Pla inum P io i y – P os a e Cance
Edi o ial by Megan E.V. Ca am and Da id C. Mille on pp. 212–214 o his issue
Managemen o Pa ien s wi h Ad anced P os a e Cance :
The Repo o he Ad anced P os a e Cance Consensus
Con e ence APCCC 2017
Silke Gillessen
a
[25_TD$DIFF]
,
*, Ge ha d A a d
b
, Tomasz M. Bee
c
, Himisha Bel an
d
, Albe o Bossi
e
,
Rob B is ow
, B e Ca e
g
, Daniel Cas ellano
h
, Byung Ha Chung
i
, Noel Cla ke
j
,
Gedske Daugaa d
k
, Ian D. Da is
l
, Johann de Bono
b
, Rodol o Bo ges dos Reis
m
,
Cha les G. D ake
n
, Ros Eeles
o
, Eleni E s a hiou
p
, Ch is ophe P. E ans
q
, S e ano Fan i
,
Felix Feng
s
, Ka im Fizazi
, Ma k F ydenbe g
u
, Ma in Glea e
, Susan Halabi
w
,
Axel Heiden eich
x
, Celes ia S. Higano
y
, Nicolas James
z
, Philip Kan o
aa
,
Pi kko-Liisa Kellokumpu-Leh inen
bb
, Raja B. Khauli
cc
, Ge o K ame
dd
, Ch is Logo he is
ee
,
Fe nando Malu
, Alicia K. Mo gans
gg
, Michael J. Mo is
hh
, Nicolas Mo e
ii
, Vedang Mu hy
jj
,
William Oh
kk
, Pie Os
ll
, Anwa R. Padhani
mm
, Ch is Pa ke
nn
, Colin C. P i cha d
oo
,
Mack Roach
s
, Ma k A. Rubin
pp
, Cha les Ryan
qq
, F ed Saad
, Oli e Sa o
ss
, Howa d Sche
,
A ishay Sella
uu
, Neal Sho e
, Ma hew Smi h
ww
, Howa d Soule
xx
, Co a N. S e nbe g
yy
,
Hi oyoshi Suzuki
zz
, Ch is ophe Sweeney
aaa
, Ma hew R. Sydes
bbb
, Ian Tannock
ccc
,
Be and Tombal
ddd
, Ricca do Valdagni
eee
, Thomas Wiegel
, Au elius Omlin
a
a
Depa men o Medical Oncology, Can onal Hospi al S . Gallen and Uni e si y o Be ne, Swi ze land;
b
Depa men o Medical Oncology, The Ins i u e o
Cance Resea ch/Royal Ma sden, London, UK;
c
O egon Heal h & Science Uni e si y Knigh Cance Ins i u e, OR, USA;
d
Depa men o Medical Oncology,
Weill Co nell Medicine, New Yo k, NY, USA;
e
Depa men o Radia ion Oncology, Geni o U ina y Oncology, P os a e B achy he apy Uni , Gous a e Roussy,
Pa is, F ance;
Depa men o Radia ion Oncology, P incess Ma ga e Cance Cen e and Uni e si y o To on o, To on o, ON, USA;
g
Depa men o U ology,
Sidney Kimmel Cen e o P os a e and U ologic Cance s, New Yo k, NY, USA;
h
[3_TD$DIFF]Depa men o Medical Oncology, Hospi al Uni e si a io 12 de Oc ub e,
Mad id, Spain;
i
Depa men o U ology, Gangnam Se e ance Hospi al, Yonsei Uni e si y Heal h Sys em, Seoul, Ko ea;
j
Depa men o U ology, The Ch is ie
and Sal o d Royal Hospi als, Manches e , UK;
k
Depa men o Medical Oncology, Copenhagen Uni e si y Hospi al, Rigshospi ale , Copenhagen, Denma k;
l
Monash Uni e si y and Eas e n Heal h, Eas e n Heal h Clinical School, Box Hill, Aus alia;
m
Depa men o U ology, Ribei a
˜o P e o Medical School,
Uni e si y o Sa
˜o Paulo, Sa
˜o Paulo, B azil;
n
Depa men o Medical Oncology, Di ision o Haema ology/Oncology, Columbia Uni e si y Medical Cen e , New
Yo k, NY, USA;
o
Depa men o Clinical Oncology and Gene ics, The Ins i u e o Cance Resea ch and Royal Ma sden NHS Founda ion T us , London, UK;
p
Depa men o Medical Oncology, Uni e si y o Texas MD Ande son Cance Cen e , TX, USA;
q
Depa men o U ology, Uni e si y o Cali o nia, Da is School
o Medicine, CA, USA;
Depa men o Nuclea Medicine, Policlinico S. O sola, Uni e si a
`di Bologna, I aly;
s
Depa men o Radia ion Oncology, Uni e si y o
Cali o nia, San F ancisco, CA, USA;
Depa men o Medical Oncology, Gus a e Roussy, Uni e si y o Pa is Sud, Pa is, F ance;
u
Depa men o Su ge y,
Depa men o Ana omy and De elopmen al Biology, Facul y o Medicine, Nu sing and Heal h Sciences, Monash Uni e si y;
Depa men o U ology,
Vancou e P os a e Cen e, Uni e si y o B i ish Columbia, Vancou e , BC, Canada;
w
Depa men o Clinical ials and S a is ics, Duke Uni e si y, Du ham,
NC, USA;
x
Depa men o U ology, Uni e si y Hospi al Ko
¨ln, Ko
¨ln, Ge many;
y
Depa men o Medicine, Di ision o Medical Oncology, Uni e si y o
Washing on and F ed Hu chinson Cance Resea ch Cen e , WA, USA;
z
Depa men o Clinical Oncology, Clinical Oncology Queen Elizabe h Hospi al
Bi mingham and[4_TD$DIFF] Uni e si y o Bi mingham, Bi mingham, UK;
aa
Depa men o Medical Oncology, Memo ial Sloan Ke e ing Cance Cen e and Weill Co nell
Medical College, New Yo k, NY, USA;
bb
Depa men o Clinical Oncology, Tampe e Uni e si y Hospi al, Facul y o Medicine and Li e Sciences, Uni e si y o
Tampe e, Finland;
cc
Depa men o U ology, Ame ican Uni e si y o Bei u Medical Cen e , Bei u , Lebanon;
dd
Depa men o U ology, Medical Uni e si y o
EUROPEAN UROLOGY 73 (2018) 178–211
a ailable a www.sciencedi ec .com
jou nal homepage: www.eu opeanu ology.com
*Co esponding au ho . Can onal Hospi al S . Gallen, Ro schache s asse 95, 9007 S . Gallen,
Swi ze land. Tel. +41 71 494 11 11; Fax: +41 71 494 63 25.
E-mail add ess: [email p o ec ed] (S. Gillessen).
h p://dx.doi.o g/10.1016/j.eu u o.2017.06.002
0302-2838/#2017 Eu opean Associa ion o U ology. Published by Else ie B.V. This is an open access a icle unde he CC
BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
Vienna, Vienna, Aus ia;
ee
[3_TD$DIFF]Depa men o Geni ou ina y Medical Oncology, MD Ande son Cance Cen e, Hous on, TX, USA;
Depa men o Medical
Oncology Hospi al Is aeli a Albe Eins ein and Depa men o Medical Oncology Bene ice
ˆncia Po uguesa de Sa
˜o Paulo;
gg
Depa men o Medical Oncology
and Epidemiology, Vande bil Uni e si y Medical Cen e , Di ision o Hema ology/Oncology, Nash ille, TN, USA;
hh
Depa men o Medical Oncology,
Memo ial Sloan Ke e ing Cance Cen e , New Yo k, NY, USA;
ii
Depa men o U ology, Uni e si y Hospi al No d S . E ienne, S . E ienne, F ance;
jj
Depa men
o Radia ion Oncology, Ta a Memo ial Cen e, Mumbai, India;
kk
Depa men o Medical Oncology, Di ision o Hema ology and Medical Oncology, Icahn
School o Medicine a Moun Sinai, The Tisch Cance Ins i u e, New Yo k, NY, USA;
ll
Depa men o Radia ion Oncology, Ghen Uni e si y Hospi al, Ghen ,
Belgium;
mm
Depa men o Radiology, Moun Ve non Cance Cen e and Ins i u e o Cance Resea ch, London, UK;
nn
Depa men o Clinical Oncology, Royal
Ma sden [26_TD$DIFF]NHS Founda ion T us , Su on, UK;
oo
Depa men o Pa hology, Uni e si y o Washing on, WA, USA;
pp
Depa men o Pa hology, Uni e si y o Be n
and he Inselspi al, Be n (CH);
qq
Depa men o Medical Oncology, Clinical Medicine and U ology a he Helen Dille Family Comp ehensi e Cance Cen e a
he Uni e si y o , Cali o nia, San F ancisco, CA, USA;
Depa men o U ology, Cen e Hospi alie de l’Uni e si e
´de Mon e
´al, Mon eal, QC, Canada;
ss
Depa men o Medical Oncology, Tulane Cance Cen e , New O leans, LA, USA;
Depa men o Medical Oncology, Geni ou ina y Oncology Se ice,
Memo ial Sloan Ke e ing Cance Cen e, New Yo k, NY, USA;
uu
Depa men o Medical Oncology, Depa men o Oncology, Assa Ha o eh Medical Cen e,
Tel-A i Uni e si y, Sackle School o Medicine, Ze i in, Is ael;
Depa men o U ology, Ca olina U ologic Resea ch Cen e , My le Beach, SC, USA;
ww
Depa men o Medical Oncology, Massachuse s Gene al Hospi al Cance Cen e, Bos on, MA, USA;
xx
[7_TD$DIFF]P os a e Cance Founda ion, San a Monica, CA, USA;
yy
Depa men o Medical Oncology, San Camillo Fo lanini Hospi al, Rome, I aly;
zz
Depa men o U ology, Toho Uni e si y Saku a Medical Cen e , Japan;
aaa
Depa men o Medical Oncology, Dana-Fa be Cance Ins i u e and B igham and Women’s Hospi al, Ha a d Medical School, Bos on, MA, USA;
bbb
MRC
Clinical T ials Uni a UCL, Ins i u e o Clinical T ials and Me hodology, Uni e si y College London, London, UK;
ccc
Depa men o Medical Oncology, P incess
Ma ga e Cance Cen e and Uni e si y o To on o, To on o, ON, Canada;
ddd
Depa men o U ology, Cliniques Uni e si ai es Sain Luc, B ussels, Belgium;
eee
Depa men o Oncology and Haema o-oncology, Uni e si a
`degli S udi di Milano. Radia ion Oncology 1, P os a e Cance P og am, Fondazione IRCCS
Is i u o Nazionale dei Tumo i, Milan, I aly;
Depa men o Radia ion Oncology, Klinik u
¨ S ahlen he apie und Radioonkologie des Uni e si a
¨ sklinikum
Ulm, Albe -Eins ein-Allee, Ulm, Ge many
A icle in o
A icle his o y:
Accep ed June 1, 2017
Associa e Edi o :
James Ca o
Keywo ds:
Ad anced and high- isk
localized p os a e cance
Cas a ion-nai e and cas a ion-
esis an p os a e cance
The apeu ics
Consensus
Oligome as a ic p os a e cance
Please isi www.eu-acme.o g/
eu opeanu ology o ead and
answe ques ions on-line.
The EU-ACME c edi s will
hen be a ibu ed
au oma ically.
Abs ac
Backg ound: In ad anced p os a e cance (APC), success ul d ug de elopmen as well as
ad ances in imaging and molecula cha ac e isa ion ha e esul ed in mul iple a eas
whe e he e is lack o e idence o low le el o e idence. The[9_TD$DIFF] Ad anced P os a e Cance
Consensus Con e ence (APCCC) 2017 add essed some o hese opics.
Objec i e: To p esen he epo o APCCC 2017.
Design, se ing, and pa icipan s: Ten impo an a eas o con o e sy in APC manage-
men we e iden ified: high- isk localised and locally ad anced p os a e cance ; ‘‘oligo-
me as a ic’’ p os a e cance ; cas a ion-naı
¨ e and cas a ion- esis an p os a e cance ;
he ole o imaging in APC; os eoclas - a ge ed he apy; molecula cha ac e isa ion o
blood and issue; gene ic counselling/ es ing; side e ec s o sys emic ea men (s);
global access o p os a e cance d ugs. A panel o 60 in e na ional p os a e cance
expe s de eloped he p og am and he consensus ques ions.
Ou come measu emen s and s a is ical analysis: The panel o ed publicly bu anony-
mously on 150 p edefined ques ions, which ha e been de eloped ollowing a modified
Delphi p ocess.
Resul s and limi a ions: Vo ing is based on panellis opinion, and hus is no based on a
s anda d li e a u e e iew o me a-analysis. The ou comes o he o ing had a ying
deg ees o suppo , as eflec ed in he wo ding o his a icle, as well as in he de ailed
o ing esul s eco ded in Supplemen a y da a.
Conclusions: The p esen ed expe o ing esul s can be used o suppo in a eas o
managemen o men wi h APC whe e he e is no high-le el e idence, bu indi idualised
ea men decisions should as always be based on all o he da a a ailable, including
disease ex en and loca ion, p io he apies ega dless o ype, hos ac o s including
como bidi ies, as well as pa ien p e e ences, cu en and eme ging e idence, and
logis ical and economic cons ain s. Inclusion o men wi h APC in clinical ials should
be s ongly encou aged. Impo an ly, APCCC 2017 again iden ified impo an a eas in
need o ials specifically designed o add ess hem.
Pa ien summa y: The second Ad anced P os a e Cance Consensus Con e ence APCCC
2017 did p o ide a o um o discussion and deba es on cu en ea men op ions o
men wi h ad anced p os a e cance . The aim o he con e ence is o b ing he expe ise o
wo ld expe s o ca e gi e s a ound he wo ld who see less pa ien s wi h p os a e cance .
The con e ence concluded wi h a discussion and o ing o he expe panel on p edefined
consensus ques ions, a ge ing a eas o p ima y clinical ele ance. The esul s o hese
expe opinion o es a e embedded in he clinical con ex o cu en ea men o men
wi h ad anced p os a e cance and p o ide a p ac ical guide o clinicians o assis in he
discussions wi h men wi h p os a e cance as pa o a sha ed and mul idisciplina y
decision-making p ocess.
#2017 Eu opean Associa ion o U ology. Published by Else ie B.V. 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/).
EUROPEAN UROLOGY 73 (2018) 178–211
179
1. In oduc ion
The panel o he 2017 Ad anced P os a e Cance Consensus
Con e ence (APCCC 2017) consis ed o 61 mul idisciplina y
cance physicians and scien is s om 21 coun ies selec ed
based on hei academic ack eco d and in ol emen in
clinical o ansla ional esea ch in he ield ad anced
p os a e cance (APC; Table 1).
Fo discussion, 10 con o e sial a eas ela ed o he
managemen o men wi h APC ha we e judged o be mos
impo an o discussion we e iden i ied:
1. Managemen o high- isk localised and locally ad-
anced p os a e cance
2. ‘‘Oligome as a ic’’ p os a e cance
3. Managemen o cas a ion-sensi i e/naı
¨ e p os a e
cance (CNCP)
4. Managemen o cas a ion- esis an p os a e cance
(CRPC)
5. Imaging in APC
6. Use o os eoclas - a ge ed he apy o skele al ela ed
e en s (SRE)/symp oma ic skele al e en s (SSE) p e-
en ion o me as a ic CRPC (mCRPC; no o os eopo-
osis/bone loss)
7. Molecula cha ac e isa ion
8. Gene ic counselling/ es ing
9. Side e ec s o sys emic ea men : p e en ion, man-
agemen , and suppo i e ca e
10. Global access o p os a e cance d ugs and ea men in
coun ies wi h limi ed esou ces
The consensus de elopmen p ocess ollowed he p oce-
du es p e iously desc ibed (Supplemen a y da a) [1].The
con e ence was o ganised a ound s a e-o - he-a lec u es
and p esen a ions and deba es by panellis s who e iewed
and discussed he e idence ele an o he abo e selec ed
opics. On he las day o he con e ence, 150 p e iously
ag eed-upon ques ions we e p esen ed wi h op ions o
answe sina mul iple-choice o ma seeSupplemen a y da a.
The ques ions we e o ed on publicly bu anonymously.
Fo all ques ions, unless s a ed o he wise, esponses
we e based on he idealised assump ions ha all diagnos ic
p ocedu es and ea men s (including expe ise in hei
in e p e a ion and applica ion) men ioned we e eadily
a ailable; he e we e no ea men con aindica ions and
no op ion o include he pa ien in a clinical ial.
In addi ion, o ing answe s apply only o i pa ien s
wi hou limi ing como bidi ies and o pa ien s wi h
p os a e adenoca cinoma (unless s a ed o he wise). When
me as ases we e men ioned, hey we e de ec ed by bone
scin ig aphy and/o c oss-sec ional imaging wi h compu ed
omog aphy (CT) and/o magne ic esonance imaging
(MRI), i no s a ed o he wise. Impo an ly, in an e o o
add ess ques ions om an e idence-based and clinical
u ili y pe spec i e, panellis s we e speci ically ins uc ed
no o conside cos , eimbu semen , and access as ac o s in
hei delibe a ions, unless o he wise s a ed, al hough
clea ly hese a e c i ical ac o s in he decision making
o he physician and indi idual pa ien .
Table 1 – Panel membe s by coun y and special y
Name Fi s name Speciali y
A a d Ge Medical Oncology
Bee Tomasz M. Medical Oncology
Bel an Himisha Medical Oncology
Bossi Albe o Radia ion Oncology,
non o ing (absence
du ing o ing)
B is ow Rob Radia ion Oncology
Ca e B e U ology
Cas ellano Daniel Medical Oncology
Chung Byung Ha U ology
Cla ke Noel U ology
Daugaa d Gedske Medical Oncology
Da is Ian[17_TD$DIFF] D. Medical Oncology
de Bono Johann Medical Oncology
Bo ges dos Reis Rodol o U ology
D ake Cha les G. Medical Oncology
Eeles Ros Clinical Oncology and Gene ics
E s a hiou Eleni Medical Oncology
E ans Ch is ophe [18_TD$DIFF] P. U ology
Fan i S e ano Nuclea Medicine,
non o ing membe
Feng Felix Radia ion Oncology
Fizazi Ka im Medical Oncology
F ydenbe g Ma k U ology
Glea e Ma in U ology
Gillessen Silke Medical Oncology
Halabi Susan Clinical T ials and S a is ics,
non o ing membe
Heiden eich Axel U ology
Higano Celes ia [19_TD$DIFF]S. Medical Oncology
James Nicolas Clinical Oncology
Kan o Philip Medical Oncology
Kellokumpu-Leh inen Pi kko-Liisa Clinical Oncology
Khauli Raja B. U ology
K ame Ge o U ology
Logo he is Ch is Medical Oncology
Malu Fe nando Medical Oncology
Mo gans Alicia K. Medical Oncology
and Epidemiology
Mo is Michael[20_TD$DIFF] J. Medical Oncology
Mo e Nicolas U ology
Mu hy Vedang Radia ion Oncology
Oh William Medical Oncology
Omlin Au elius Medical Oncology,
non o ing membe
Os Pie Radia ion Oncology
Padhani Anwa [21_TD$DIFF] R. Radiology, non o ing membe
Pa ke Ch is Clinical Oncology
P i cha d Colin[22_TD$DIFF] C. Pa hology, non o ing membe
Roach Mack Radia ion Oncology
Rubin Ma k[23_TD$DIFF] A. Pa hology, non o ing membe
Ryan Cha les Medical Oncology
Saad F ed U ology
Sa o Oli e Medical Oncology
Sche Howa d Medical Oncology
Sella A ishay Medical Oncology
Sho e Neal U ology
Smi h Ma hew Medical Oncology
Soule Howa d P os a e Cance Founda ion,
non o ing membe
S e nbe g Co a N. Medical Oncology
Suzuki Hi oyoshi U ology
Sweeney Ch is ophe Medical Oncology
Sydes Ma hew R[24_TD$DIFF]. Clinical T ials and S a is ics,
non o ing membe
Tannock Ian Medical Oncology
Tombal Be and U ology
Valdagni Ricca do Radia ion Oncology
Wiegel Thomas Radia ion Oncology
EUROPEAN UROLOGY 73 (2018) 178–211
180
The esul s a e in ended o se e only as a guide o
clinicians o assis in he discussions wi h pa ien s as pa o
a sha ed and mul idisciplina y decision-making p ocess.
Fo he de ini ions used o APCCC 2017 please e e o
Supplemen a y da a.
The panel consis ed o o ing (52) and non o ing
membe s (9). The non o ing membe s we e panellis s, o
example, adiologis s, pa hologis s, and s a is icians who a e
no in ol ed in clinical managemen decision making, and
one clinical expe who was no p esen du ing he o ing.
The op ion ‘‘unquali ied o answe ’’ (sho o m ‘‘unquali-
ied’’) should ha e been chosen i a panellis lacked
expe ience o a speci ic ques ion; he ‘‘abs ain’’ op ion
should ha e been chosen i a panellis el unable o o e o a
bes choice o any eason o had p ohibi o y con lic s o
in e es . The con e ence also included an explici app oach o
managemen o con lic s o in e es (Supplemen a y da a).
De ailed o ing eco ds o each o he ques ions b ough
o he panel a e p o ided in he Supplemen a y da a. The
denomina o was based on he numbe o panel membe s
who o ed on he pa icula ques ion, excluding hose who
o ed ‘‘unquali ied o answe .’’ In case o ques ions ela ed
o a opic o a p e ious ques ion whe e only a subse o he
panellis s had o ed o a speci ic answe op ion he o es o
panel membe s who o ed ‘‘abs ain’’ and ‘‘unquali ied o
answe ’’ we e excluded.
Consensus was decla ed i 75% o he panellis s who did
no o e o ‘‘unquali ied’’ o ‘‘abs ain’’ chose he same
op ion [2]. Th oughou , he pe cen age o o ing panellis s
who ga e a pa icula esponse a e epo ed, he numbe o
o e s, and he numbe o panellis s o each answe a e
p o ided in he Supplemen a y da a. All panellis s ha e
con ibu ed o he designing o he ques ions, edi ing he
manusc ip , and ha e app o ed he inal documen .
Impo an ly, his p ocess was uniquely able o highligh
a eas o disag eemen and iden i ied p io i ies o u u e
clinical esea ch, meaning a eas whe e addi ional da a
acquisi ion is wa an ed.
2. High- isk localised and locally ad anced p os a e
cance
The panellis s no ed ha he e is lack o p ecision in he use
o he e m ‘‘high isk’’ in localised p os a e cance ha is in
pa in luenced by a discipline speci ic pe spec i e. The
commonly used de ini ions o high- isk localised pa ien s
by a ious socie ies plus he de ini ions used in he
STAMPEDE ial a e summa ised in Supplemen a y da a.
High- isk localised pa ien s ha e ela i ely good long- e m
ou comes [3,4]. Fo he APCCC 2017 con e ence, he
Eu opean Associa ion o U ology (EAU) guideline de ini ion
was used [5].
2.1. Pa hology in locally ad anced p os a e cance
Pa hology epo ing o adical p os a ec omies (RP) should
adhe e o he ecen ly published Ame ican Join Commi ee
on Cance eigh h edi ion cance s aging manual [6]. The
new guidelines include he adop ion o P ognos ic Gleason
G oups along wi h Gleason sco es, he collapsing o pT2 o
one single g oup, and he use o ele a ed p os a e-speci ic
an igen (PSA) o inc ease clinical s aging. RP epo s should
commen on umou Gleason sco es using he In e na ional
Socie y o U ological Pa hology guidelines [7,8].
In men wi h posi i e lymph nodes, he o al numbe o
nodes wi h me as ases, he umou olume wi hin he
lymph node, and ex acapsula nodal ex ension a e poo
p ognos ic ac o s [9].
In issue om pa ien s who ha e p e iously been ea ed
wi h and ogen dep i a ion he apy (ADT) and/o o he
sys emic ea men o adia ion he apy (RT) no Gleason
sco e should be epo ed.
The panel unanimously ag eed (100%) ha apa om
mo phology and umou s age, he ollowing ac o s should be
epo ed om a RP sample: (1) seminal esicle in ol emen , (2)
ex ap os a ic ex ension, (3) posi i e su gical ma gins (num-
be , leng h and loca ion, g ade a ma gin), (4) Gleason sco e,
and (5) g ade g oup. The e was also consensus ha he
ollowing ac o s should be epo ed: (1) ex en o p os a ic
in ol emen (96%), (2) numbe and ana omic egion o
esec ed lymph nodes and numbe and loca ion o in ol ed
lymph nodes (94%), (3) e ia y Gleason g ade (94%), and (4)
mic ome as ases e sus mac ome as ases in in ol ed lymph
nodes (81%), ex anodal ex ension (81%), and me as a ic
deposi s in pe inodal a issue (79%; Table 2).
Cu en guidelines (EAU, Na ional Comp ehensi e
Cance Ne wo k [NCCN]) ecommend pe o ming ex end-
ed pel ic lymph node dissec ion o men wi h high- isk
and locally APC ea ed by RP pa icula ly i he isk o
lymph node me as ases based on a ailable nomog ams is
es ima ed o be 5% despi e he ac ha he e a e no da a
om andomised p ospec i e ials suppo ing an im-
p o emen in ou come wi h lymph node dissec ion [10–
12]. The impac o minimal empla e e sus ex ended
lymph node dissec ion is no known and he pa hological
p ocessing and epo ing o he dissec ed ma e ial is no
well de ined.
The e was a consensus (84%) ha a lymph node dissec ion
should be pe o med in he majo i y o men wi h cN0 cM0 high-
isk p os a e cance unde going RP whe eas 9% o ed o a
lymph node dissec ion in a mino i y o selec ed pa ien s and 5%
did no o e o a lymph node dissec ion.
Rega ding he minimum numbe o lymph nodes o
cons i u e an adequa e dissec ion in he majo i y o men wi h
cN0 cM0 high- isk p os a e cance 76% o he panellis s o ed
o a minimum o 11 lymph nodes (49% o 11–19 lymph
nodes and 27% o [1_TD$DIFF]20 lymph nodes); 15% o he panellis s
o ed o i e o 10 lymph nodes, 9% abs ained.
Rega ding he empla e o lymph node dissec ion in men
wi h high- isk and locally ad anced p os a e cance , he e was
a consensus ha he ob u a o egion (98%), in e nal iliac
egion (90%), and ex e nal iliac egion (85%) should be
dissec ed. Rega ding he p esac al lymph nodes, 51% o he
panellis s o ed agains and 46% in a ou o dissec ion,
simila ly o common iliac lymph nodes 52% o he panellis s
o ed agains and 45% in a ou o dissec ion. The e was a
consensus (95%) agains ou ine dissec ion o pa a-ao ic
lymph nodes (Table 3).
EUROPEAN UROLOGY 73 (2018) 178–211
181
2.2. Adju an adia ion he apy a e RP
Adju an adia ion he apy (ART) is la gely conside ed as
he adminis a ion o ex e nal beam RT in he pos ope a i e
phase in absence o objec i e e idence ha disease has
ecu ed o pe sis ed. In he case o p os a e cance his
would mean deli e ing RT when he PSA is ‘‘unde ec able.’’
In e es ingly, he de ini ion o ‘‘unde ec able’’ has a ied
o e he pas 25 y by nea ly 100 old om <0.3 ng/ml in o
he pg/ml ange mo e ecen ly [13].
Th ee andomised con olled ials ha e demons a ed
ha ART in case o un a ou able pa hological ea u es (eg,
pT3b, R1) a e RP delays PSA ecu ence ee su i al; in
one o hese ials me as ases- ee su i al and o e all
su i al (OS) we e also imp o ed. In e p e a ion o hose
esul s is gene ally biased by he inclusion o men wi h
pe sis en disease e idenced by low bu de ec able PSA
le els [14–16]. Thus, in ac many o hese pa ien s ea ed
on he ART a m should be desc ibed as ecei ing ea ly
sal age adia ion he apy (SRT) [17,18].
Because se e al e ospec i e s udies ha e shown ha
SRT, o e ed a PSA ecu ence, may be e icien and since
his app oach may sa e some men he applica ion o ART,
many physicians de e ea men un il he e is e idence o
ecu en disease. Un o una ely he e is no p ospec i e
andomised ial compa ing ‘‘pu e’’ ART a unde ec able PSA
le els as cu en ly de ined e sus SRT a ‘‘app op ia ely’’
low PSA le els.
2.2.1. ART o high isk localised p os a e cance pN0
The opic o ART was add essed in men pos -RP wi hou
lymph node in ol emen on su gical pa hology (pN0), wi h
unde ec able pos ope a i e PSA, and who ha e eco e ed
u ina y con inence.
The e was no consensus on ART in high- isk localised
p os a e cance pa ien s. Fo y-eigh pe cen o he panellis s
o ed o ART o any posi i e su gical ma gins, whils 27% o
he panel o ed o ART only in case o mul i ocal o ex ensi e
ma gins. Twen y-one pe cen o he panel did no o e o ART
in his se ing.
In he p esence o seminal esicle in ol emen alone 38% o
he panel o ed o ART in he majo i y o pa ien s, 32% o he
panel o ed o ART only i combined wi h posi i e su gical
ma gins. Twen y-six pe cen o he panel did no o e o ART a
all in his se ing.
Fi y- i e pe cen o panellis s did no o e o ART in he
case o Gleason 8–10 (Gleason G ade G oup 4 o 5) as he only
ad e se ac o , 20% o he panel o ed o ART in case o Gleason
8–10 (Gleason G ade G oup 4 o 5) alone o he majo i y o
pa ien s, and 23% in a mino i y o selec ed pa ien s.
Rega ding adia ion ield, 51% o he subse o panellis s who
o ed o ART o ed o ea men o he whole pel is and
p os a ic bed, while 41% o ed o ea ing only he p os a ic
bed.
Thi y-six pe cen o he subse o panellis s who o ed o
ART o ed o adding ADT in he majo i y o pa ien s, 32% in a
mino i y o selec ed pa ien s, and 32% did no o e o he
addi ion o ADT a all. F om he subse o panellis s who o ed
o addi ion o ADT o ART, 69% o ed o his combined
ea men in men wi h ei he pT s age 3b and/o Gleason
sco e 8 (G ade g oup 4–5); 28% o ed o combined ea men
in men wi h pT s age 3b alone independen o Gleason sco e;
Table 3 – Lymph node (LN) dissec ion in localised p os a e cance
(which LN egions should be sampled [minimal equi emen ] in
men wi h cN0 cM0 high- isk p os a e cance ?)
LN egion Yes (%) No (%) Abs ain (%)
Ob u a o 98 2 0
In e nal iliac 90 10 0
Ex e nal iliac 85 15 0
P esac al 46 51 3
Common iliac 45 52 3
Pa a-ao ic 5 95 0
Table 2 – P os a ec omy pa hology epo ing (as clinicians, which ac o s do you wan o be epo ed om a p os a ec omy specimen in men
wi h locally-ad anced p os a e cance apa om mo phology and umou s age?)
Fac o Yes, use ul es o majo i y
o pa ien s (influences you
managemen decision; %)
Only o mino i y
o selec ed
pa ien s (%)
No (%) Abs ain (%)
Seminal esicle in asion 100 0 0 0
Ex ap os a ic ex ension 100 0 0 0
Posi i e su gical ma gins: numbe , leng h and
loca ion as well as g ade a ma gin
100 0 0 0
Gleason sco e and g ade g oup 100 0 0 0
Ex en o p os a ic in ol emen 96 2 2 0
I lymphadenec omy is pe o med: numbe and
ana omic egion o esec ed lymph nodes and
numbe and loca ion o in ol ed lymph nodes
94 6 0 0
Te ia y Gleason sco e 94 4 2 0
In any in ol ed lymph nodes: mic o- s mac ome as ases 81 9 10 0
In any in ol ed lymph nodes: ex anodal ex ension 81 9 10 0
In any in ol ed lymph nodes: me as a ic deposi s
in pe inodal a issue
79 15 6 0
C ib i o m g ow h pa e n and in aduc al umou sp ead 73 14 13 0
Lympho ascula in asion 68 18 14 0
In aduc al ca cinoma 67 21 12 0
Ma ke s o inflamma ion (eg, inflamma ion wi hin
p os a e cance issue, umou infil a ing lymphocy es)
23 24 53 0
EUROPEAN UROLOGY 73 (2018) 178–211
182

and 3% o ed o combined ea men in men wi h Gleason 8–
10 (Gleason G ade G oup 4 o 5) alone. Rega ding he o m o
ADT 61% o he subse o panellis s o ed o a lu einizing
ho mone- eleasing ho mone (LHRH) agonis /an agonis , 24%
o combined ADT, and 15% o an and ogen ecep o
an agonis mono he apy. Rega ding du a ion o ADT, 39% o
he subse o panellis s o ed o 3–6 mo, 43% o 6–12 mo, and
18% o 18–36 mo o ADT.
2.2.2. ART o pN1 p os a e cance
Fo men wi h p os a e cance and lymph node in ol emen ,
cance mo ali y ises signi ican ly when >2 posi i e lymph
nodes a e p esen [19].
The ques ion o ART in men wi h pN1 disease (assuming
adequa e lymph node sampling, sec ion 2.1) and no local
ad e se ac o s (no pT3b, no R1) and unde ec able
pos ope a i e PSA and who ha e eco e ed u ina y con i-
nence was add essed by he consensus panel.
The e was no consensus on ART in pN1 disease. Twen y-six
pe cen o he panel o ed o ART in men wi h pN1 disease in a
majo i y o pa ien s, 29% o ed o ART in a mino i y o selec ed
pa ien s, while 43% o he panel did no o e o ART in his
se ing.
Rega ding adia ion ield, 97% o he subse o panellis s who
o ed o ART o ed o he whole pel is plus p os a ic bed as
adia ion ield.
The subse o panellis s who o ed o ART also o ed on
ac o s ha in luenced hei decision o ecommend ART: 62%
o ed o aking bo h he numbe and loca ion o posi i e
lymph nodes in o conside a ion when ecommending ART, 33%
based hei decision only on he numbe o in ol ed lymph
nodes, and 5% only on he loca ion o in ol ed lymph nodes.
Fi y pe cen o his subse o panellis s o ed o ART in men
wi h one o wo posi i e lymph nodes in he p esence o
in e media e- o high-g ade, nono gan-con ined disease and in
hose wi h h ee o ou lymph nodes i espec i e o g ade and
T-s age, 17% o ed o ART in all pa ien s, 15% o ed o ART in
pa ien s wi h 2 posi i e lymph nodes independen o g ade
and T-s age, and 15% in pa ien s wi h 4 posi i e lymph nodes
independen o g ade and T-s age.
O he panellis s who o ed o ART o pN1 disease, 100%
o ed o adding ADT o ART. Rega ding he du a ion o ADT in
his si ua ion, 18–36 mo was o ed o by 57% o hese
panellis s, 6–12 mo by 30%; 11% o ed o 3–6 mo, while 2%
o ed o li e-long ADT.
2.3. Sal age adia ion he apy a e RP
While RP gene ally yields excellen esul s in pa ien s wi h
localised p os a e cance , he ecu ence a es a e RP o
high- isk p os a e cance may ise as high as 50–80% [15].In
he case o ecu ence, SRT is a ea men op ion [20].
The app op ia e PSA le el a which o ini ia e SRT is s ill
unclea . Eu opean guidelines ecommend ini ia ing SRT
be o e he pos -RP PSA le el exceeds 0.5 ng/ml, whils NCCN
guidelines ecommend SRT in pa ien s wi h con i med
inc easing PSA [21,22].
Two mul i-ins i u ional e ospec i e s udies showed an
imp o ed eedom om biochemical p og ession and
dis an me as ases ollowing e y ea ly SRT a a PSA
<0.2 ng/ml as opposed o pa ien s in which SRT was
ini ia ed a a PSA le el o 0.2–0.5 ng/ml e sus highe PSA
alues [23,24]. Such analyses a e con ounded by lead- ime
and leng h- ime bias and he opic emains an a ea o
unce ain y.
Acco ding o he cu en EAU guidelines, he SRT dose
should be a leas 66 Gy bu he op imal dose may be
highe ; he op imal dose and ac iona ion is unclea and is
being add essed in se e al ongoing ials.
Combining SRT wi h ADT may be an op ion, pa icula ly
in men wi h high- isk disease. In he GETUG-AFU 16 ial,
he 5-y eedom om biochemical p og ession was 80%
wi h SRT plus 6 mo o ADT e sus 62% wi h SRT alone
[25]. In he RTOG 9601 ial, OS was imp o ed wi h SRT plus
2 y o high-dose bicalu amide (150 mg daily) compa ed
wi h SRT plus placebo bu a signi ican p opo ion o
included men had PSA le els 0.7 ng/ml [26].
Rega ding he con i med PSA le el a which o ini ia e
SRT, 44% o he panel o ed o 0.2 ng/ml, whils 38% o ed
o 0.1ng/ml,10% o ed o 0.5ng/ml,and4% o <0.1 ng/ml.
The panel eached no consensus ega ding a le el o PSA
abo e which SRT would no be ecommended. Twen y- i e
pe cen o he panellis s conside ed 2 ng/ml he maximum
alue, 19% conside ed 1 ng/ml he maximum alue, 11% chose
0.5 ng/ml as a maximum alue, and 19% o he panel o ed ha
he e should be no maximal uppe limi o PSA.
The subse o panellis s who o ed o SRT also o ed on
he addi ion o ADT. Six y-one pe cen o ed o ADT in he
majo i y o men, 29% in a mino i y o selec ed pa ien s, o
example, based on PSA le el and PSA doubling- ime, and 10%
o hesepanellis sdidno o e o headdi iono ADT.
Rega ding he du a ion o ADT in combina ion wi h SRT, 34%
o hese panellis s who op ed o he addi ion o ADT
o ed o 3–6 mo, 41% o 6–12 mo, and 25% o 18–36 mo o
ADT.
2.4. Discussion o high- isk localised and locally ad anced
p os a e cance
The consensus ques ions ocused on men unde going RP
and he opics o ART and SRT. The choice o p ima y
ea men o high- isk and locally ad anced p os a e cance
is also an a ea o con o e sy, bu was no add essed a his
con e ence.
The o es o he panel showed a consensus on he
equi ed in o ma ion o pa hology epo ing in men
unde going a RP.
The e was a lack o consensus ega ding he ole o ART
and SRT e lec ing he many unce ain ies and mul iple
unanswe ed ques ions in bo h opics. One o he easons o
unce ain y is ha he ART ials did no ha e an ea ly SRT
a m as a compa a o and as such a e no compa able o
cu en p ac ice. Ano he weakness o hese ials is he
ela i ely high PSA a which ‘‘adju an ’’ RT was s a ed,
again no compa able o cu en p ac ice.
As wi h any adju an ea men , ART bea s he isk o
o e ea men and can esul in acu e side e ec s as well as
dele e ious e ec s on long- e m unc ional ou come
EUROPEAN UROLOGY 73 (2018) 178–211
183
(eg, po ency, con inence) bu such po en ial isks mus be
balanced agains he po en ial bene i s, namely imp o ed
oncological ou comes [18,27,28].
The ques o de ine ‘‘unnecessa y’’ RT and how o selec
which pa ien s eally equi e ART and o which pa ien s
SRT is app op ia e is cu en ly ongoing. Se e al well-
powe ed phase 3 ials (RADICALS, RAVES, and GETUG-17)
will p o ide e idence on which o base upda ed discussions.
In he mean ime, ega ding SRT, ecen e ospec i e
s udies sugges ha ini ia ing SRT a lowe PSA alues (<
0.2 ng/ml) imp o es biochemical p og ession ee su i al
as compa ed wi h using he adi ional ecommended
con i med alue o 0.2 ng/ml and ising o de ini ion o
biochemical elapse (BCR) [23,24]. These da a we e
e lec ed by he o es o he panel whe ein a signi ican
p opo ion o panellis s would ini ia e SRT below he PSA
h eshold ecommended by cu en guidelines.
The addi ion o ADT o RT as p ima y ea men o he
p os a e is a well-es ablished concep [29–33]. Bu he
addi ion, iming, and du a ion o ADT, speci ically o ART
bu also o SRT, a e less well examined [26]. Acco dingly,
he e was no consensus ega ding he ole o adding ADT o
ART and SRT.
P ospec i ely alida ed p ognos ic and p edic i e mo-
lecula bioma ke s a e equi ed ha will imp o e he
pe o mance o clinical and pa hological ea u es bu his
can only be de e mined in he con ex o la ge phase
3 andomised ials wi h adequa e long- e m ollow-up.
Addi ionally, he inc easing use o nex -gene a ion imaging
me hods in combina ion wi h mo e sensi i e PSA assays
may also al e ea men app oaches in he u u e.
3. Oligome as a ic p os a e cance
3.1. De ini ion o oligome as a ic p os a e cance
Hellman and Weichselbaum [34] p oposed he e m
‘‘oligome as ases’’ in 1995 o de ining a disease s age wi h
a limi ed numbe o clinically de ec able me as ases.
The biological de ini ion o oligome as a ic p os a e
cance is open o in e p e a ion as is he en i e concep
ha his is a p ognos ic and he apeu ically dis inc subse
o pa ien s ha alls somewhe e in-be ween localised and
me as a ic disease. No o mal cu -o o ‘‘oligo’’ has been
de ined in he li e a u e [35]. Some de ini ions inco po a e
bo h he si e o me as ases in addi ion o he numbe o
lesions o de ine he oligome as a ic s a e [35,36]. Va iables
o include in he desc ip ion o men wi h oligome as a ic
disease include: he dis inc ion o synch onous e sus
me ach onous me as ases, he numbe and si e o lesions,
and whe he he pa ien is cas a ion-naı
¨ e o cas a ion-
esis an [36]. O impo ance is also he imaging me hod
used o de ine oligome as a ic disease. Newe imaging
echniques will de ec mo e me as ases in many pa ien s
classi ied as ‘‘oligome as a ic’’ by con en ional imaging (CT
and bone scin ig aphy). Many pa ien s conside ed as M0 on
con en ional imaging may u n ou o ha e oligome as a ic
disease especially when imaging is pe o med a lowe PSA
le els han in he pas .
The panel did no each consensus on wha cons i u ed he
de ini ion o oligome as a ic disease. Six y-one pe cen o he
panellis s o ed o a limi ed numbe o bone and/o lymph
nodes as a clinically meaning ul de ini ion o oligome as a ic
p os a e cance ha in luences ea men decisions (local
abla i e ea men o all lesions
sys emic he apy), 10% o he
panellis s o ed o an oligome as a ic de ini ion which includes
only pa ien s wi h a limi ed numbe o lymph node me as ases,
13% o ed o pa ien s wi h a limi ed numbe o me as ases a any
loca ion (including isce al disease), and 10% o he panellis s did
no belie e ha oligome as a ic p os a e cance exis s as a
clinically meaning ul en i y
.
The subse o panellis s who belie ed in he concep o
oligome as a ic p os a e cance o ed on he numbe o lesions.
Rega ding he cu -o o he numbe o me as ases o conside
a p os a e cance pa ien as oligome as a ic 14% o ed o 2
me as ases, 66% o 3 me as ases, and 20% o hese panellis s
o ed o 5 me as ases as a cu -o . O [27_TD$DIFF] he panellis s belie ing
in he oligome as a ic concep , 52% o ed o a biopsy (i
easible) o an oligome as a ic lesion o diagnos ic pu poses in
a mino i y o selec ed pa ien s, while 34% o ed o biopsy in
he majo i y o pa ien s and 14% o hese panellis s did no o e
o a biopsy.
3.2. Synch onous ‘‘oligome as a ic’’ cas a ion-nai e p os a e
cance
This sec ion add esses pa ien s diagnosed wi h de no o
appa en oligome as a ic disease in he cas a ion-naı
¨ e
s a e, ha is, hey p esen wi h synch onous oligome as-
ases and an un ea ed p ima y. In such pa ien s, no
p ospec i e andomised da a a e a ailable o show a bene i
o abla i e ea men o all lesions including he p ima y—
ei he wi h o wi hou sys emic he apy.
Fo men who p esen wi h de no o oligome as a ic disease,
a o al o 25% o he panellis s o ed o li elong ADT
six cycles
o doce axel wi hou local abla i e ea men . Eigh pe cen o
panellis s o ed o local abla i e ea men o all lesions
including he p ima y (su ge y o RT) wi hou any sys emic
ea men , 22% o panellis s o ed o local abla i e ea men
wi h a sho cou se (6–12 mo) o ADT doce axel, 31% o
panellis s o ed o local abla i e ea men and an in e media e
long cou se (24–36 mo) o ADT doce axel, 8% o panellis s o ed
o local abla i e ea men and li e-long ADT doce axel
.
Among he panellis s who o ed o local abla i e ea men
plus ADT in men wi h de-no o oligome as a ic p os a e cance
and an un ea ed p ima y, 28% o ed o he addi ion o
doce axel in he majo i y o pa ien s, 39% o ed o he addi ion
o doce axel in a mino i y o selec ed pa ien s; 33% o hese
panellis s did no o e o he addi ion o doce axel in his
si ua ion. I hey o ed o ea men o he p ima y umou in
his si ua ion, 45% o ed o RT, 22% o ed o su ge y, and 31%
o ed o ei he RT o su ge y.
3.3. Me ach onous oligome as a ic cas a ion-naı
¨ e p os a e
cance
This sec ion add esses men who p esen wi h ecu en
appa en oligome as a ic p os a e cance in he cas a ion-
EUROPEAN UROLOGY 73 (2018) 178–211
184
naı
¨ e s a e; ha is, hey p esen wi h me ach onous
me as ases a e local ea men o he p ima y. No
p ospec i e andomised da a a e a ailable o show a bene i
o adical abla i e ea men o all lesions wi h o wi hou
sys emic he apy as compa ed wi h s anda d o ca e (ADT

doce axel) [37]. A me a-analysis o 20 small s udies o local
lymph node only ecu ence a e p ima y ea men sug-
ges ed ha , despi e a lack o high-le el e idence, abla i e
node-di ec ed he apy may yield in good sho - e m oncologic
ou comes and may de e he need o sys emic ea men [38].
The e was no consensus on ea men op ions. Fo
ea men o men wi h asymp oma ic oligome as a ic ecu -
en CNPC 32% o he panel o ed o sys emic he apy wi h
li elong ADT
doce axel wi hou local abla i e he apy o he
me as ases. Twel e pe cen o ed o local abla i e he apy o he
me as ases wi hou addi ional sys emic he apy, while 30% o ed
o local abla i e he apy wi h a sho cou se (6–12 mo) o ADT 
doce axel, 18% o local abla i e he apy wi h a longe cou se
(24–36 mo) o ADT doce axel, and 4% o ed o local abla i e
he apy and li elong ADT doce axel
.
Among he panellis s who o ed o local abla i e ea men
in men wi h oligome as a ic ecu en CNPC limi ed o lymph
node me as ases in he pel is, 23% o ed o sal age lymph
node dissec ion, 19% o sal age lymph node dissec ion plus RT
o he pel is (i no p io whole-pel is RT), 16% o hese
panellis s o ed o ocal RT, and 42% o whole pel is RT (i no
p io whole-pel is RT)
a boos o he suspicious nodes
.
3.4. Rising PSA on ADT (mCRPC) and oligome as a ic disease
This sec ion add esses pa ien s diagnosed wi h oligome a-
s a ic disease p og ession in he cas a ion esis an s a e.
No p ospec i e andomised da a a e a ailable demons a -
ing a bene i o local adical ea men o all lesions in
addi ion o ADT, compa ed wi h s anda d o ca e, ha is, he
addi ion o a new sys emic ea men o ADT.
Among he panellis s who belie ed ha oligome as a ic
mCRPC is a meaning ul en i y he e was no consensus on
ea men op ions. Fo y- ou pe cen o hese panellis s o ed
o con inua ion o ADT and adding addi ional sys emic he apy,
29% o local abla i e ea men o all lesions in combina ion
wi h ongoing ADT and addi ion o sys emic ea men , 25% o
local abla i e ea men o all lesions while con inuing ADT
wi hou addi ion o sys emic ea men and 2% o ed o local
abla i e ea men o all lesions and he cessa ion o ADT.
3.5. Discussion o oligome as a ic p os a e cance
In addi ion o p os a e cance , he oligome as a ic s a e is o
in e es in a g owing numbe o o he cance ypes, o
example, b eas , enal cell, colo ec al, gas ic, and non-small
cell lung cance . Like in p os a e cance , in hese diseases he
majo i y o da a a e e ospec i e in na u e and he e o e
di icul o in e p e . In some cases, ea men o local disease
appea s obe associa ed wi hlong- e msu i al.P ospec i e
ials a e ongoing in se e al o hese en i ies.
The concep o oligome as ases implies ha a local
he apy di ec ed a he p ima y cance and/o me as ases
migh imp o e su i al hough he e is no s ong e idence
o suppo his. The e was no consensus on ea men
op ions, bu om he o ing i seems ha he en husiasm
o he opic exceeds he e idence epo ed o da e. The
a ailable da a a e no p ospec i e, a e subjec o selec ion
bias, and hus equi e alida ion in p ospec i e andomised
con olled ials. Such ials should ocus on OS as an
endpoin , since ea lie endpoin s such as p og ession- ee
su i al (PFS) o ime o sys emic he apy a e no well
de ined and hei clinical impo ance is less clea . Dis in-
guishing be ween synch onous and me ach onous lesions,
and sepa a ing pel ic nodal elapse om M1 disease is also
likely o be impo an . S udies o pa ien s wi h oligome a-
s a ic disease a e o inc easing impo ance, since mo e
sensi i e imaging echniques a e an icipa ed o inc ease he
p opo ion o men wi h adiog aphically de ec ed lesions.
A he e y leas , un il andomised clinical ial da a a e
a ailable, la ge collabo a i e na ional and in e na ional
egis ies o men ea ed o oligome as a ic p os a e cance
should be ini ia ed o p ospec i ely collec da a on
consecu i ely ea ed pa ien s.
4. Cas a ion-nai e p os a e cance
The e was inconsis en use in discussions o he e ms
cas a ion-naı
¨ e o cas a ion-sensi i e, o designa e p os-
a e cance ei he no p e iously ea ed wi h ADT, o
cance s demons a ing ongoing sensi i i y o ADT. The e m
cas a ion-naı
¨ e is used in his manusc ip o simplici y o
co e bo h clinical scena ios.
4.1. When o s a ADT (pos -RP WRT o [28_TD$DIFF]pos RT)
The op imal iming o ini ia ion o ADT, du a ion, speci ic
ADT modali y, and he indica ions o ini ia ing ADT a e no
well de ined. Fo pa ien s p esen ing wi h me as ases wi h
impending complica ions and especially i symp oma ic, an
ini ial sho cou se o AR an agonis ea men o p e en
he unwan ed clinical consequences o es os e one su ge is
ecommended when LHRH agonis s a e ini ia ed.
Fo pa ien s wi h BCR, he decision o ini ia e ADT will
likely depend upon se e al pa ame e s including li e
expec ancy, ime o PSA elapse a e local he apy, PSA
kine ics, absolu e PSA le el, age, sexual unc ion, baseline
a igue, ca dio ascula isk, and neu ologic and cogni i e
s a us. Fo pa ien s wi h BCR wi hou o e me as a ic
disease, he decision o p oceed wi h in e mi en ADT
e sus con inuous ADT should also be conside ed.
In men wi h nonme as a ic disease and con i med ising
PSA (pos local he apy
SRT), 65% o he panellis s o ed o he
ini ia ion o ADT only in a mino i y o selec ed men, o example,
in case o a PSA 4 ng/ml and ising wi h doubling ime less han
6 mo o a PSA 20 ng/ml (STAMPEDE inclusion c i e ia). Twen y-
one pe cen o ed o s a ing ADT in he majo i y o men
i espec i e o hese ac o s and 12% o ed o s a ing ADT only
a e de ec ion o me as ases
.
4.1.1. Moni o ing o es os e one
Cu en da a do no p o ide cla i y ega ding he op imal
le el o es os e one supp ession o be achie ed in men
EUROPEAN UROLOGY 73 (2018) 178–211
185
wi h ad anced p os a e cance on ADT. The egula o y-
app o ed le el o less han 50 ng/dl, pe Food and D ug
Adminis a ion and Eu opean Medicines Agency, was based
upon he ini ial leup olide egis a ion ial and 50 ng/dl
was he lowes limi o de ec ion o he adioimmunoassay
used a ha ime [39]. Ensuing ials ha e sugges ed ha
eaching a es os e one le el o 20 ng/dl may achie e a
delay in ime owa d he de elopmen o cas a ion
esis ance; howe e , his h eshold, as well as he in e al
a which o measu e se um es os e one le els emains
unce ain [40].
In men wi h p os a e cance esponding o ADT, 44% o he
panel o ed o egula moni o ing o es os e one le els (apa
om measu ing es os e one a biochemical p og ession) and
34% o he panellis s o ed o measu ing es os e one in a
mino i y o selec ed pa ien s (eg, ailu e o achie e PSA nadi <
0.2 ng/ml), 22% o he panel did no o e o egula
es os e one measu emen in esponding pa ien s.
Fi y- ou pe cen o he panel o ed o a es os e one le el
<50 ng/dl (<1.73 nmol/l) as app op ia e o men on ADT, 36%
o ed o a es os e one le el <20 ng/dl (<0.69 nmol/l), while
10% abs ained.
The e was no consensus on he he apeu ic app oach o men
wi h ising PSA on a LHRH agonis whose es os e one le el is
con i med as being noncas a e (apa om uling ou
applica ion e o s and/o poo compliance). Despi e he lack
o e idence, 36% o he panel o ed o a change o a LHRH
an agonis , 26% o addi ion o a i s -gene a ion AR an ago-
nis , 20% o a change o an al e na i e LHRH agonis , and 14%
o ed o o chiec omy.
4.2. Chemo he apy in cas a ion-naı
¨ e nonme as a ic p os a e
cance
The e is some e idence o suppo combina ion ea men
as an up on al e na i e o single-modali y he apy o men
who p esen wi h high- isk localised p os a e cance . Such
app oaches gene ally combine ADT wi h RT and doce axel-
based chemo he apy. A o al o h ee andomised ials in
such pa ien s ha e been epo ed. The GETUG-12 ial
showed an imp o emen in ailu e- ee su i al (FFS) wi h
ou cycles o doce axel and es amus ine plus ADT as
compa ed wi h ADT alone [41,42]. The second ial, RTOG
0521, so a only p esen ed as an abs ac , examined he
combina ion o six cycles o adju an doce axel pos adical
RT wi h ADT o 24 mo (NCT00288080). The STAMPEDE ial
allowed inclusion o high- isk localised as well as biochem-
ical ecu en and me as a ic pa ien s. The numbe o
e en s o de ini i e in e p e a ion o su i al o M0
pa ien s in he doce axel a m o STAMPEDE is oo low
and no conclusions ega ding he e ec o addi ion o
doce axel on OS in his ial can be d awn [43].
A me a-analysis epo ed a consis en e ec on FFS o
chemo-ho monal he apy in he M0 subg oup as opposed o
ADT alone [44]. Da a o OS a e no ye ma u e.
Fo men wi h N1 M0 CNPC, 71% o he panel did no o e o
he addi ion o doce axel o ADT, 25% o ed o he addi ion in a
mino i y o mino i y o selec ed pa ien s, and 4% o he
majo i y o pa ien s.
Fo men wi h biochemical elapse only, he e was a
consensus (90%) o no adding doce axel o ADT.
4.3. Cas a ion-nai e p os a e cance M1 (me as a ic)
Tes os e one supp ession alone has long been he s anda d
ea men o pa ien s wi h me as a ic p os a e cance
commencing sys emic ea men [45]. Al hough he majo -
i y o men wi h mCNPC expe ience a PSA decline wi h ADT,
he median FFS in a coho o newly diagnosed mCNPC was
app oxima ely app oxima ely 1 y , wi h a wide ange
[46]. Subg oup analyses om ecen clinical ials showed
ha highe olume o me as ases and p esen a ion wi h de
no o me as a ic disease a e isk ac o s associa ed wi h a
sho e OS wi h ADT alone. O he pu po ed poo p ognos ic
clinical ac o s include highe Gleason sco e, pain, and
ele a ed alkaline phospha ase [45,47,48].
Doce axel gi en a he s a o ADT was he i s d ug
shown o imp o e he OS o men wi h mCNPC in wo la ge
ials [43,49]. The i s phase 3 s udy o doce axel in mCNPC,
GETUG 15, showed an imp o emen in PFS bu no OS [47].
The e is ongoing discussion on he de ini ion o ‘‘high-
olume’’ disease and whe he he e is a de ini ion ha is
p ognos ically ele an o p edic i e o ea men bene i .
Fo a de ini ion o high- olume disease, 74% o he panellis s
o ed o he de ini ion, as used in CHAARTED ( isce al [lung o
li e ] and/o 4 bone me as ases, a leas one beyond pel is
and e eb al column), ei he wi h s anda d imaging (59%) o
wi h any imaging (15%), 6% o ed o he high- olume
de ini ion de eloped by SWOG ( isce al [lung o li e ] and/
o any appendicula skele al in ol emen ) and 6% o ed o a
simpli ied e sion o high- olume o isce al and/o 4 bone
lesions ega dless o dis ibu ion and imaging used. [29_TD$DIFF]Fou een
pe cen o he panellis s had he opinion ha high- olume
disease is no a clinically meaning ul en i y.
Fo men wi h high- olume mCNPC, 68% o he panellis s
o ed o con inuous ADT using a LHRH agonis (plus a sho
cou se o i s -gene a ion AR an agonis o p e en es os e -
one su ge) as hei p e e ed ho mone he apy, ano he 10% o
s a ing wi h an LHRH an agonis (no la e-up p e en ion
needed) and swi ching o an LHRH agonis in he cou se o
ea men . Con inuous LHRH an agonis ea men was o ed
o by 6%, o chiec omy by 2%, and con inuous combined ADT by
14% o he panellis s. None o he panellis s o ed o any o m
o in e mi en ADT o AR-an agonis mono he apy in he high-
olume M1 se ing.
No all men a e sui able o chemo he apy wi h
doce axel and he c i e ia ende ing a pa ien ‘‘unsui able’’
o doce axel a e no well de ined.
The panel o ed on ac o s hey would conside
ende ing a man ‘‘un i ’’ o doce axel.
The e was a consensus o se e e hepa ic impai men (96%),
neu opa hy g ade 2 (82%), and pla ele s <50 10
9
[2_TD$DIFF]/l and/o
neu ophils <1.0 10
9
/l (81%). Fo he o he p oposed ac o s
alone he e was no consensus (Table 4).
In he o iginal publica ion o he CHAARTED ial, he
subg oup o men wi h high- olume disease showed a
clinically signi ican su i al bene i and he poin es ima e
o he low olume pa ien s was he same in ha
EUROPEAN UROLOGY 73 (2018) 178–211
186
5.5. Moni o ing in men wi h mCRPC ea ed wi h adium-223
The phase 3 adium-223 ial (ALSYMPCA) en olled pa ien s
wi h symp oma ic mCRPC [72]. Pa ien s we e andomised
o six injec ions o adium-223 adminis e ed e e y 4 wk o
o bes s anda d o ca e alone. OS was imp o ed in he
in en o ea analysis o pa ien s andomized o adium-
223 [72]. Subs an ial declines in PSA and/o lac a e
dehyd ogenase we e uncommon in bo h a ms. Howe e ,
alkaline phospha ase (ALP) le els showed a decline in he
adium ea ed pa ien s wi h 87% o adium ea ed pa ien s
showing some decline in ALP a wk 12 [84].
In he subse o panellis s who use adium-223 in men wi h
mCRPC 43% o ed o es ing o PSA e e y cycle, 43% o e e y
2–4 mo; 8% o ed o PSA es ing only i clinically indica ed, and
6% o no PSA es ing in his si ua ion.
Rega ding ALP es ing hese panellis s o ed o ei he e e y
cycle (49%) o e e y 2–4 mo (37%). Eigh pe cen o ed o ALP
es ing only i clinically indica ed and 6% o ed o no ALP
es ing.
Since he ALSYMPCA ial did no manda e any imaging
o esponse moni o ing, he ole o imaging in men ea ed
wi h adium-223 is no well documen ed. Symp oma ic and
PSA la es a e adium-223 ha e been desc ibed and can be
accompanied by bone scin ig aphy la e [85]. Ea ly changes
in bone scin ig aphy and CT assessmen s end o be
un eliable o bone esponse assessmen and mus hus
be in e p e ed wi h cau ion. In a e ospec i e se ies o
130 men ea ed wi h adium-223 ha had baseline
imaging and moni o ing by imaging a e h ee and six
cycles, he esul s showed a signi ican a e o p og ession
ou side o he bone de ec ed by CT scanning [85].
In he subse o panellis s who use adium-223 in men wi h
mCRPC he e was consensus (75%) o use CT and bone
scin ig aphy o s aging and moni o ing o men on adium-
223, while 23% o he panellis s o ed o one o he nex -
gene a ion imaging me hods. Rega ding imaging equency o
men ea ed wi h adium-223, 41% o hese panellis s o ed o
e e y 3–4 mo, 27% o ed o imaging a e 6 mo (comple ion o
adium-223) and e e y 3–4 mo he ea e , 24% o ed o
imaging a e 6 mo (comple ion o adium-223) and ollow-up
imaging a p og ession, 4% o ed o imaging only as clinically
indica ed.
5.6. ‘‘Oligo-p og essi e’’ mCRPC
Wi h he in oduc ion o abi a e one and enzalu amide as
i s -line ea men o asymp oma ic men wi h mCRPC,
he e a e men in whom, o example, a single lymph node
p og esses in size wi h adiological s abili y o he o he
lesions. The e m oligo-p og essi e is no well-de ined in
APC bu in lung cance pa ien s on no el a ge ed agen s
such as anaplas ic lymphoma kinase (ALK) inhibi o s he e
is g owing li e a u e on de ini ion and ea men s a egies
o oligo-p og essi e disease [86].
The e was no consensus as o he mos meaning ul
de ini ion o oligo-p og essi e p os a e cance (mCRPC). Fo y
pe cen o he panel o ed ha hey did no belie e in oligo-
p og essi e disease as a meaning ul clinical en i y, 33% o ed
o he de ini ion o only one p og essing p e-exis ing lesion
wi h o he wise s able/ esponding me as a ic disease, 23%
o ed o 3 p og essing p e-exis ing lesions wi h o he wise
s able/ esponding me as a ic disease.
The subse o he panel who belie ed in oligo-p og essi e
mCRPC o ed on biopsy o a p og essing lesion ( o diagnos ic
pu poses). Twen y-nine pe cen o he panellis s o ed o a
biopsy in he majo i y o pa ien s, 52% o a biopsy in a mino i y
o selec ed pa ien s (eg, om isce al me as ases), while 19%
did no o e o a biopsy. These panellis s also o ed on he
ea men o men wi h oligo-p og essi e mCRPC: 40% o ed
o a change o addi ion o sys emic he apy wi hou local
ea men , 47% o local ea men o he p og essing lesion(s)
while con inuing sys emic he apy unchanged, and 13% o
local ea men o he p og essing lesion(s) plus adding o
changing he sys emic ea men .
5.7. Discussion o CRPC
We ha e wi nessed he success ul de elopmen o agen s
including he no el and ogen signalling inhibi o s abi -
a e one and enzalu amide o ea lie s age mCRPC. Mo e
ecen ly, a signi ican su i al ad an age by in oducing
doce axel ea men in he cas a ion-nai e s a e was
con i med. I hus appea s ha we a e mo ing ou he apies
ea lie in he disease, while he ques ion o op imal
sequencing o he ea men op ions is s ill unanswe ed.
We know ha a dis inc subse o pa ien s will no espond
o ea men also depending on he sequence, o may
expe ience unwa an ed oxici y. Mo eo e , i is possible
ha wi h he app op ia e sequencing we may augmen he
OS bene i o ou pa ien s.
T ea men sequencing in APC is go e ned by a numbe o
pa ame e s ha un o una ely do no ye se e he ul ima e
goal o maximizing clinical ou come. Clinical decision-
making is s ill la gely dependen on local eimbu semen
policies and on a numbe o a iables ha a e no uly
objec i e. The e a e no alida ed clinical o molecula
p edic i e ma ke s o guiding ou choice hus p ede e -
mining a mo e a ou able cos /bene i a io o ou pa ien s.
Inc eased bene i is encompassing longe li e wi h im-
p o ed quali y whe eas minimising cos including compo-
nen s such as oxici y, inancial bu den, and unce ain y.
Choices made in he clinic a e in pa based on objec i e
da a such as a ailable le el I e idence and access o agen s.
Ye , p o essional speciali y and expe ience a ec hese
choices. The p esence o absence o symp oms clea ly
in luenced ea men selec ion o he panellis s.
We a e also being challenged by he as-ye unp o en
hypo hesis ha combina o ial app oaches may enhance
ou come by po en ial syne gis ic ac i i y o delay o
esis ance o ea men . We a e an icipa ing esul s om
se e al ele an phase 3 ials and should he e o e a oid
implemen a ion o such app oaches as long as hey a e
unp o en especially since conce ns o oxici y a ise.
Rega ding he agg essi e a ian o CRPC, he majo i y o
he panel ecognises i s exis ence and ha i is impo an o
ecognise i since hese pa ien s may be less likely o
espond o subsequen AR-di ec ed he apies; howe e ,
EUROPEAN UROLOGY 73 (2018) 178–211
193

he e was no consensus o he exac de ini ion. Wi h a
mo e p o ound and e en ually ea lie supp ession o AR
pa hways in he disease his o y, iden i ying and ea ing AR
independen a ian s will become inc easingly impo an
[87]. The de elopmen o obus bioma ke s is an a ea o
ac i e esea ch. We may need a combina ion o clinical and
molecula ea u es o iden i y agg essi e a ian s, encom-
passing bu no limi ed o hose wi h neu oendoc ine
ca cinoma mo phology de ec ed on biopsy, as a ge ed
ea men app oaches based on a molecula subclassi ica-
ion o APC a e de eloped. Unde s anding he ole o DNA
epai in con ibu ing o he pheno ype, media ing esponse
o PARP inhibi ion, and also pla inum sensi i i y and
po en ial immuno he apy ea men sensi i i y is also
impo an .
6. Imaging in APC
Rep oducible and alida ed me hods o de ec ing and
quan i ying me as a ic disease a e needed o manage
pa ien s wi h APC. Cu en ly, ecommended me hods o
me as a ic imaging assessmen , ha is, wi h bone scin ig-
aphy and CT scans, ha e signi ican limi a ions in de ec ing
me as ases as well as in moni o ing esponse o ea men
bu emain he s anda d o ca e in mos se ings [1,21,88–
91]. Due o limi a ions in sys ema ically conduc ed
p ospec i e s udies, he use o nex -gene a ion imaging
has no been shown o impac on clinical ou come.
6.1. Nodal disease assessmen s in APC
Mo phologic assessmen s o possible nodal disease using
CT and MRI scans a e based on he e alua ion o de ec ed
nodes based la gely on size c i e ia. O he mo phologic
c i e ia, such as he nodal shape, loss o nodal hilum a ,
clus e ing, ex anodal disease, and enhancemen cha ac e -
is ics can se e as addi ional aids o diagnosis. Un o u-
na ely, mo phologic imaging is unable o iden i y
mic ome as ases o o dis inguish la ge hype plas ic benign
om malignan nodes. Thus, he gene al es pe o mance
o mo phologic imaging emains limi ed when his ologic
co ela ions using empla e lymphadenec omy a e used as
he s anda d o e e ence. A me a-analysis showed a CT scan
sensi i i y o 42% and speci ici y o 82%, while mo phologic
MRI had a sensi i i y o 39% and a speci ici y o 82%
[92]. While posi on emission omog aphy (PET)/CT has
imp o ed sensi i i y, i is impo an o keep in mind ha
he spa ial esolu ion o PET/CT is app oxima ely 4 mm.
6.2. Bone disease assessmen s in APC
Fo he sensi i e de ec ion o me as a ic bone disease, he
use o cu en ecommenda ion o bone scin ig aphy and CT
scans has low sensi i i y and speci ici y [93].
Sys ema ic analyses, p ospec i e clinical s udies, and
me a-analyses ha e shown compa a i e es pe o mance
o whole-body di usion weigh ed MRI (WB-MRI) o NaF
and choline PET/CT o he skele al assessmen s in APC
[94,95]. A ecen me a-analysis unde lined he use ulness o
WB-MRI as a me hod ha imp o es he MRI de ec ion o
bone me as ases [96]. When e alua ing he esul s o he
abo e me a-analyses and indeed in all s udies epo ing es
pe o mance, he eade s should no e ha he e a e
in insic e i ica ion biases ha a e pa icula ly p e alen
a lesion le el analyses, because i is no possible o ob ain
his opa hology o e e y bone lesion de ec ed. As a esul ,
mos s udies a e pa ien le el analyses, using combina ions
o imaging me hods and/o ollow-up as he s anda ds o
e e ence [93,94].
PET/CT can de ec a la ge numbe o skele al lesions
han bone scin ig aphy [97]. Rega ding he PET/CT ace s
compa a i e s udies be ween p os a e-speci ic memb ane
an igen (PSMA) and choline ha e demons a ed supe io i y
o PSMA o iden i y bone lesions [98]. The PET ace
18
F-
luciclo ine has ecen ly been app o ed o use in No h
Ame ica; a ailable da a indica e good de ec ion a es bo h
o lymph nodes and o bone disease in biochemical
ecu ence o p os a e cance [99]. The diagnos ic pe o -
mance o luciclo ine PET was ound o be supe io o CT
and o choline PET bu he e a e no compa a i e da a e sus
WB-MRI and PSMA PET [100].
Impo an ly, all ou p ognos ic models and clinical ials
in APC we e de eloped using CT scan and bone scin ig aphy
and he essence o de ec ion o disease a diagnosis is one o
isk de e mina ion. Nex gene a ion imaging may ha e
supe io pe o mance cha ac e is ics compa ed wi h olde
modali ies, bu clinical alida ion wi h ega d o he
ques ion o impac on ou come has no ye been pe o med.
6.3. Imaging o locally ad anced p os a e cance
In men p esen ing wi h high- isk o locally ad anced
p os a e cance and wi h biochemical ecu ence a e local
he apy, imaging o documen po en ial me as ases may be
impo an . A his s a e o he disease me as ases a e mos
commonly loca ed wi hin egional (N1) and non egional
lymph nodes as well as in bone (M1).
The e was no consensus ega ding he imaging modali y o
‘‘exclude’’ dis an me as ases in high- isk and locally ad anced
p os a e cance : 41% o he panel o ed o a combina ion o CT
and bone scin ig aphy, while 47% o he panel o ed o nex -
gene a ion imaging me hods (37% o ed o a PET/CT wi h any
o he ace s PSMA, choline, o luciclo ine and 10% o ed o a
WB-MRI).
6.4. Imaging in he se ing o BCR (PSA)
Clinical symp oms and PSA alone a e no good indica o s o
absence o me as ases, wi h 32% o clinical M0 CRPC
pa ien s being ound o be me as a ic when imaging was
pe o med [101].
Rega ding PET/CT in BCR, a me a-analysis including bo h
C-11 and F-18 choline-based echniques epo ed de ec ion
a es g ea e han 50% o PSA alues abo e 2 ng/ml, wi h
apid PSA kine ics and ele a ed Gleason sco e posi i ely
ela ed o highe de ec ion a es [102–105]. The main
limi a ion o choline PET/CT is he low sensi i i y when PSA
alues a e <1 ng/ml. In BCR he e a e compa a i e s udies
EUROPEAN UROLOGY 73 (2018) 178–211
194
be ween Ga-PSMA and choline demons a ing he supe i-
o i y o Ga-PSMA in e ms o de ec ion a es a any PSA le el
[106–108]. Guidelines (NCCN, EAU) ha e men ioned
choline PET/CT in he si ua ion o BCR [21,22].
The use o nex -gene a ion imaging modali ies has led o
iden i ica ion o me as a ic oci a lowe PSA le els. T ea ing
physicians may eel mo e com o able o e ing abla ion o
limi ed me as ases in hese cases, bu as o now he e a e no
p ospec i e da a o show ha ea lie de ec ion o me as a ic
disease wi h nex -gene a ion imaging esul s in a mean-
ing ul long- e m clinical imp o emen .
Imaging in men wi h ising PSA a e RP be o e s a ing
SRT was o ed o by 44% o he panellis s in he majo i y o
pa ien s independen o PSA le el, by 29% o panellis s in men
wi h a PSA >0.5 ng/ml, by 12% o he panellis s in men wi h a
PSA >1 ng/ml and by 13% o he panellis s in men wi h a PSA
>2ng/ml.
Fo imaging in men wi h oligome as a ic ecu en disease
a e local ea men o p os a e cance wi h cu a i e in en
(
SRT), 78% o he subse o panellis s who belie ed in he
oligome as a ic ecu en s a e o ed o one o he nex -
gene a ion imaging me hods o de ec me as a ic disease: namely
47% o ed o a PET/CT (PSMA, choline, o luciclo ine) alone, 2%
o ed o a WB-MRI alone, 25% o he panel membe s o ed o a
combina ion o a pel ic MRI and a PET/CT, 4% o he panellis s
o ed o a combina ion o a pel ic MRI and a WB-MRI, and 22% o
he panellis s o ed o imaging by CT and/o MRI and bone
scin ig aphy
.
In men wi h de no o appa en oligome as a ic disease, 72%
o he subse panellis s who belie ed in he oligome as a ic
s a e o ed o one o he nex -gene a ion imaging me hods o
suppo his diagnosis (apa om local s aging): namely 34%
o ed o a PET/CT (PSMA, choline, o luciclo ine), 4% o ed o
a WB-MRI, 34% o ed o ei he a PET/CT o WB-MRI, and 26% o
hese panellis s o ed o imaging by CT and/o MRI and bone
scin ig aphy.
Asked abou he ecommended ace in case o a PET/CT in
men wi h appa en oligome as a ic cas a ion-naı
¨ e disease,
he e was a consensus (76%) amongs he panel membe s o
PSMA as ace , 10% o ed o luciclo ine as a ace , and 6%
o ed o choline; 4% o he panellis s o ed o any o he h ee
ace s.
In men wi h ising PSA on ADT (CRPC) and po en ially
oligome as a ic disease, 74% o he subse o panellis s who
belie e in oligome as a ic disease in mCRPC o ed o one o he
nex -gene a ion imaging me hods o con i m his diagnosis:
namely 48% o ed o a PET/CT (PSMA, choline, o luciclo ine),
6% o ed o a WB-MRI, 18% o he panel membe s o ed o a
combina ion o a pel ic MRI and a PET/CT, 2% o he panellis s
o ed o a combina ion o a pel ic MRI and a WB-MRI, and 26%
o he panellis s o ed o imaging by CT and/o MRI and bone
scin ig aphy.
6.5. S aging and moni o ing in mCNCP
In mCNPC, wha is equi ed is an imaging modali y ha
con i ms he p esence o me as ases and de ines hei
loca ion. This is impo an o assessing p ognosis and o
ea men decisions. Cu en guidelines (NCCN, EAU) do no
commen on imaging me hods o men wi h mCNPC
because o lack o da a.
In mCNPC, 51% o he panel o ed o baseline imaging and
ollow-up imaging a PSA nadi /comple ion o six cycles o
doce axel as pa o chemo-ho monal he apy and again a
p og ession (con i med PSA ise and/o clinical p og ession),
31% o he panel o ed o baseline imaging and egula
moni o ing by imaging e e y 3–6 mo, and 18% o he panel
o ed o baseline imaging only and moni o ing by PSA alone
wi h u he imaging a p og ession.
Rega ding he ecommended imaging modali y o s aging
and moni o ing o men wi h mCNPC, 73% o he panel o ed o
CT and bone scin ig aphy and 25% o he panellis s o ed o
one o he nex -gene a ion imaging me hods.
6.6. S aging and moni o ing in mCRPC
The ea ly iden i ica ion o ea men ailu e in men wi h
mCRPC on sys emic he apy would help in spa ing some
pa ien s u ile ea men and po en ial oxici y as well as in
educing he cos s o ine ec i e ea men s and dec easing
he ime o ini ia ion o a nex -line, po en ially e ec i e
ea men [110]. Recen da a indica e ha he e a e a
subs an ial numbe o pa ien s who ha e adiog aphic
p og ession wi hou PSA p og ession, including some
pa ien s wi h agg essi e a ian p os a e cance [111]. Im-
aging be o e ea men ini ia ion and on- he apy may be
impo an in p edic ing bo h bene i and mo e impo an ly
nonbene i o ea men s.
An ideal imaging me hod o moni o esponse o he apy
should enable he e alua ion o umou cell iabili y,
especially o bone disease. Techniques such as bone
scin ig aphy, CT scans, and NaF PET ely on umou ma ix
in e ac ions and a e only indi ec indica o s o umou cell
iabili y. Imaging assessmen s should always be combined
wi h clinical s a us and o he ac o s as also ecommended
by he PCWG3 g oup [109].
Fo moni o ing by imaging in men wi h mCRPC on i s -line
he apy, 54% o he panel o ed o baseline imaging and
egula moni o ing by imaging e e y 3–6 mo, 28% o he
panellis s o ed o baseline imaging and ollow-up imaging a
PSA nadi and again a p og ession (con i med PSA ise and/o
clinical p og ession); 16% o he panel o ed o baseline
imaging only and moni o ing by PSA alone wi h u he
imaging a p og ession.
Rega ding imaging modali y o s aging and moni o ing in
men wi h mCRPC, 74% o he panel o ed o CT and bone
scin ig aphy and 24% o he panellis s o ed o one o he nex -
gene a ion imaging me hods.
Fo moni o ing o pa ien s wi h a diagnosis o agg essi e
a ian mCRPC, 62% o he panellis s o ed o s anda d
imaging by CT and bone scin ig aphy, 2% o ed o CT alone,
and 36% o ed o nex -gene a ion imaging modali ies.
6.7. Discussion o imaging in APC
The e a e su icien da a indica ing ha nex -gene a ion
imaging echnologies ha e be e accu acy o de ec ing
me as ases han CT and bone scin ig aphy. Howe e , hei
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195
cu en use is dependen on cos s, local a ailabili y, and
expe ise o in e p e a ion and he be e accu acy has no
been shown o co ela e wi h imp o emen o clinical
ou comes.
The pe o mance o PET/CT wi h new ace s (PSMA and
luciclo ine) as indica o s o ea men e icacy and as
p edic o s o pa ien ou come has ye o be assessed. PSMA
PET/CT should be in e p e ed wi h cau ion since he e a e
da a sugges ing co ela ion be ween PSMA exp ession and
AR signalling [112–117]. Tumou oci no exp essing PSMA
(o lesions in o gans wi h high PSMA exp ession, eg, li e )
may no be assessable o esponse using PSMA PET/CT.
No ably, o he umou ypes (eg, lung cance , enal cell
cance ) and nonmalignan p ocesses like Page ’s disease
and haemangioma can exp ess PSMA [118,119].
The use o hese nex -gene a ion imaging modali ies
may be especially aluable in si ua ions whe e he umou
bu den assessmen s a e needed o ea men decisions
and/o when high sensi i i y is a equi emen . This may be
pa icula ly applicable when mul imodali y sal age he a-
py is being conside ed. Howe e , he p oo ha hei use
leads o be e ea men decisions and ul ima ely leads o
imp o ed ou comes is pending also in his si ua ion.
Fo e alua ion o esponse in men wi h mCRPC i is
e iden ha nex -gene a ion imaging (MRI and PET) may
p o e o be mo e accu a e o e alua ing esponse o
ea men [120]. Howe e , i should be no ed ha he
ecen ly published PCWG3 do no ecommend he ou ine
use o nex -gene a ion imaging me hods o men wi h APC
ea ed on clinical ials mainly due o he lack o
a ailabili y, ou come da a, and s anda disa ion ac oss
global si es [109]. The ecen ly published guideline on
epo ing WB-MRI in men wi h APC is a s ep in o he igh
di ec ion bu hese ecommenda ions need o be adop ed,
applied, and alida ed in clinical ials wi h p ima y
endpoin o clinical ou come [88]. As an example, he
sys ema ic e alua ion o FDG-PET s udies in pa ien s wi h
Hodgkin’s disease has esul ed in a educ ion in ea men
in ensi y leading o educ ion o oxici y [121]. Such ials
wi h nex -gene a ion imaging a e la gely missing in men
wi h APC [122].
The clinical in oduc ion o po en ially impac ul imag-
ing echnologies has c ea ed an oppo uni y o p og ess by
linking ana omy o unde lying biology bu he e is also a
isk o up-s aging o many men in e e y disease s a e. The
con ibu ion o he nex -gene a ion imaging echniques o
he wel a e o pa ien s depends on pe o mance o he
pu pose hey a e being applied (‘‘ i o use’’) and hei
clinical u ili y (pa ien bene i ). The ea ly assessmen o
new echnologies is he e o e encou aged bu hei gene al
accep ance be o e measu es o pe o mance and e idence
o bene i a e a leas es ima ed should no be suppo ed.
No el imaging echniques should be clinically deployed
ideally in a ial se ing bu a leas in egis ies wi h he
goal o e icien ly es ima ing pe o mance and u ili y.
Finally, i is impo an o ecognise ha he clinical ials
ha o m he basis o he cu en ly app o ed ea men
op ions a e based on e alua ions wi h CT and bone
scin ig aphy.
7. Use o os eoclas - a ge ed he apy o SRE/SSE
p e en ion o mCRPC (no o os eopo osis/bone loss)
In p os a e cance , wo bone-di ec ed agen s, zoled onic
acid and denosumab ha e been shown o p e en o delay
he onse o SREs. Nei he o he d ugs in luences OS o PFS
signi ican ly [123,124].
O he bisphosphona es, zoled onic acid is he only one
ha has shown a p o ec i e e ec agains SRE in pa ien s
wi h mCRPC [124,125]. Denosumab is a ully human
monoclonal an ibody ha speci ically a ge s ecep o
ac i a o o nuclea ac o kappa-B ligand hus e ec i ely
inhibi ing os eoclas unc ion and bone eso p ion. In he
se ing o mCRPC, denosumab (120 mg subcu aneous e e y
4 wk) compa ed wi h zoled onic acid (4 mg in a enous
e e y 4 wk) signi ican ly imp o ed he ime o i s SRE
[123].
A he p esen ime, hese agen s ha e p o en ele an
e icacy only in pa ien s wi h bone mCRPC. The e is no
e idence o suppo hei use in he nonme as a ic CRPC
se ing and he e is e idence no o use i in he mCNPC
se ing apa om os eopo osis p e en ion, using a di e en
egimen, and dosage o bo h d ugs [43,126,127].
When looking a SSE, wo p ospec i e andomised
s udies in men wi h mCRPC demons a ed an ad an age.
The TRAPEZE s udy showed a signi ican delay in SSEs when
doce axel was combined wi h zoled onic acid as compa ed
wi h doce axel alone and ha he combina ion was sa e, bu
he e was no imp o emen in OS [128]. In e es ingly, he
bene i in delaying SSEs was in he same ange as wha was
seen in he pi o al zoled onic acid s udy when chemo he -
apy was no in use. Also, he ecen analysis o he la ge
pi o al denosumab ial con i med a bene i in p e en ing
SSEs [129]. Hypo hesis-gene a ing esul s ha e been p e-
sen ed om he ALSYMPCA ial whe e he subg oup o
pa ien s ecei ing a combina ion o adium-223 plus an
os eoclas a ge ed he apy had a educ ion in SSE
compa ed wi h adium-223 alone [72,130].
In an e a o li e p olonging he apies o mCRPC ha can
also p e en o delay SREs, he added bene i o os eoclas [36_TD$DIFF]-
a ge ed he apy is di icul o es ima e gi en he limi ed
numbe o well designed, adequa ely powe ed s udies wi h
long e m ollow-up.
Rega ding he equency o adminis a ion o hese bone-
di ec ed agen s a ecen andomised ial in di e en umou
ypes also including 689 men wi h p os a e cance showed
no inc eased isk o skele al e en s wi h zoled onicacid e e y
12 wk compa ed wi h e e y 4 wk [131]. Howe e , he
p opo ion o pa ien s wi hCNPC e sus CRPC is no epo ed
and bo h we e acc ued o he ial. No i m conclusions can be
made om his ial because o his a iable.
Fo educing he isk o skele al complica ions in men wi h
mCRPC and bone me as ases, 86% o he panel we e in a ou o
some o m o os eoclas - a ge ed he apy, 54% o he panel
o ed o denosumab, 8% o ed o zoled onic acid, 24% o he
panellis s o ed o ei he zoled onic acid o denosumab, and
10% did no o e o an os eoclas - a ge ed he apy a all.
O hose panellis s who o ed o an os eoclas - a ge ed
he apy in men wi h mCRPC, 68% o ed o a ea men
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196
du a ion o abou 2 y and 32% o ed o no limi a ion o
ea men du a ion.
The ques ion o equency and du a ion o os eoclas -
a ge ed he apy in he absence o signi ican oxici y o
asymp oma ic men wi h mCRPC and bone me as ases
esponding o i s -line sys emic mCRPC ea men is no
esol ed.
In he subse o panellis s who o ed o os eoclas - a ge ed
he apy in men esponding o i s -line mCRPC he apy, 17% o
he panellis s o ed o e e y 4 wk wi hou a de ined
maximum du a ion, 37% o ed o e e y 4 wk o app oxi-
ma ely 2 y and hen less equen ly, 15% o ed o e e y 3 mo,
and 27% o he panel did no o e o an os eoclas - a ge ed
he apy in his si ua ion. In he same pa ien popula ion, bu
when hese men a e no longe esponding o i s -line he apy,
27% o he panellis s o ed o os eoclas - a ge ed he apy
e e y 4 wk wi hou a de ined maximum du a ion and 53% o
he panel o ed o e e y 4 wk o abou 2 y and hen less
equen ly.
Os eonec osis o he jaw (ONJ) is a possible se e e side
e ec o os eoclas - a ge ed he apy ha inc eases wi h he
du a ion o ea men [132,133]
In men wi h mCRPC who de elop ONJ while on os eoclas -
a ge ed he apy, he e was consensus (84%) o discon inue
os eoclas - a ge ed he apy pe manen ly while 16% o he
panellis s o ed o discon inua ion o he os eoclas - a ge ed
he apy and es a ing a e comple e wound healing.
7.1. Discussion o he use o os eoclas - a ge ed he apy o
SRE/SSE p e en ion o mCRPC
The op imal iming, schedule, and du a ion o os eoclas -
a ge ed he apy and he o e all balance o bene i and isk
as well as e icacy in he e a o no el mCRPC ea men s a e
s ill a ma e o deba e as he e is no Le el I e idence o
guide decision making.
E ec i e os eoclas inhibi o s a e commonly ecom-
mended as pa o he o e all he apeu ic app oach o
mCRPC also in an e a o mul iple li e p olonging agen s.
Thei use in combina ion wi h app o ed li e p olonging
mCRPC ea men s may enhance hei u ili y in e ms o
educing he isk o o skele al complica ions and o
main ain quali y o li e—bu hese da a ha e been de i ed
om pos hoc and subg oup analyses and need o be
add essed in p ospec i e clinical ials. In daily clinical
p ac ice, he isk o side e ec s—especially ONJ—which
inc eases wi h du a ion o he apy, by he ea ly use o
os eoclas - a ge ed he apy o men wi h mCRPC has o be
weighed up agains he po en ial bene i o educ ion in isk
o SRE/SSE [133].
8. Molecula cha ac e isa ion
8.1. Tumou biopsy in APC
Since clinical he e ogenei y is common, mCRPC umou
biopsies should be e iewed and in e p e ed in he
app op ia e clinical con ex . This is especially impo an
o uncommon ye challenging cases wi h small cell o
neu oendoc ine di e en ia ion o umou s ha lack ex-
p ession o classical p os a e ma ke s such as PSA o AR.
Fu he mo e, no all pa ien s wi h clinical ea u es sugges-
i e o and ogen independence demons a e small cell o
neu oendoc ine ea u es on umou biopsy al hough hey
may s ill bene i om pla inum based chemo he apy. These
da a may po en ially be explained by molecula o e lap
wi h neu oendoc ine p os a e cance [81,134].
Mo ing o wa d, inco po a ing molecula bioma ke s
will likely imp o e he clinical diagnosis o non-AR d i en
mCRPC and may help in pa ien selec ion o cu en
he apies and selec ion o bioma ke s a i ied clinical
ials [134–140]. Genomic al e a ions en iched in mCRPC
wi h eme ging p ognos ic and/o ea men implica ions
include AR gene mu a ion and ampli ica ion, phosphoinosi-
ide 3-kinase/Ak /phospha ase and ensin homolog pa h-
way al e a ions, DNA epai de ec s including loss o
homologous ecombina ion (eg, BRCA1/2, ATM), and
misma ch epai (wi h mic osa elli e ins abili y [MSI] and
hype -mu a ed pheno ype), TP53 dele ion/mu a ion, and
RB1 loss [134,140–144]. Al e a ions in ol ing RB1 and TP53
a e uni e sal in small cell cance s a ising elsewhe e in he
body, such as[15_TD$DIFF] lung cance , and a e en iched in p os a e
cance pa ien s wi h luminal o basal cell lineage swi ching
and neu oendoc ine bioma ke exp ession and a e mecha-
nis ically in ol ed in he de elopmen o ‘‘and ogen
indi e en ’’ esis ance [136,139,140,143].
The panel o ed on molecula ac o s ha should be
epo ed in a umou biopsy in men wi h mCRPC apa om
epo ing umou mo phology (Table 10).
The e was a consensus (78%) ha BRCA1, BRCA2, and ATM
mu a ions should be epo ed because ha knowledge will
likely in luence managemen decisions. Fo all o he ac o s
he e was no consensus (Table 10).
8.2. And ogen ecep o splice a ian -7 and AR ampli ica ion/
mu a ion
Using liquid biopsies in mCRPC pa ien s s a ing abi a e -
one o enzalu amide, s a is ically signi ican associa ions
wi h wo se ou come ha e been epo ed o de ec ion o AR
splice a ian s including he AR-V7 ansc ip s in ci cula -
ing cells o in exosomes, AR-V7 p o ein in he ci cula ing
umo cell nucleus, o by analysing plasma cell- ee DNA AR
gene copy numbe gain assessed ia cell- ee DNA o
soma ic poin mu a ions simila ly quan i ied [145–150]. All
s udies o da e we e single-a m ials, and s a is ically
signi ican associa ions wi h esponse we e no ed—al-
hough he co ela ion wi h esponse has ocused la gely
on a es o PSA declines. Mo eo e , e idence emains ha
some men wi h AR-V7 posi i e mCRPC may s ill espond o
abi a e one/enzalu amide.
The e was a consensus (96%) no o use AR-V7 es ing in
daily ou ine clinical p ac ice o he majo i y o men wi h
mCRPC. Simila ly, he e was a consensus (92%) no o use cell-
ee DNA AR ampli ica ion and AR mu a ion es ing in daily
ou ine clinical p ac ice o he majo i y o men wi h mCRPC.
EUROPEAN UROLOGY 73 (2018) 178–211
197
8.3. Soma ic mu a ions
Recen genomic s udies o me as a ic p os a e cance ha e
iden i ied new molecula a ge s in he AR signalling
pa hway, phosphoinosi ide 3-kinase pa hway, WNT pa h-
way, cell cycle pa hways, and pe haps mos impo an ly, in
DNA epai pa hways [135,141,151].
Fi y-nine pe cen o he panellis s did no o e o DNA
sequencing o umou biopsies in he majo i y o men wi h
mCRPC in ou ine daily clinical p ac ice, 37% o he panellis s
o ed o a a ge ed/panel sequencing app oach, and 4% o ed
o whole genome o exome sequencing.
8.4. DNA epai es ing in daily ou ine clinical p ac ice
Recen s udies ha e shown ha men wi h APC commonly
ha e soma ic abe a ions o genes ha make up a ious
elemen s o he DNA epai machine y wi h 20–30% o APCs
ha ing loss o unc ion o p o eins implica ed in homolo-
gous ecombina ion epai , including BRCA2,BRCA1,ATM,
PALB2, and o he s [141]. These abe a ions lead o
homologous ecombina ion de iciency (HRD) de ec able
by nex -gene a ion sequencing o hese genes o o he
genomic sca s esul ing om his epai de ec es ima ed as
an HRD sco e. A clinical ial (TOPARP) o he PARP inhibi o ,
olapa ib, has shown an i umou ac i i y agains p os a e
cance s wi h HRD [142].
HRD de ec s ha e been p e iously epo ed o sensi ise
umou cells o pla inum-based chemo he apy [152]. Clini-
cal da a a e now eme ging ha HRD de ec s in p os a e
cance s also sensi ise o pla inum-based chemo he apy
[153] in keeping wi h p e ious epo s ha sa apla in has
an i umou ac i i y agains his disease [76,154].
Soma ic dele e ious abe a ions o misma ch epai
genes (MSH2,MSH6,MLH1,PMS2) ha e been ound in
APC, and a e possibly associa ed wi h duc al pa hology,
al hough hei p ecise equency emains unce ain and is
in he ange o 5% o 15% [144,155,156].
8.4.1. DNA epai de ec s in CNPC
The p esence o DNA epai de ec s (ge mline o soma ic) in men
wi h newly diagnosed mCNPC does no change he s anda d
ea men ecommenda ion o 49% o he panel. Twen y- h ee
pe cen o he panellis s we e mo e likely o gi e doce axel in
addi ion o ADT and 22% o he panel we e mo e likely o include
a pla inum agen in he chemo-ho monal ea men egimen.
8.4.2. DNA epai de ec s in mCRPC
When es ing o DNA epai de ec s was conside ed o men
wi h mCRPC, and no ecen mCRPC issue biopsy issue was
a ailable, 70% o he subse o panellis s who suppo ed es ing
in his si ua ion o ed o a esh mCRPC umou biopsy, 16% o
he panellis s o ed o es ing in a chi al issue, and 14% o ed
o es ing in ci cula ing cell- ee DNA.
Six y- i e pe cen o he panel o ed o ea men wi h
olapa ib, o ano he PARP inhibi o i a ailable and app o ed,
in men wi h mCRPC and he p esence wi h DNA epai de ec s
(ge mline o soma ic) based on he phase 2 da a wi h olapa ib,
29% o he panel o ed o such ea men in a mino i y o
selec ed pa ien s and 4% did no o e o i a all.
Some panel membe s o ed ha i was app op ia e o
ex apola e he phase 2 da a om olapa ib o pla inum agen s
o men wi h mCRPC and p esence o DNA epai de ec s
(ge mline o soma ic): 45% in he majo i y o pa ien s and 14%
in a mino i y o selec ed pa ien s; howe e 35% o he panellis s
did no suppo his ex apola ion.
Table 10 – As a clinician, which ac o s do you wan o ha e epo ed back o you in men wi h me as a ic cas a ion- esis an p os a e cance
who unde go a me as a ic umou biopsy apa om umou mo phology and di e en ia ion? The ques ion is only abou managemen o a
speci ic pa ien , no abou amilial implica ions, and based on knowledge in e ms o es accu acy/ alidi y and a ailable ea men s
Fac o Yes, use ul es o majo i y
o pa ien s (influences you
managemen decision; %)
Only o mino i y o
selec ed pa ien s (%)
No (%) Abs ain (%)
BRCA1, BRCA2, and ATM mu a ions 78 20 2 0
PSA IHC 72 18 10 0
O he DNA epai genes (eg, CHEK2,
PALB2, and o he s)
64 22 12 2
MMR gene al e a ions (MSI, MMR
p o ein IHC, o by di ec sequencing)
54 22 20 4
Ch omog anin, synap ophysin, CD56/NSE 50 31 17 2
Loss o PTEN 44 26 26 4
AR amplifica ion and/o AR mu a ion 43 18 37 2
TP53 and RB1 34 22 40 4
Nuclea AR 34 18 46 2
AR-V7 33 26 37 4
PSMA 32 22 44 2
Ki67/MiB1 28 26 42 4
P os a e acid phospha ase 26 18 54 2
PD-1/PD-L1 22 31 45 2
NKX3.1 12 33 49 6
ERG IHC 12 30 56 2
ERG FISH 11 23 64 2
AR = and ogen ecep o ; FISH = fluo escen in si u hyb idiza ion; IHC = immunohis ochemis y; MMR = misma ch epai ; MSI = mic osa elli e ins abili y; PD-
1 = p og ammed cell dea h-1; PD-L1 = p og ammed dea h-ligand 1; PSA = p os a e-specific an igen; PSMA = p os a e-specific memb ane an igen;
PTEN = phospha ase and ensin homolog.
EUROPEAN UROLOGY 73 (2018) 178–211
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Six y-se en pe cen o he panel o ed o s anda d i s -line
mCRPC he apy in men wi h mCRPC and p esence o DNA
epai de ec s (ge mline o soma ic) p og essing on ADT, 21% o
he panellis s o ed o a pla inum-based combina ion, and 10%
o a PARP inhibi o .
In men wi h mCRPC and a p esence o DNA epai de ec s in
he second-line se ing (a e s anda d i s -line he apy), 40%
o he panellis s o ed o a pla inum-based combina ion, 33%
o he panel o ed o s anda d second-line mCRPC ea men ,
21% o ea men wi h a PARP-inhibi o , and 4% o a pla inum
mono he apy.
8.5. Discussion o molecula cha ac e isa ion
Gi en men wi h mCRPC a e su i ing longe , and wi h
se e al ea men op ions a ailable, biopsies o me as a ic
lesions a e mo e commonly pu sued o ule ou small cell
ca cinoma, an agg essi e a ian , o a second malignancy.
Bu he eal place o me as ases biopsy emains unclea in
e e yday p ac ice. Wi h a mul i ude o po en ial p edic i e
and p ognos ic ma ke s ha can be es ed in a mCRPC
umou biopsy, i is impo an o p o ide some guidance. As
o Ma ch 2017, he e was only consensus om he panel o
es ing o BRCA1,BRCA2, and ATM mu a ions in mCRPC
issue.
Se e al egis a ion ials a e now being conduc ed wi h
di e en PARP inhibi o s o men wi h APC and e idence o
DNA epai de ec s (eg, NCT02952534, NCT02975934,
NCT02854436, NCT03012321) and in he absence o
app o ed PARP inhibi o s o mCRPC, en olmen o men
in clinical ials is s ongly ecommended.
Addi ionally, he e a e also p ospec i e ials o pla i-
num-based he apy ongoing in men wi h ad anced
molecula ly selec ed p os a e cance s, which may demon-
s a e ha his is an impo an he apeu ic s a egy o his
subg oup o pa ien s (eg, NCT02598895, NCT02311764,
NCT02955082).
Al hough ueMSIis a einp os a ecance ,i sp esence
is impo an because MSI+ cance s ha e a high a e o
du able esponses o immune checkpoin blockade using
d ugs ha block he p og ammed cell dea h-1/p o-
g ammeddea h-ligand1in e ac ion[157]. Based on
149 pa ien s wi h MSI-H o dMMR cance s en olled ac oss
i e uncon olled, mul i-coho , mul i-cen e , single-a m
clinical ials pemb olizumab has been app o ed by he
FDA o use in MSI high and dMMR cance pa ien s
ega dless o his ology. This app o al is o clea in e es o
clinicians and o[16_TD$DIFF] pa ien s wi h p os a e cance and[37_TD$DIFF]
e idence o hese al e a ions.
Al hough a p opo ion o he panel o ed o using a
PARP inhibi o o pla inum-based chemo he apy in mCRPC,
e en in he i s -line se ing, he e is no e idence ha such a
s a egy is o ad an age as compa ed wi h he s anda d
app o ed mCRPC ea men s o da e. The e o e, in he
absence o p ospec i e andomised ials showing clinical
bene i o a s a egy using a PARP-inhibi o o a pla inum-
based chemo he apy, he use o hese subs ances as i s -
line mCRPC ea men ou side o clinical ials should no be
gene ally ecommended.
Fo he liquid bioma ke s, namely AR-V7 and AR
mu a ion o ampli ica ion, he e was a consensus ha
cu en ly none o hese ma ke s should be es ed in ou ine
p ac ice o decision making. This consensus agains es ing
is in pa based upon he low de ec ion le els o AR-V7 p io
o i s - and second-line he apies and he high p obabili y
ha pa ien s would ecei e abi a e one o enzalu amide in
his si ua ion. These es s need o be alida ed and u he
s udies need o be pe o med o de e mine hei impac on
long- e m ou comes.
9. Ge mline gene ic counselling/ es ing
The ae iology o p os a e cance is no well unde s ood,
al hough epidemiological s udies demons a ing a con e -
gence o incidence a es in some popula ions mig a ing
be ween a eas wi h a low incidence o hose wi h high
incidence sugges en i onmen al and li es yle isk ac o s
play a ole [158]. Ha ing a posi i e amily his o y and/o a
ce ain e hnic backg ound such as A o-Ca ibbean is a isk
ac o o p os a e cance de elopmen . E idence om
s udies whe e monozygo ic wins we e compa ed wi h
dizygo ic wins sugges ha 57% o he isk o p os a e
cance p os a e cance is due o gene ic ac o s [159]. Nu-
me ous s udies o isks o ela i es o p os a e cance cases
show a highe ela i e isk o de eloping p os a e cance ,
which inc eases as he age o he p oband dec eases, and he
numbe o a ec ed ela i es inc eases. Fi s deg ee ela i es
o p os a e cance pa ien s ha e wice he isk o de eloping
he disease compa ed wi h he gene al popula ion [160].In
men diagnosed unde he age o 60 y , he isk o hei i s
deg ee ela i es is mo e han ou old ha o hose wi hou
a amily his o y [161]. The a ia ion in incidence acco ding
o e hnici y also sugges s a gene ic componen ; a es a e
highe in A ican Ame ican men compa ed wi h Asian-
Ame ican men [162].
S udies o amilial inhe i ance and seg ega ion analyses
ha e p oposed a ious gene ic models (au osomal domi-
nan , ecessi e, and X-linked) [163]. I is now ecognised
ha gene ic p edisposi ion o p os a e cance is composed
o common (>[1_TD$DIFF]5%) lowe isk a ian s single nucleo ide
polymo phisms—mos o which a e no in coding egions
and a e highe isk a ian s (coding mu a ions in genes).
O e 100 single nucleo ide polymo phisms associa ed wi h
he de elopmen o p os a e cance ha e been iden i ied
hus a [164].
Ra e a ian s a e hose which ha e a mino allele
equency o <5%, and occu oo in equen ly o be de ec ed
on a genome-wide associa ion s udy. Nex -gene a ion
sequencing o a ge ed a eas o whole genome/exome
sequencing has enabled he de ec ion o hese a e a ian s.
Resul s showed ha men om amilies whe e emales had
de eloped b eas and o a ian cance caused by BRCA
mu a ions ha e a i e- old ela i e isk o p os a e cance
when hey ha bou a ge mline BRCA2 mu a ion compa ed
wi h men wi hou a mu a ion. This ela i e isk inc eases o
up o se en- old i he men in he amily de elop p os a e
cance below he age o 65 y [165]. In a la ge s udy,
2000 men wi h p os a e cance we e sc eened. This showed
EUROPEAN UROLOGY 73 (2018) 178–211
199
ha jus o e 1% o men who de eloped p os a e cance
below he age o 65 y ca ied a dele e ious BRCA2 mu a ion
and o en hey did no ha e a posi i e amily his o y
[166]. Fo men who a e ca ie s o a BRCA1 mu a ion, s udies
ha e shown ha he e is an app oxima ely ou - imes
ela i e isk o de eloping p os a e cance o men aged
unde 65 y compa ed wi h hose wi hou he mu a ion
[167]. I has been subsequen ly shown in men wi h a amily
his o y o a leas h ee cases o p os a e cance ha hey
ha e a ge mline mu a ion in DNA epai genes in 7.3% and
ha he disease was mo e likely o be agg essi e [168].
Se e al g oups ha e shown ha BRCA1 and BRCA2
mu a ion ca ie s ha e a mo e agg essi e o m o p os a e
cance and also ha e a wo se p ognosis [169,170]. Mu a ion
ca ie s a e also likely o p esen wi h a highe isk o local
nodal in ol emen as well as wi h dis an me as a ic
disease [171]. The op imal adical ea men op ion o
hese pa ien s is ye o be de e mined, bu RP may be he
mos sui able, al hough he numbe s o pa ien s s udied a e
ela i ely small [172].
Rema kably, ge mline mu a ions ha e been ound in
abou hal o he men wi h umou HR DNA epai gene
de ec s and abou one in i e men wi h an misma ch epai
DNA epai gene de ec [141,173]. In a la ge mul i-
ins i u ional s udy o almos 700 men wi h me as a ic
p os a e cance unselec ed o age o amily his o y, 11.8%
o e all we e ound o ha e mode a e o high pene ance
ge mline mu a ions in one o 16 DNA epai genes, wi h 7.8%
o mu a ions in BRCA2,BRCA1, and ATM [173]. Two la ge
single-ins i u ion s udies o me as a ic p os a e cance ound
simila a es o ge mline BRCA2,BRCA1,andATM mu a ions,
wi h much lowe a es in low isk indolen disease [174,175].
Rega ding gene ic counselling and es ing o men wi h
newly diagnosed me as a ic p os a e cance , 20% o he panel
o ed o do i in a majo i y o pa ien s: 62% o he panel o ed in
a ou o gene ic counselling/ es ing in a mino i y o selec ed
pa ien s and 18% did no o e o do i a all.
The subse o panellis s who had o ed o gene ic es ing in
a mino i y o selec ed pa ien s suppo ed gene ic counselling
and es ing in men wi h a posi i e amily his o y o p os a e
cance (95%); also, 93% o hese panellis s suppo ed counsel-
ling/ es ing in men wi h a posi i e amily his o y o o he
cance synd omes (eg, he edi a y b eas and o a ian cance
synd ome and/o panc ea ic cance o Lynch synd ome).
Fu he , 74% o hese panellis s o ed o gene ic counselling
and es ing in men wi h p os a e cance diagnosed a 60 y
bu 26% o hese panellis s did no o e o gene ic counselling
and es ing based on an age cu -o alone.
Among he subse o panellis s who ecommended gene ic
es ing, 61% o ed o la ge panel es ing including homologous
ecombina ion and misma ch DNA epai (eg, comp ehensi e
cance isk assessmen panels), 15% o ed o BRCA1 and
BRCA2 es ing only, 15% o ed o BRCA1, BRCA2, and ATM
es ing, and 9% o ed o la ge panel es ing including
homologous ecombina ion DNA epai (eg, panels ha a e
also used o assess b eas cance isk).
The e was a consensus (92%) ha in he p esence o a
ge mline BRCA1, BRCA2, o ATM mu a ion a p ophylac ic RP
was no ecommended.
The panel was asked whe he he p esence o a ge mline
BRCA1, BRCA2, o ATM mu a ion would in luence hei
ea men decision in men wi h low- isk localised p os a e
cance . Fo y- i e pe cen o ed agains ac i e su eillance in
hese pa ien s, 35% o ed o s anda d ea men op ions
(including ac i e su eillance), and 20% o ed o ano he
ea men op ion.
The panel was asked whe he he p esence o a ge mline
BRCA1, BRCA2, o ATM mu a ion would in luence hei
ea men decision in men wi h in e media e- o high- isk
localised p os a e cance . Fi y- wo pe cen o he panel o ed
o a RP o e RT, 44% o he panel o ed o s anda d
ecommenda ions, and 4% o ed o RT o e a RP.
9.1. Discussion o ge mline gene ic counselling/ es ing
The unde s anding o he ole o gene ics in p os a e cance
de elopmen is e ol ing apidly, which is e lec ed by he
ac ha 20% o he panellis s ecommended gene ic
counselling and es ing in a majo i y o men wi h me as a ic
p os a e cance i espec i e o amily his o y. Age a
diagnosis i sel does no seem o be he bes selec ion
ma ke , bu 74% o he panel who ecommended gene ic
counselling and es ing in selec ed pa ien s would es in
men aged 60 y . The impac o a BRCA2 ge mline mu a ion
on he managemen in an o he wise heal hy man is no
clea and in he absence o any p ospec i e da a he e was a
consensus no o ecommend p ophylac ic RP in such men.
Cu en ly, o p os a e cance ca e p o ide s o de ing
ge mline gene ic cance panel es ing o o de ing his
es ing in he nea u u e, he e a e se e al impo an poin s
o conside including which genes o es o . The e a e
eme ging p os a e cance p ac ice ecommenda ions only
o BRCA1,BRCA2, and ATM mu a ions, ye mos nex -
gene a ion sequencing cance panels include many mo e
DNA epai genes o he same cos . The e a e cu en ly no
gene-speci ic da a on ea men p edica ion o p os a e
cance isk o mos DNA epai genes. Ge mline gene ic
es ing should be o de ed wi h adequa e p e es and/o
pos es gene ic counselling. In pa icula , he e is a need o
counsel abou he possibili y o a a ian o unce ain
signi icance (VUS) being de ec ed and/o a pa hogenic
mu a ion in a gene in which he e a e no adequa e da a o
al e managemen o p os a e cance . Pa ien s wi h VUS
should be managed he same as pa ien s wi h a nega i e
es esul , and he e is a dange ha in daily p ac ice VUS
may be misin e p e ed as a posi i e esul . The ques ion o
es ing o amily membe s is unanswe ed and sc eening
ecommenda ions i mu a ions a e de ec ed need o be
gene a ed. The e a e da a sugges ing ea lie PSA sc eening
in men wi h BRCA2 and po en ially also in men wi h BRCA1
ge mline mu a ions [176]. Mo e da a a e needed o
app op ia e counsel una ec ed male amily membe s abou
p os a e cance isk and make sc eening ecommenda ions.
La ge collabo a i e e o s a e unde way (eg,
NCT00261456, PRACTICAL conso ium) o add ess some
o he open ques ions. Howe e , in o de o mo e he ield
o wa d mo e e o s a e needed o collabo a e—especially
on p os a e cance s wi h ge mline mu a ions ha occu a a
EUROPEAN UROLOGY 73 (2018) 178–211
200
low equency. The panel ecommends o be especially
ca e ul (no o e in e p e ) abou ea men ecommenda-
ions based on ge mline mu a ions in men wi h localised
p os a e cance .
10. Side e ec s o sys emic ea men : p e en ion,
managemen , and suppo i e ca e
A subs an ial p opo ion o men wi h APC will die o a
noncance - ela ed cause and mus li e wi h he acu e and
ch onic side e ec s o ea men . Mos men wi h localised
p os a e cance do no die o hei disease, bu will spend
he es o hei li es managing he e ec s o he ea men
hey ha e unde gone. The wishes o ou pa ien s and hei
amilies a e clea : hey wish o be cu ed o hei disease o o
ha e hei su i al p olonged, bu no necessa ily a he cos
o in ole able side e ec s o ea men . Some imes i is easy
o lose sigh o his goal in he sea ch o be e oncological
ou comes.
One-hund ed pe cen o he panel belie ed ha he e was a
leas mode a e e idence ha ADT inc eases he isk o bone loss
and/o ac u es; 87% belie ed his e idence was s ong.
Baseline measu emen o i amin D o men wi h p os a e
cance s a ing on ADT was o ed o in he majo i y o pa ien s
by 43% o he panellis s, in a mino i y o pa ien s by 26% and
31% o he panellis s did no o e o i .
Rou ine supplemen a ion o calcium and i amin D o men
wi h p os a e cance s a ing on ADT was o ed o by 73% o
he panel, only o i amin D by 13%, only calcium by 2%, and
12% o he panel did no o e o ou ine supplemen a ion.
A baseline measu emen o bone mine al densi y in men
wi h p os a e cance s a ing on ADT was o ed o by 62% o
he panellis s in he majo i y o pa ien s, by 15% only in pa ien s
wi h nonme as a ic disease and 21% did no o e o i a all.
D ug he apy o p e en bone loss and/o ac u es wi h
denosumab o a bisphosphona e in he dose and schedule o
os eopo osis p ophylaxis in men wi h p os a e cance s a ing
on ADT was o ed o in he majo i y o pa ien s by 16% o he
panellis s, by 70% o panellis s only in pa ien s wi h
documen ed os eopenia o os eopo osis, and 12% did no o e
o i .
Thi y- i e pe cen o he panellis s el ha he e is s ong
e idence ha ADT inc eases he isk o diabe es, 46% el ha
he e is mode a e, and 17% ha he e is weak e idence o his
co ela ion. Two[38_TD$DIFF] pe cen belie e ha ADT does no change he
isk o diabe es.
Fo ca dio ascula disease, 12% o he panellis s el ha
he e is s ong e idence ha ADT inc eases he isk, 39% el
ha he e is mode a e, and 45% ha he e is weak e idence o
his co ela ion. Fou [38_TD$DIFF] pe cen belie e ha ADT does no change
he isk o ca dio ascula disease.
A his o y o ecen /se e e ca dio ascula disease in luenced
he choice o ADT in men wi h me as a ic p os a e cance o
29% o he panellis s in he majo i y o pa ien s, o 41% o he
panellis s o a mino i y o selec ed pa ien s, and o 28% o he
panellis s i did no in luence hei choice o ADT.
Fo he subse o panellis s whose decisions was in luenced
by a his o y o ecen /se e e ca dio ascula disease, 11% o ed
o using LHRH agonis s, 52% o use o LHRH an agonis s, 6%
o o chiec omy, 20% o any o m o in e mi en ADT, and 11%
o ed o bicalu amide 150 mg/d in such a pa ien .
Eigh [38_TD$DIFF] pe cen o he panellis s belie ed ha he e is s ong
e idence ha ADT inc eases he isk o cogni i e changes and/
o demen ia, 29% el ha he e is mode a e, and 50% ha he e
is weak e idence o his co ela ion. Thi een[38_TD$DIFF] pe cen belie e
ha ADT does no change he isk o cogni i e changes and/o
demen ia.
Fo dep ession, 6% o he panellis s belie ed ha he e is
s ong e idence ha ADT inc eases he isk, 46% el ha he e
is mode a e, and 44% ha he e is weak e idence o his
co ela ion. Fou [38_TD$DIFF] pe cen belie e ha ADT does no change he
isk o dep ession.
A mul idisciplina y managemen eam can include he
necessa y expe ise o deal wi h hese issues [177]. Im-
p o ed ou comes a e appa en wi h in ol emen o
p os a e cance nu ses and ca e coo dina o s. Endoc inol-
ogis s and and ologis s can p o ide ad ice on he manage-
men o diabe es, me abolic synd ome, bone heal h,
ca dio ascula , and sexual heal h. Psychologis s can p o ide
suppo o he common p oblems o suicidal isk, dis ess,
and long- e m psychological and sexual mo bidi y [178–
181]. The exe cise physiologis can p o ide p og ams o
coun e ac he e ec s o ADT, imp o e psychological
symp oms, and imp o e o e all and disease-speci ic
su i al [182–184]. The di ec p o ide o ca e o men
wi h APC can also lea n such skills.
Comp ehensi e ge ia ic assessmen has been shown o
be associa ed wi h a highe p obabili y o comple ing a
ea men cou se, ewe modi ica ions o ea men , and
lowe oxici y [185,186].
Rou ine in ol emen o a mul idisciplina y/mul ip o es-
sional eam o p e en ion o managemen o ADT ela ed
ad e se e ec s was o ed o by 42% o he panellis s o he
majo i y o pa ien s, by 39% in a mino i y o selec ed pa ien s,
and 17% did no o e o i .
Six y-one pe cen o he panellis s o ed o ea ly access o
an expe in symp om pallia ion o a dedica ed pallia i e ca e
se ice and 39% o he panellis s did no o e o i .
The e was consensus (94% o he panellis s) o access o
opia e pain medica ion o men wi h me as a ic p os a e
cance and se e e pain when lowe le el pain medica ion is no
su icien .
Thi y[38_TD$DIFF] pe cen o he panellis s o ed o a heal h s a us
assessmen in men wi h APC 70 y be o e ea men decision
in he majo i y o pa ien s, 42% o ed o i in a mino i y o
selec ed pa ien s, and 24% did no o e o i .
The subse o panellis s who o ed o a heal h s a us
assessmen o ed o comp ehensi e ge ia ic assessmen in
26%, G8 and Mini-COG in 29%, G8 alone in 30%, and ano he ool
in 15%.
The e was consensus (98% o he panellis s) o egula
physical exe cise in men wi h p os a e cance s a ing on ADT.
10.1. Discussion o side e ec s o sys emic ea men :
p e en ion, managemen , and suppo i e ca e
The aging popula ion o men wi h APC is now su i ing
longe , allowing longe - e m complica ions o ea men o
EUROPEAN UROLOGY 73 (2018) 178–211
201
become appa en and o a ec unc ion and symp oms. The
e idence ha ADT nega i ely impac s bone heal h and he
a endan isk o ac u es is conside ed s ong by a
majo i y o he panel. ADT has also been associa ed wi h an
inc eased isk o me abolic synd ome, ype 2 diabe es, and
sa copenia; howe e , e idence linking ADT di ec ly as a
cause o ascula disease is weak and he e is no con incing
e idence ha ADT is linked causally o he de elopmen o
demen ia as e lec ed in he o e o he panellis s [187–
196]. Men should be in o med abou he acu e bu also he
long- e m side e ec s o ADT and impo an ly he possible
p e en i e measu es.
In e es ingly, he e was no consensus o he ou ine
assessmen o heal h s a us in men aged 70 y , likely based
on he ac ha he e a e no la ge p ospec i e clinical ials
[39_TD$DIFF]which ha e shown ha using heal h s a us assessmen in
men wi h me as a ic p os a e cance has a ele an impac
on ou come, especially when compa ed wi h he judgemen
o expe ienced physicians. This ecommenda ion could also
e lec a lack o consensus on wha would cons i u e such a
‘‘heal h s a us assessmen .’’ Finally, he e is a need o
clinical ials and egis a ion s udies speci ically in his
pa ien popula ion.
11. Global access o p os a e cance d ugs and
ea men in coun ies wi h limi ed esou ces
The panel o ed on a numbe o ques ions ega ding
ea men op ions in men wi h APC in lowe and middle-
income coun ies (LMIC) because he opic o global access
o APC ea men s was discussed a APCCC 2017.
I li ing in a coun y wi h limi ed esou ces a ailable o
heal h ca e, 90% o he panellis s o ed o o chiec omy as ADT
in he me as a ic se ing. The emaining 10% o ed o an LHRH
agonis .
As second-line endoc ine manipula ions in LMIC in men
wi h mCRPC p og essing on ADT, 44% o he panellis s o ed
o a i s gene a ion AR an agonis , 24% o s e oid mono-
he apy, 20% o ke oconazole, 8% o oes ogens, and 4% o
es amus ine.
Each o he ollowing d ugs is on he Wo ld Heal h
O ganiza ion (WHO) essen ial medicines lis and/o hey
can be sou ced a an a o dable p ice om gene ic
manu ac u e . The panel o ed on app op ia e ea men
op ions in he se ing o limi ed heal h ca e esou ces in
men wi h mCRPC who a e p og essing on o a e doce axel:
77% o he panellis s o ed o a pla inum, 19% did no o e o
i . Mi oxan one was o ed o by 69% o he panellis s. Thi y-
nine pe cen o ed o he use o cyclophosphamide, 53% did
no . The e was a consensus no o use pacli axel (78%) o
doxo ubicin (84%) in his si ua ion.
11.1. Discussion o global access o p os a e cance d ugs and
ea men in coun ies wi h limi ed esou ces
P os a e cance gene ally is mo e common in highe income
coun ies, bu his is changing as men in LMIC li e longe ,
due o be e con ol o in ec ious disease and o he causes
o ea ly mo ali y. Men in LMIC end o p esen wi h mo e
ad anced disease and access o he su i al p olonging
agen s o mCRPC is limi ed o many men in LMIC.
Al hough he panel ecommended o chiec omy as i s
choice o ADT in men p esen ing wi h me as a ic p os a e
cance , he socio-cul u al and psychological ba ie s o such
an in e en ion mus be aken in o conside a ion in such
ea men decisions.
As seconda y ho monal ea men op ion o men wi h
mCRPC, endoc ine manipula ions including glucoco icoids,
oes ogens, i s gene a ion and ogen ecep o inhibi o s,
and ke oconazole a e a ailable and he panel conside ed
especially i s -gene a ion AR inhibi o s a alid ea men
op ion in LMIC.
Abi a e one and enzalu amide a e examples o high-cos
d ugs wi h limi ed access in LMIC. Bo h d ugs we e
de eloped subs an ially h ough esea ch in academic
labo a o ies and cance cen es. In he USA, app o ed doses
a e ma ke ed a US$ 7000/mo, while publicly unded
heal h sys ems such as B i ain and Canada ha e been able o
nego ia e a subs an ially lowe p ice o $3000/mo. Gene ic
abi a e one (bu no enzalu amide) is a ailable in India o
abou $450/mo, which is, howe e , s ill oo expensi e o
many men wi h mCRPC in India.
The ollowing d ugs which ha e shown some an i umou
ac i i y bu no OS bene i in men wi h mCRPC and a e on he
WHO essen ials medicine lis : ca bopla in, pacli axel,
doxo ubicin, and cyclophosphamide. Ca bopla in was
ecommended by a majo i y o he panellis s. Mi oxan one
is no on he WHO essen ials medicine lis bu has shown a
pain pallia ion bene i and could be sou ced a a easonable
p ice. Many o hese d ugs a e subs an ially cheape han
he app o ed and su i al p olonging agen s o mCRPC and
hey can be used some imes as subs i u es o newe agen s
in LMIC. While his is a easonable s a egy, i alls a sho
o he ideal o p o iding he mos e ec i e ea men s o all
men wi h APC.
A majo goal o his consensus con e ence is o imp o e
he managemen and ou comes o men wi h APC. Howe e ,
i is a subop imal clinical achie emen o show ha new
ea men s can imp o e he du a ion and quali y o su i al
o men wi h APC, bu o ha e such ea men s una ailable o
a la ge segmen o he global popula ion o men wi h APC.
The a ailabili y o RT as a e y e ec i e bone pain pallia ion
he apy is no gi en in many coun ies. We canno easily
change he way ha d ugs a e de eloped and ma ke ed o
p o i by academic, pha maceu ical, and bio echnology
companies, and we ce ainly espec and collabo a e wi hin
his sys em o he de elopmen o needed new ea men s
o men wi h APC. Bu men wi h APC a e s ill unable o
access op imal ea men s, o en imes no because hey
could no be made a ailable, bu because hey a e no made
a ailable a an a o dable p ice. Hence, we encou age
ongoing mul idisciplina y and s akeholde dialogue o
u he add ess his global issue.
12. Conclusions
In he absence o Le el I e idence and in a eas whe e he e
a e con lic ing da a o con lic ing in e p e a ion o a ailable
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