce ain whe he cu en s aging
accu a ely e lec s na u al beha io and agg essi e-
ness, o whe he any changes o he cu en s aging
sys em should be conside ed.
Pa ien s and Me hods
S UDy DeSIgN
A modi ied e sion o he AJCC .7 s aging c i e-
ia (mAJCC .7; Table 1), whe e pa ien s diagnosed
wi h li e me as ases (T2b) we e classi ied as a sep-
a a e g oup (g oup C) ega dless o node (N) s a us
(any N) and in he absence o o he si es o dis-
an me as ases (M0), was gene a ed. G oups we e
de ined as ollows: g oup A (s ages I- III [exclud-
ing T2bN0M0]); g oup B (s age IVa [excluding
T2bN1M0]); g oup C (li e me as ases: mul iple
li e lesions, wi h o wi hou ascula in asion [T2b,
any N, M0], g oup o in e es ); and g oup D (s age
IVb [M1 ex ahepa ic disease]).
The p ima y objec i e o his s udy was o apply
bo h he AJCC .7 and mAJCC .7 classi ica ion o
assess whe he pa ien s wi h li e me as ases ( ega d-
less o lymph node s a us; g oup C) had a di e -
en p ognosis compa ed o o he ea ly- s age disease
(s ages I- III; g oup A), using o e all su i al (OS) as
he p ima y end- poin (de ined as he ime om i s
diagnosis o dea h/las isi ). Gi en ha he AJCC .8
classi ica ion does no di e en ia e be ween numbe
o li e lesions (T2 s age includes soli a y lesions wi h
ascula in asion and mul iple li e lesions wi hin he
same g oup), he analysis was pe o med using he
AJCC .7 (which p o ides he dis inc ion be ween
T2a and T2b subg oups).
The seconda y objec i e was o c ea e a modi ied
AJCC .8 (mAJCC .8) ha could be used o he
de elopmen o u u e AJCC e sions.
Hepa ology, June 2021LAMARCA ET AL.
2314
aBle 1.Cu en S aging o CCa (aJCC 7 h and 8 h edi ions and Co esponding Modi ied Ve sions)
iCCA
AJCC .7
mAJCC .7 Modi ied e sion used o
assess impac o li e me as ases AJCC .8
mAJCC .8 P oposed modi ied
e sion o he cu en AJCC .8
P ima y umo (T)
TX P ima y umo canno
be assessed.
P ima y umo canno be assessed. P ima y umo canno be
assessed.
P ima y umo canno be
assessed.
T0 No e idence o p ima y
umo
No e idence o p ima y umo No e idence o p ima y umo No e idence o p ima y umo
Tis Ca cinoma in si u (in a-
duc al umo )
Ca cinoma in si u (in aduc al
umo )
Ca cinoma in si u (in aduc al
umo )
Ca cinoma in si u (in aduc al
umo )
T1 Soli a y umo wi hou
ascula in asion
Soli a y umo wi hou ascula
in asion
— —
T1a — — Soli a y umo ≤5 cm wi hou
ascula in asion
Soli a y umo ≤5 cm wi hou
ascula in asion
T1b — — Soli a y umo >5 cm wi hou
ascula in asion
Soli a y umo >5 cm wi hou
ascula in asion
T2 — — Soli a y umo wi h in ahe-
pa ic ascula in asion o
mul iple umo s wi h o
wi hou ascula in asion
Soli a y umo wi h in ahepa ic
ascula in asion
T2a Soli a y umo wi h
ascula in asion
Soli a y umo wi h ascula in asion — —
T2b Mul iple umo s, wi h
o wi hou ascula
in asion
Mul iple umo s, wi h o wi hou
ascula in asion
— —
T3 Tumo pe o a ing he
isce al pe i oneum
o in ol ing local
hepa ic s uc u es by
di ec in asion
Tumo pe o a ing he isce al pe i-
oneum o in ol ing local hepa ic
s uc u es by di ec in asion
Tumo pe o a ing he isce al
pe i oneum
Soli a y umo pe o a ing he
isce al pe i oneum
T4 Tumo wi h pe iduc al
in asion
Tumo wi h pe iduc al in asion Tumo in ol ing local ex a-
hepa ic s uc u es by di ec
in asion
Soli a y umo in ol ing local
ex ahepa ic s uc u es by
di ec in asion
Regional lymph
nodes (N)
NX Regional lymph nodes
canno be assessed.
Regional lymph nodes canno be
assessed.
Regional lymph nodes canno
be assessed.
Regional lymph nodes canno be
assessed.
N0 No egional lymph node
me as asis
No egional lymph node me as asis No egional lymph node
me as asis
No egional lymph node
me as asis
N1 Regional lymph node
me as asis p esen
Regional lymph node me as asis
p esen
Regional lymph node me as-
asis p esen
Regional lymph node me as asis
p esen
Dis an me as asis
(M)
M0 No dis an me as asis No dis an me as asis No dis an me as asis No dis an me as asis
M1 M1a: li e me as ases: mul iple
li e lesions, wi h o wi hou
ascula in asion
Dis an me as asis
p esen
Dis an me as asis p esen Dis an me as asis p esen M1b: Dis an (ex ahepa ic)
me as asis p esen
P ognos ic s age
g oups
0 Tis, N0, M0 Tis, N0, M0 Tis, N0, M0 Tis, N0, M0
I T1, N0, M0 T1, N0, M0 (g oup A) — T1, N0, M0
Ia — — T1a, N0, M0 T1a, N0, M0
Ib — — T1b, N0, M0 T1b, N0, M0
II T2a/b, N0, M0 T2a, N0, M0 (g oup A) T2, N0, M0 T2, N0, M0
Hepa ology, Vol. 73, No. 6, 2021 LAMARCA ET AL.
2315
In o de o gene a e he abo e- men ioned s ag-
ing g oups, indi idual pa ien da a on he T, N, and
me as asis (M) s age was indi idually e iewed and
s aging g oups de ined o indi idual pa ien s. As a
quali y con ol, pa ien s wi h misma ching in o ma-
ion we e e iewed (i equi ed) o excluded (i unable
o sa is ac o ily eply o issued que ies).
DeFINI IoN oF a MoDIFIeD
S agINg SyS eM: RaININg
aND IN eRNal ValIDa IoN
CoHoR S
Da a om pa ien s included in he ENS- CCA
egis y up o Feb ua y 2019 we e e ospec i ely
analyzed. In o de o da a o be included in he eg-
is y, indi idual si es in ol ed had ob ained app op i-
a e e hical app o al; e hical guidelines o he 1975
Decla a ion o Helsinki we e me . Eligible pa ien s
we e hose wi h a diagnosis o iCCA wi h a ailable
da a o su i al and s aging (acco ding o AJCC
.7). Pa ien s diagnosed wi h mixed HCC- iCCA o
wi h di e en sub ypes o CCA we e excluded. Two
coho s o pa ien s we e analyzed: (1) he aining
coho , including consecu i e pa ien s in he ENS-
CCA egis y om The Ch is ie NHS Founda ion
T us , who had been diagnosed be ween 2013 and
2017; (2) he in e nal alida ion coho , including
consecu i e pa ien s in he ENS- CCA egis y om
The Ch is ie NHS Founda ion T us , who had been
diagnosed be ween 2017 and 2018, along wi h all
pa ien s included in he ENS- CCA egis y by o he
con ibu ing cen e s (2013- 2018). The aim was o
use he aining coho o building a modi ied s ag-
ing sys em and o hese esul s o be alida ed in he
in e nal alida ion coho . By doing so, lessons lea ned
om he aining coho could be used o imp o e he
modi ied s aging sys em be o e i s applica ion in he
in e nal alida ion coho , should his be equi ed.
All eligible pa ien s included in his s udy we e
s aged as pe AJCC .7 and mAJCC .7 classi ica ion.
The ollowing assump ions we e made a ime o da a
in e p e a ion: i me as a ic si es we e no epo ed, M
s age was assumed o be M0; when p esence/absence o
lymph node me as ases we e unknown (Nx), hese we e
assumed o be N0 disease; i wo sepa a e T o N s ages
we e epo ed, he highes s age was used o analysis
pu poses. Pa ien s wi h M0 disease wi h epo ed T2
umo s we e excluded om he analysis i no u he
speci ica ion ega ding T2a/T2b was p o ided.
S a is ical analysis
The las upda e o clinical da a was in Feb ua y
2019. Pa ien s who we e ali e a he ime o he las
ollow- up we e censo ed. Su i al analysis was i s
pe o med in he aining coho , and hen indings
we e alida ed in he in e nal alida ion coho . Chi-
squa e, Fishe ’s exac - es , and es we e used when-
e e app op ia e. The Kaplan- Meie me hod was used
o es ima e median OS. Addi ional su i al analy-
ses wi h uni a ia e Cox eg ession and a log- ank
es we e also pe o med. S ep- wise Cox eg ession,
including all baseline cha ac e is ics collec ed as pa
o he ENS- CCA egis y (including s aging), was
used o iden i ica ion o a iables o in e es o be
included in he mul i a iable Cox eg ession model
(P alue cu o , 0.05). In o de o adjus he mul i-
a iable Cox eg ession model o po en ial con ound-
ing ac o s impac ing on pa ien s’ ou come o which
elying on s a is ical signi icance in he s ep- wise Cox
eg ession model alone would no be ully app op ia e,
iCCA
AJCC .7
mAJCC .7 Modi ied e sion used o
assess impac o li e me as ases AJCC .8
mAJCC .8 P oposed modi ied
e sion o he cu en AJCC .8
III T3, N0, M0 T3, N0, M0 (g oup A) — —
IIIa — — T3, N0, M0 T3, N0, M0
IIIb — — T4, Any N, M0 o any T, N1, M0 T4, N0, M0 o any T, N1, M0
IV — Any T, any N, M1 —
IVa T4, N0, M0 o any T,
N1, M0
T4, N0, M0 o any T (excep T2b), N1,
M0 (g oup B)
— Any T, any N, M1a
— — T2b, any N, M0 (g oup C) — —
IVb Any T, any N, M1 Any T, any N, M1 (g oup D) — Any T, any N, M1b
aBle 1.Con inued
Hepa ology, June 2021LAMARCA ET AL.
2316
a ew a iables wi h a well- de ined p ognos ic impac
we e p eselec ed o be included in he mul i a iable
Cox eg ession model ega dless o he s ep- wise Cox
eg ession indings. These ac o s included: s age and
pe o mance s a us, in iew o p e ious e idence sug-
ges ing hei impac on OS in his disease g oup.(16)
Two- sided P alues o <0.05 we e conside ed s a-
is ically signi ican . S a a so wa e ( e sion 12.0;
S a aCo p LP, College S a ion, TX) was used o he
s a is ical analysis.
Sensi i i y analysis
In o de o con i m ha ou o iginally p oposed
de ini ion o g oup C was adequa e, a sensi i i y anal-
ysis was pe o med. Gi en ha he impac o lymph
node posi i i y (N1) in he p esence o li e me as ases
(T2b) is unce ain, a sensi i i y analysis in he whole
ENS- CCA se ies by limi ing g oup C o pa ien s wi h
N0 disease only (pa ien s wi h N1 disease would be
classi ied as g oup B) was comple ed. In he sensi i i y
analysis, g oup B was de ined as “s age IVa, includ-
ing T2b, N1, M0”) and g oup C as “T2b, N0, M0”
(ins ead o “T2b, any N, M0” as de ined o he es
o he analysis in his a icle). A decision was made o
keep pa ien s wi h N1 in g oup B ins ead o emo ing
hem om he analysis o explo e whe he p ognosis
was d i en by li e me as ases (T2b) on hei own and
independen om he p esence o N1 disease.
eX eRNal ValIDa IoN:
SURVeIllaNCe, epIDeMIology,
aND eND ReSUl S RegIS Ry
Da a ex ac ed om he Su eillance, Epidemiology,
and End Resul s (SEER) egis y we e used o ex e nal
alida ion.(29) Cases epo ed om 1975 h ough 2016
wi h a ailable da a on su i al and s age (as pe AJCC
.7) we e deemed eligible. The s aging assump ions
used o he ENS- CCA coho we e applied o he
SEER egis y. Ex e nal alida ion wi h SEER da a was
aimed a con i ming whe he pa ien s wi h li e me as-
ases ( ega dless o lymph node s a us; g oup C) had
indeed a di e en ou come compa ed o o he “ea ly-
s age” disease (s ages I- III; g oup A). Su i al analysis
wi h SEER da a was pe o med using Cox eg ession
analysis (mul i a iable analysis pe o med wi h ENS-
CCA da a was planned o be ep oduced, i a iables o
in e es we e a ailable in he SEER da ase ; o he wise,
only a uni a ia e analysis would be conduc ed).
DeFINI IoN oF He pRopoSeD
UpDa eD aJCC ClaSSIFICa IoN
Based on he in o ma ion de i ed om mAJCC .7
and he ou come o he cu en s aging g oup, changes
o he cu en AJCC .8 in he o m o an mAJCC
.8 we e p oposed, and ou comes o each speci ically
de ined g oup we e assessed in he joined ENS- CCA
and SEER coho . Su i al analysis was pe o med
acco ding o he p e iously indica ed me hodology.
Resul s
pa IeN CHaRaC eRIS ICS:
eNS- CCa RegIS Ry
O he 1,820 pa ien s included in he ENS- CCA
egis y, 810 had been diagnosed wi h iCCA and we e
assessed o eligibili y. A o al o 574 pa ien s we e eli-
gible (141 wi hin he aining coho [24.56%] and 433
in he in e nal alida ion coho [75.44%]). Figu e 1A
summa izes pa ien low o he ENS- CCA coho .
Pa ien baseline cha ac e is ics, including ea men ,
o bo h he aining and in e nal alida ion coho s,
a e summa ized in Table 2. Median ollow- up ime
was 11.01 mon hs ( ange, 0.00- 183.12; in e qua ile
ange [IQR], 4.03- 23.89) o he whole coho ; 8.99
( ange, 0.00- 57.96; IQR, 3.48- 18.01) o he aining
coho ; and 11.39 ( ange, 0.00- 183.12; IQR, 4.31-
25.93) o he in e nal alida ion coho (P=0.0017).
Fo he whole coho , median age a diagnosis was
66.16 yea s ( ange, 26- 92); he majo i y o pa ien s
we e Eas e n Coope a i e Oncology G oup pe o -
mance s a us (ECOG- PS) 0 (41.99%) o 1 (35.89%).
Obesi y and diabe es we e p esen in 20.21% and
20.21% o pa ien s, espec i ely. Wi h espec o ea -
men s, 47.21% o pa ien s unde wen p e ious su gi-
cal esec ion (5.67% and 60.74% in he aining and
in e nal alida ion coho s, espec i ely; P < 0.001),
whe eas pallia i e chemo he apy was o e ed o 39.37%
o pa ien s (60.28% and 32.56% in he aining and
in e nal alida ion coho s, espec i ely; P<0.001).
S agINg oF iCCa: eNS- CCa
RegIS Ry
S aging g oups in he ENS- CCA egis y, acco d-
ing o he AJCC .7, mAJCC .7, and mAJCC .7
adjus ed o sensi i i y analysis a e shown in Table 3.
Hepa ology, Vol. 73, No. 6, 2021 LAMARCA ET AL.
2317
When he whole popula ion was s aged based on he
AJCC .7 classi ica ion, 46.52%, 22.3%, and 31.18%
o pa ien s we e s ages I- III, IVa, and IVb disease,
espec i ely. When applying he mAJCC .7 classi-
ica ion, a o al o 114 o he 395 (28.9%) pa ien s
p e iously s aged as I- IVa we e eclassi ied in o g oup
C (75 N0; 39 N1), wi h 33.45%, 15.51%, 19.86%, and
31.18% o pa ien s s aged wi hin g oups A, B, C, and
D, espec i ely.
SURVIVal aNalySIS: eNS- CCa
RegIS Ry
Es ima ed median OS was 9.98 (95% CI, 6.96-
11.99; 135 e en s; 95.74% o pa ien s), 18.52 (95%
CI, 15.44- 22.07; 280 e en s; 64.67% o pa ien s),
and 15.01 mon hs (95% CI, 12.64- 16.95; 415 e en s;
75.30% o pa ien s) o he aining, in e nal alida-
ion, and whole ENS- CCA coho s, espec i ely.
In he aining coho , uni a ia e su i al analy-
sis con i med ha bo h s aging sys ems (AJCC .7
and mAJCC .7) had an impac on OS (Suppo ing
In o ma ion S1A), wi h pa ien s wi h dis an me as-
ases (s age IVb) demons a ing sho e OS. Simila
indings we e ob ained in he uni a ia e analysis
using he in e nal alida ion coho (Suppo ing
In o ma ion S1B).
S ep- wise mul i a iable Cox eg ession analy-
sis pe o med in he aining coho (Suppo ing
In o ma ion S2) iden i ied s age (HR, 1.37; 95% CI,
1.10- 1.69; P = 0.004), obesi y (HR, 0.56; 95% CI,
0.34- 0.91- 1.69; P = 0.018), and ECOG- PS (HR,
1.89; 95% CI, 1.51- 2.39; P < 0.001) as p ognos ic
a iables o in e es o be included in he mul i a i-
able analysis. P esence o backg ound li e ci hosis
did no impac on OS (P=0.917). The mul i a iable
Cox eg ession model, adjus ed o hese a iables in
he aining coho , con i med ha pa ien s classi ied
FIg. 1. Pa ien low. N e e s o numbe o pa ien s. (A) Pa ien low o pa ien s included in he ENS- CCA egis y. (B) Pa ien low
o pa ien s included in he SEER egis y.
A
Pa ien s included in he
ENS-CCA egis y
N=1,820
Pa ien s diagnosed wi h iCCA
N=810
Eligible pa ien s (ENS-CCA coho )
N=554
T aining se (N=141)
In e nal alida ion se (N=433
Excluded (N=1,010)
• Hila cholangioca cinoma (N=609)
• Dis al cholangioca cinoma (N=309)
• Mixed HCC-CCA (N=32)
• No speci ied (N=60)
Excluded (N=256)
• No su i al/s aging da a a ailable (N=256)
B
Pa ien s included in he SEER
egis y
Pa ien s diagnosed wi h iCCA
N=15,601
Eligible pa ien s (SEER coho )
N=4,171
Ex e nal alida ion se (N=4,171)
Excluded (N=11,430)
• No s aging da a a ailable (N=11,421)
• No su i al da a a ailable (N=9)
Hepa ology, June 2021LAMARCA ET AL.
2318
in g oup C (li e me as ases) as pe he mAJCC .7
had a wo se ou come han pa ien s wi h ea ly s age
(g oup C [ s. g oup A] HR, 2.53; 95% CI, 1.18-
5.42; P = 0.017). These indings we e alida ed in
he in e nal alida ion coho (g oup C [ s. g oup A]
HR, 2.93; 95% CI, 2.04- 4.19; P<0.001; Suppo ing
In o ma ion S3).
SeNSI IVI y aNalySIS: eNS- CCa
RegIS Ry
Fo he sensi i i y analysis, only he 75 pa ien s
wi h pT2bN0 we e included in g oup C (Table 3),
whe eas pa ien s wi h T2bN1 disease we e classi-
ied as g oup B (128 pa ien s). When aking his
app oach, mul i a iable Cox eg ession analysis
applied o he whole se ies con i med ha li e
me as ases had a p ognos ic e ec , which was inde-
penden om lymph node s a us (g oup C [ s.
g oup A] HR, 2.51; 95% CI, 1.76- 3.56; P<0.001;
Suppo ing In o ma ion S4). When he ou come o
pa ien s wi h T2bM0 disease we e analyzed acco d-
ing o N s a us ( o al o 114 pa ien s; 75 T2bN0
and 39 T2bN1), N1 disease was shown o be asso-
cia ed wi h wo se OS (median OS o pa ien s wi h
T2bN0 was 11.82 mon hs [95% CI, 7.89- 20.19],
median OS o pa ien s wi h T2bN1 was 8.99
mon hs [95% CI, 5.02- 14.61]; T2bN1 [ s. T2bN0]
HR, 1.68; 95% CI, 1.10- 2.57; P=0.015). These wo
obse a ions suppo ed ou analysis o con inue wi h
he o iginally p oposed de ini ion o g oup C (T2b,
any N, M0).
aBle 2.pa ien Baseline Cha ac e is ics and Summa y o ea men s Recei ed (eNS- CCa Regis y)
Pa ien Cha ac e is ics
Whole ENS- CCA Se ies
(N=574)
T aining Coho
(N=141)
In e nal Valida ion
Coho (N=433)
P Value
(T aining
s. In e nal
Valida ion)N % N % N %
Sex Female 279 48.61 88 62.41 191 44.11 <0.001
Male 295 51.39 53 37.59 242 55.89
Age (yea s) Median ( ange) 66.16 (26- 92) 65.83 (28- 90) 66.15 (26- 92) 0.4462
E hnici y Caucasian 539 93.90 122 86.52 417 96.30 <0.001
O he 20 3.49 7 4.97 13 3.01
No epo ed 15 2.61 12 8.51 3 0.69
Obesi y Yes 116 20.21 28 19.86 88 20.32 0.693
Diabe es melli us Yes 116 20.21 27 19.15 89 20.55 0.709
Li e ci hosis Yes 53 9.23 3 2.13 50 11.55 <0.001
P ima y scle osing
cholangi is
Yes 10 1.74 0 0.00 10 2.31 0.130
ECOG- PS 0 241 41.99 22 15.60 219 50.58 <0.001
1 206 35.89 58 41.13 148 34.18
2 78 13.59 35 24.82 43 9.93
3 43 7.49 24 17.02 19 4.39
4 5 0.87 2 1.42 3 0.69
No epo ed 1 0.17 0 0 1 0.23
Pa ien ea men N % N % N %
P e ious su ge y Yes 271 47.21 8 5.67 263 60.74 <0.001
Adju an
ea men *
Yes 49 8.54 1 0.71 48 11.09 0.314
Tumo ecu ence Yes 113 19.69 7 4.96 106 24.48 <0.001
Clinical ials Yes 37 6.45 21 14.89 16 3.70 <0.001
Pallia i e
chemo he apy
Yes 226 39.37 85 60.28 141 32.56 <0.001
N e e s o numbe , % o pe cen age.
*Adju an ea men was no s anda d o ca e a he ime hese pa ien s we e ea ed. Chi- squa e, Fishe ’s exac es , and es P alues a e
p o ided (as app op ia e).
Hepa ology, Vol. 73, No. 6, 2021 LAMARCA ET AL.
2319
eX eRNal ValIDa IoN: SeeR
RegIS Ry
Among 15,601 eco ds p o ided by he SEER
da abase, 4,171 we e deemed eligible (Fig. 1B); hei
baseline and s aging cha ac e is ics a e summa ized in
Suppo ing In o ma ion S5. All eligible pa ien s we e
diagnosed be ween 2010 and 2015. Median ollow- up
was 8 mon hs ( ange, 0- 83; IQR, 2- 18). Median OS
was 10 mon hs (95% CI, 9- 10; 3,434 e en s; 82.33%
o pa ien s), wi h 17.31% o pa ien s classi ied in
g oup C (li e me as ases).
Uni a ia e su i al analysis con i med ha pa ien s
classi ied in g oup C (li e me as ases) as pe he
mAJCC .7 had a poo e ou come han pa ien s wi h
ea ly s age (g oup C [ s. g oup A] HR, 1.88; 95% CI,
1.68- 2.09; P<0.001; Suppo ing In o ma ion S1D).
Since obesi y and ECOG- PS da a was no a ailable,
mul i a iable analysis could no be pe o med.
oU CoMeS FoR eaCH S age
gRoUp
Figu e 2 summa izes pa ien s’ ou come o each
disease s age, ollowing bo h he s anda d AJCC .7
(Fig. 2A) and he mAJCC .7 (Fig. 2B) o ENS-
CCA (whole popula ion). Ou comes o mAJCC
.7 in he SEER coho a e also shown (Fig. 2C).
The upda ed mAJCC .7 classi ica ion in he ENS-
CCA coho (Fig. 2B) and SEER egis y (Fig. 2C)
showed ha compa ed o s age I disease, isk o
dea h s eadily inc eased h ough s age p og ession
(s age I > s age II [excluding T2bN0M0] > s age
III>s age IVa [excluding T2bN1M0]>li e me as-
ases [T2bN0/1M0]>s age IVb).
Da a om he ENS- CCA egis y (Fig. 2B) showed
ha when g oup C was used as he e e ence g oup,
pa ien s diagnosed wi h ea ly- s age disease g oup A
(s ages I- III) had a lowe isk o dea h han g oup
C (s age I [ s. li e me as ases]; HR, 0.28; 95% CI,
0.19- 0.40; P < 0.001; s age II [ s. li e me as ases];
HR, 0.48; 95% CI, 0.28- 0.81; P=0.007). Compa ed
o g oup C, g oups B and D showed a end owa d
longe and sho e su i al, espec i ely, bu di e -
ences did no each s a is ical signi icance (P=0.118
and P=0.247, espec i ely).
Su i al analysis con i med simila ends in he
SEER egis y (Fig. 2C). Pa ien s diagnosed wi h
s age I and s age II had a lowe isk o dea h com-
pa ed o g oup C. Di e ences be ween g oup A/
s age III and g oup C ( e e ence ca ego y) did no
each s a is ical signi icance (P = 0.302). Simila o
wha had been iden i ied in he ENS- CCA coho ,
g oup B (P=0.016) and g oup D (P<0.001) showed
longe and sho e su i al compa ed o g oup C,
espec i ely.
aBle 3.S aging o pa ien s: aJCC .7 and p oposed maJCC Classi ica ion (eNS- CCa Regis y)
S aging o Pa ien s
Whole ENS- CCA Se ies
(N=574)
T aining Coho
(N=141)
In e nal Valida ion Coho
(N=433)
N % N % N %
AJCC .7 S ages I- III (including T2bN0M0; li e
sa elli e lesions)
267 46.52 43 30.50 224 51.73
S age IVa (including T2bN1M0) 128 22.30 28 19.86 100 23.09
S age IVb (dis an m s) 179 31.18 70 49.65 109 25.17
mAJCC G oup A: s ages I- III (excluding T2bN0M0) 192 33.45 13 9.22 179 41.34
G oup B: s age IVa (excluding T2bN1M0) 89 15.51 20 14.18 69 15.94
G oup C: s age T2bN0/1M0: li e m s 114 19.86 38 26.95 76 17.55
N0 75 30 45
N1 39 8 31
G oup D: s age IVb 179 31.18 70 49.65 109 25.17
mAJCC (sensi i i y
analysis)
G oup A: s ages I- III (excluding T2bN0M0) 192 33.45 13 9.22 179 41.34
G oup B: s age IVa (including T2bN1M0) 128 22.30 28 19.86 100 23.09
G oup C: s age T2bN0M0: li e m s 75 22.30 30 21.28 45 10.39
G oup D: s age IVb 179 31.18 70 49.65 109 25.17
N e e s o numbe , % o pe cen age.
Abb e ia ion: m s, me as ases.
