EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands

h ps://doi.o g/10.1007/s00259-022-05727-7
GUIDELINES
EANM dosime y commi ee ecommenda ions o dosime y
o 177Lu‑labelled soma os a in‑ ecep o ‑ andPSMA‑ a ge ing ligands
Ka a inaSjög eenGleisne 1 · NicolasChouin2· PabloMinguezGabina3,4· F ancescoCicone5,6· Sil anoGnesin7·
Ca olineS okke8,9· Ma kKonijnenbe g10,11· Ma aC emonesi12· F ede ikA.Ve bu g10· Pe e Be nha d 13,14·
U aEbe lein15· Jona hanGea 16
Recei ed: 4 No embe 2021 / Accep ed: 13 Feb ua y 2022
© The Au ho (s) 2022
Abs ac
The pu pose o he EANM Dosime y Commi ee is o p o ide ecommenda ions and guidance o scien is s and clinicians on
pa ien -speci ic dosime y. Radiopha maceu icals labelled wi h lu e ium-177 (177Lu) a e inc easingly used o he apeu ic
applica ions, in pa icula o he ea men o me as a ic neu oendoc ine umou s using ligands o soma os a in ecep o s
and p os a e adenoca cinoma wi h small-molecule PSMA- a ge ing ligands. This pape p o ides an o e iew o epo ed
dosime y da a o hese he apies and summa ises cu en knowledge abou adia ion-induced side e ec s on no mal is-
sues and dose-e ec ela ionships o umou s. Dosime y me hods and da a a e summa ised o kidneys, bone ma ow,
sali a y glands, lac imal glands, pi ui a y glands, umou s, and he skin in case o adiopha maceu ical ex a asa ion. Whe e
applicable, aking in o accoun he p esen s a us o he ield and ecen e idence in he li e a u e, guidance is p o ided. The
pu pose o hese ecommenda ions is o encou age he p ac ice o pa ien -speci ic dosime y in he apy wi h 177Lu-labelled
compounds. The p oposed me hods should be wi hin he scope o cen es o e ing he apy wi h 177Lu-labelled ligands o
soma os a in ecep o s o small-molecule PSMA.
Keywo ds Dosime y· Lu e ium-177· Soma os a in- ecep o ligands· PSMA- a ge ing ligands· Neu oendoc ine· P os a e
adenoca cinoma
P eamble
The Eu opean Associa ion o Nuclea Medicine (EANM) is a
p o essional nonp o i medical associa ion ha acili a es com-
munica ion wo ldwide among indi iduals pu suing clinical
and esea ch excellence in nuclea medicine. The EANM was
ounded in 1985. These guidelines a e in ended o assis p ac-
i ione s in p o iding app op ia e nuclea medicine ca e o
pa ien s. They a e no in lexible ules o equi emen s o p ac-
ice and a e no in ended, no should hey be used, o es ablish
a legal s anda d o ca e. The ul ima e judgemen ega ding he
p op ie y o any speci ic p ocedu e o cou se o ac ion mus be
made by medical p o essionals aking in o accoun he unique
ci cums ances o each case. Thus, he e is no implica ion ha
an app oach di e ing om he guidelines, s anding alone, is
below he s anda d o ca e. On he con a y, a conscien ious
p ac i ione may esponsibly adop a cou se o ac ion di e -
en om ha se ou in he guidelines when, in he easonable
judgemen o he p ac i ione , such cou se o ac ion is indi-
ca ed by he condi ion o he pa ien , limi a ions o a ailable
esou ces, o ad ances in knowledge o echnology subsequen
o he publica ion o he guidelines. The p ac ice o medicine
in ol es no only he science bu also he a o dealing wi h
he p e en ion, diagnosis, alle ia ion, and ea men o dis-
ease. The a ie y and complexi y o human condi ions make i
impossible o always each he mos app op ia e diagnosis o o
p edic wi h ce ain y a pa icula esponse o ea men . The e-
o e, i should be ecognised ha adhe ence o hese guidelines
will no ensu e an accu a e diagnosis o a success ul ou come.
All ha should be expec ed is ha he p ac i ione will ollow a
easonable cou se o ac ion based on cu en knowledge, a ail-
able esou ces, and he needs o he pa ien o deli e e ec i e
and sa e medical ca e. The sole pu pose o hese guidelines is
o assis p ac i ione s in achie ing his objec i e.
This a icle is pa o he Topical Collec ion on Dosime y
* Ka a ina Sjög een Gleisne
ka a ina.sjog[email p o ec ed]
Ex ended au ho in o ma ion a ailable on he las page o he a icle
/ Published online: 14 Ma ch 2022
Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
Backg ound in o ma ion
Lu e ium‑177
The adionuclide lu e ium-177 (177Lu) is a a e ea h me al
ha unde goes β− decay o s able ha nium-177 wi h a hal -
li e o 6.647 days [1]. On decay 177Lu, emi s elec ons,
including β− pa icles and in e nal con e sion elec ons
wi h a mean kine ic ene gy o 147 keV pe decay and max-
imum elec on ene gy o 497 keV. These ene gies co e-
spond o anges (con inuous slowing down app oxima ion)
in uni -densi y so issue o 0.28 and 1.8 mm, espec i ely
[2]. The decay o 177Lu also esul s in emission o gamma
pho ons wi h ene gies (yields) o 112.9 keV (6.2%), 208.4
keV (10.4%), 249 keV (0.2%), and 321 keV (0.2%), whe e
he wo i s a e use ul o pa ien imaging. P oduc ion o
177Lu can be made by wo possible ou es, ei he h ough
neu on cap u e 176Lu(n,γ)177Lu, o indi ec ly h ough he
eac ion 176Yb(n,γ)177Yb→177Lu. In he o me ou e, he
long-li ed isome 177mLu is also p oduced (hal -li e 160.44
days), o ming a low-amoun adionuclide impu i y mainly
o impo ance o was e managemen [3, 4].
177Lu‑labelled soma os a in‑ ecep o ligands
The soma os a in ecep o (SSR) is a G-p o ein coupled ans-
memb ane ecep o wi h he ho mone soma os a in as i s main
ligand. Cu en ly, i e dis inc sub ypes o his ecep o ha e
been iden i ied. De i a i es o soma os a in, which bind pa -
icula ly o SSR sub ypes 2 and, o a lesse deg ee, 5, mos
no ably oc eo ide and oc eo a e, ha e been adap ed o adi-
olabelling o con ain he chela o dodecane e aace ic acid
(DOTA). This has esul ed in he well-known DOTA-TOC
[5] and DOTA-TATE [6] ha can be labelled wi h adionu-
clides such as 111In, 68Ga, 90Y, o 177Lu.In he u he ex ,
he di e en 177Lu-labelled soma os a in- ecep o a ge ing
ligands a e collec i ely e e ed o as [177Lu]Lu-SSRT.
The e is gene ally a much highe le el o SSR exp ession
on neu oendoc ine umou (NET) cells o meningiomas han
in no mal issues [7]. The highes accumula ion o [177Lu]
Lu-SSRT in no mal issues is seen in he li e , he spleen,
he kidneys, and he pi ui a y gland, due o di e en mecha-
nisms o up ake.
Radionuclide he apy wi h [177Lu]Lu-DOTA-TATE
(Lu a he a®) was app o ed o he ea men o p og essi e,
well-di e en ia ed soma os a in ecep o -posi i e gas oen-
e opanc ea ic NETs ollowing he esul s o phase 3 NET-
TER-1 ial. The ial andomly assigned 229 pa ien s wi h
well-di e en ia ed me as a ic midgu NETs o ecei e ei he
[177Lu]Lu-DOTA-TATE (7.4 GBq, ou in usions e e y 8
weeks) plus long-ac ing soma os a in analogues o long-ac -
ing soma os a in analogues alone. Twen y-mon h p ojec ed
p og ession- ee su i al (PFS) was 65.2 s. 10.8% in he
ea men and he con ol a m, espec i ely (p < 0.0001).
The [177Lu]Lu-DOTA-TATE ea men p oduced only an-
sien haema ological oxici y, wi h g ade 3/4 neu openia,
h ombocy openia, and lymphopenia occu ing in 1%, 2%,
and 9% o pa ien s, espec i ely [8].
177Lu‑labelled ligands o p os a e‑speci ic
memb ane an igen
P os a e-speci ic memb ane an igen (PSMA), also known
as glu ama e ca boxypep idase II o ola e hyd olase I, is a
ansmemb ane glycop o ein exp essed on p os a e cells [9,
10]. Small-molecule ligands o PSMA, e.g., PSMA-617 [11,
12] and PSMA imaging and he apy (I&T) [13, 14], ha e
been adiolabelled wi h 177Lu o he ea men o me a-
s a ic p os a e adenoca cinoma.In he u he ex , he di e -
en 177Lu-labelled small-molecule PSMA- a ge ing ligands
a e collec i ely e e ed o as [177Lu]Lu-PSMA.
The e is g ea e PSMA exp ession in p os a e cance
cells han in benign p os a e cells, hus p o iding a ela-
i ely speci ic a ge o pa ien s wi h his neoplasm [15].
PSMA is exp essed in o he issues besides p os a e cance
and benign p os a e epi helium, including p oximal enal
ubules o kidneys, b ain, in es ine, and in he neo ascula u e
o mos solid neoplasms [15, 16]. The highes accumula ion
o PSMA in no mal issues ele an wi h ega ds o [177Lu]
Lu-PSMA he apiesis in he sali a y and lac imal glands
[12, 17–23]. Fo sali a y glands, immuno-his ochemis y
e ealed ocal exp ession o PSMA, and he high up ake o
[177Lu]Lu-PSMA is belie ed o be he esul o bo h spe-
ci ic and non-speci ic up ake mechanisms [24–26]. The apy
wi h [177Lu]Lu-PSMA may ha e p o ound clinical bene-
i s o some pa ien s, as occasional comple e adiological
and biochemical esponses ha e been epo ed [27, 28]. In
mos pa ien s, howe e , [177Lu]Lu-PSMA he apydoes
no esul in he ull disappea ance o disease on imaging
[28]. Recen ly, esul s o he phase 3 VISION ial we e
published [29], showing a signi ican su i al bene i o
he addi ion o [177Lu]Lu-PSMA-617 o he s anda d o
ca e o e he s anda d o ca e alone in 831 pa ien s wi h
me as a ic cas a ion- esis an p os a e cance (median PFS:
8.7 s. 3.4 mon hs; median o e all su i al: 15.3 s. 11.3
mon hs, espec i ely, bo h p < 0.001).
Radiobiological e ec s onno mal issues
and umou s
Blood elemen s andbone ma ow
As [177Lu]Lu-SSRT and [177Lu]Lu-PSMA a e adminis-
e ed in a enously, he blood elemen s a e he i s o be
1779Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
exposed o adia ion. The majo de e minan o adia ion
exposu e o he haema opoie ic s em cells is adiopha -
maceu ical ci cula ion wi hin he bone ma ow. Howe e ,
speci ic a ge ing mechanisms o mo e di e en ia ed blood
cell p ogeni o s may also con ibu e. Fo ins ance, SSRs
a e o e exp essed on ac i a ed leucocy e sub ypes, such
as lymphocy es and monocy es [30]. Addi ional ac o s
a ec ing haema ologic oxici y a e he ex en o bone
me as a ic in ol emen and p e ious his o y o myelo oxic
chemo he apy o bone ma ow i adia ion. Haema ologic
oxici y is he mos common ad e se e en a e 177Lu
he apy. G ade 3–4 oxici y, mos o en h ombocy ope-
nia, has been obse ed in 10–15% o pa ien s ea ed wi h
[177Lu]Lu-SSRT [7, 31–33] and in app oxima ely 10% o
hose ea ed wi h [177Lu]Lu-PSMA [34]. The occu ence
o seconda y myelodysplas ic synd ome o acu e leukae-
mia has been obse ed se e al yea s a e ea men wi h
[177Lu]Lu-SSRT [33, 35, 36].
Weak bu signi ican co ela ions be ween image-based
es ima es o he ed-ma ow abso bed dose and haema o-
logical oxici y ha e been demons a ed [37–40]. Mo eo e ,
ele a ed le els o DNA damage in pe iphe al blood lympho-
cy es ha e been iden i ied using bioma ke s such as γ-H2AX
and 53BP1 [41–44]. The h eshold bone-ma ow abso bed
dose o se e e haema ologic oxici y is gene ally conside ed
o be 2 Gy, in analogy o he expe ience wi h 131I he apy
[45], bu con i ma ion o his 2 Gy h eshold is s ill needed
o applica ions wi h 177Lu-based he apies. In e es ingly, in
a phase I ial o he apy wi h he SSRT-an agonis [177Lu]
Lu-sa o eo ide e axe an, pa ien s (3/20) wi h a bone ma -
ow abso bed dose abo e 1.5 Gy de eloped g ade 4 h om-
bocy openia [46].
Kidneys andli e
Abdominal o gans a e i adia ed in [177Lu]Lu-SSRT and
[177Lu]Lu-PSMA he apies due o adiopha maceu ical-
speci ic up ake o hei physiological exc e o y unc ions.
The kidney is gene ally conside ed he dose-limi ing o gan
in he apy wi h [177Lu]Lu-SSRT, owing o unspeci ic
up ake mechanisms by p oximal ubula cells [47]. Acu e
adia ion neph opa hy mani es s be ween 6 mon hs and 1
yea a e i adia ion wi h ypical signs o enal ailu e,
including p o einu ia, anaemia, hype ension, and conges-
i e hea ailu e. Ch onic adia ion-induced neph opa hy
consis s o ascula damage in combina ion wi h p og es-
si e loss o pa enchymal cells. This may ollow he acu e
synd ome o p esen yea s a e i adia ion [48–51]. To
educe he isk o enal oxici y a e adminis a ion o
[177Lu]Lu-SSRT, p o ocols o enal p o ec ion ha e been
de eloped in ol ing co-in usion o amino acids ha com-
pe e o he megalin ecep o on ubula cells. Immedia e
and e e sible side e ec s ollowing he apy, like omi ing
and c amps, a e asc ibed o enal-p o ec ion p o ocols
a he han adia ion exposu e [52, 53]. Fo [177Lu]Lu-
SSRT, including concu en kidney p o ec ion, he le el o
epo ed neph o oxici y is limi ed o disease- ela ed e en s,
and o  he apy wi h [177Lu]Lu-PSMA, i appea s o be
negligible a cu en ac i i ies [28, 54]. This indica es ha
he ole ance abso bed doses o kidneys exceed hose gi en
so a , possibly owing o nonuni o m i adia ion and modes
abso bed dose a es. Wi h he ambi ion o inc ease he ea -
men e icacy, dosime y-guided clinical ials o he apy o
NETs wi h [177Lu]Lu-SSRT ha e been unde aken [32, 40,
55] applying enal abso bed dose o biologically e ec i e
dose (BED) cons ain s ex apola ed om ex e nal-beam
adio he apy (EBRT) o ei he 23 Gy o 28 Gy [51, 56],
o 40 Gy o pa ien s wi hou isk ac o s [57]. In he apy
using [90Y]Y-SSRT, a BED-dependen annual c ea ine
clea ance loss was iden i ied [58], and e ospec i e da a
analysis indica ed a BED limi o app oxima ely 39 Gy o
a 5% incidence [57, 59].
The li e is gene ally no conside ed an o gan a isk
o [177Lu]Lu-SSRT o [177Lu]Lu-PSMA he apies,
and he li e unc ion has been shown o imp o e a e
[177Lu]Lu-SSRT he apy [60]. Howe e , he li e needs
o be moni o ed in case o concomi an ea men s and
o he apy wi h la ge molecules such as 177Lu-labelled
monoclonal an ibodies [61]. Classic adia ion-induced
li e disease de elops a ew weeks a e i adia ion and
shows he ypical pa hologic appea ance o eno-occlusi e
disease o he cen al lobule and he small b anches o he
hepa ic eins [62].
Sali a y, lac imal, andpi ui a y glands
The majo sali a y glands comp ise h ee pai s o glands,
he pa o id, submandibula , and sublingual glands. Recen ly,
a ou h pai o sali a y glands we e iden i ied a e analys-
ing [68Ga]Ga-PSMA PET imaging, he uba ial glands in
he nasopha ynx egion [63]. Radia ion exposu e may cause
xe os omia, a educ ion o sali a y low in he o al ca i y.
Xe os omia is a documen ed side e ec in pa ien s gi en
[177Lu]Lu-PSMA [28, 54], al hough he ole ance abso bed
dose o sali a y glands has no ye been iden i ied. Expe i-
ence om EBRT indica es a low incidence o oxici y below
a mean abso bed dose o bo h pa o id glands o app oxi-
ma ely 10 Gy, and an abso bed dose limi o 20 Gy has been
p oposed [64]. Me hods o he p o ec ion o sali a y glands,
such as he adminis a ion o olic polyglu ama e able s o
cooling wi h icepacks, a e being e alua ed clinically [65].
The lac imal glands a e pai ed exoc ine glands in he uppe
la e al egion o he wo eye o bi s. [177Lu]Lu-PSMA exhib-
i s accumula ion in he lac imal glands [66], which ha e been
iden i ied as possibly dose-limi ing [67], al hough no signi ican
occu ence o xe oph halmia (d y eyes) has been epo ed so
1780 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
a . Xe oph halmia has occasionally been shown o be he dose-
limi ing oxici y a e [225Ac]Ac-PSMA-617 he apy a he
highes adminis e ed ac i i ies [26]. In EBRT, an abso bed dose
cons ain o he lac imal glands o 25 Gy was indica ed [68].
The pi ui a y gland, o hypophysis, is loca ed a he base o he
b ain in a skele al hollow e med sella u cica (“Tu kish saddle”).
I has a high exp ession o SSRs and is hus a ge ed by [177Lu]
Lu-SSRT. Radia ion exposu e may a ec he hypo halamic-
pi ui a y axis, a key egula o o endoc ine unc ion. Di e en
ho mone-sec e ing cell ypes ha e di e en adiosensi i i y, wi h
soma o opic and hy o opic cells being he mos and leas adio-
sensi i e pi ui a y cells, espec i ely. In EBRT, an abso bed dose
limi o 20 Gy is ecommended o a oid g ow h ho mone (GH)
de iciency. The abso bed dose limi o panhypopi ui a ism is
45 Gy [68]. Complex eedback loops compensa e o ho mo-
nal a ia ions, which make i challenging o assess sho - e m
mild endoc ine oxici ies. The ew a ailable s udies on pi ui a y
unc ion ollowing [177Lu]Lu-SSRT sugges he occu ence o
mild ch onic impai men o he GH/IGF-1 and gonado opin axes
a e epea ed ea men cycles [69, 70].A s a is ically signi ican
dec ease in he IGF-1 le els wasobse ed, which co ela ed wi h
bo h he numbe o gi en cycles and he es ima ed abso bed dose
o he pi ui a y gland [69].
Tumou s
In [177Lu]Lu-SSRT he apy o NETs cu en e idence
poin s a he exis ence o ela ionships be ween he abso bed
dose and esponse, al hough da a a e ye limi ed and he a -
ge abso bed dose o an e ec i e ea men is o be de ined.
A umou - olume educ ion was obse ed in he he apy o
mixed NETs using 86Y-based dosime y o [90Y]Y-DOTA-
TOC he apy [71]. Fo [177Lu]Lu-DOTA-TATE, ela ion-
ships o he diame e - o olume- educ ion and hei associa-
ion wi h he cumula i e abso bed dose e alua ed a he ime
o bes esponse we e p esen ed o bo h panc ea ic NET and
small-in es inal NETs [72, 73]. Fo [177Lu]Lu-PSMA, he e
we e obse a ions o a signi ican ly highe abso bed dose
o PSA- esponde s (median o 14 Gy) e sus non espond-
e s (median < 10 Gy) when he mean abso bed dose was
calcula ed ac oss all me as ases [74].
Abso bed dose calcula ion o 177Lu
Following he medical in e nal adia ion dose (MIRD) o -
malism [75–78], he mean abso bed dose a e

D(
T
,
)
o a
a ge egion
T
om he ac i i y A
(
S
,
)
loca ed in a sou ce
egion
S
a ime
a e adiopha maceu ical adminis a ion
is gi en by
The
S
- alue,
S(
T
←
S
,
)
, desc ibes he mean abso bed
dose a e a ime
deli e ed o
T
pe uni o ac i i y in
S
. Usually, he ime-independen
S
- alue,
S(
T
←
S),
is
assumed.
S(
T
←
S)
is de i ed om basic physical p in-
ciples ollowing
whe e
m(
T)
is he a ge egion mass, and
𝜙
is he abso bed
ac ion (AF), i.e., he ac ion o he ene gy emi ed om
S
ha is abso bed in
T
. The adionuclide-speci ic ac o s
Ei
and
Yi
ep esen he mean ene gy emi ed in a gi en nuclea
ansi ion and he co esponding yield. Fo 177Lu, he mean
ene gy emi ed pe decay can be g ouped in o
Δ
177
Lu
,
ph
o
pho on emissions (gamma-pho ons and X- ays) and
Δ
177
Lu
,
e
o elec on emissions (
𝛽−
pa icles, con e sion, and Auge
elec ons). Values o
Δ
177
Lu
,
ph
and
Δ
177
Lu
,
e
based on di e -
en adionuclide da a se s and used in di e en dosime y
so wa e a e summa ised in Table1.
I is no ed ha
Δ177Lu,e
is 4.2–4.4 imes highe han
Δ
177
Lu
,
ph
. I is also seen ha al hough di e en da a se s
a e simila , hey a e no iden ical:
Δ177Lu,e
is 0.5% highe
o ICRP 107 compa ed o mo e ecen NuDa 2 da a, and
Δ
177
Lu
,
ph
om bo h HPS and ICRP 107 a e 5% highe han
o NuDa 2. Fo dosime y, he impo an poin is o be
awa e ha di e en se s o
S
- alues a e based on di e en
se s o adionuclide da a.
F om Eqs.1 and 2, he mean abso bed dose o a a ge
egion is calcula ed by in eg a ion o e ime:
(1)

D(
T,
)
=
∑
S
A
(
S,
)
S
(
T← S,
).
(2)
S(
T← S
)
=
1
m
(
T)∑
i
EiYi𝜙
(
T← S,Ei
),
Table 1 Emi ed ene gy pe 177Lu decay om pho on (
Δ177Lu,ph
) and elec on (
Δ177Lu,e
) emissions
# Heal h Physics Socie y (HPS) h p:// hps. o g/ publi cin o ma i on/ ada decay da a. c m
## www. nndc. bnl. go / nuda 2/
Use
𝚫177𝐋𝐮,𝐩𝐡
𝚫177𝐋𝐮,𝐞
Re e ence
Olinda .1 and .2 [79] 35.1 keV Bq−1 s−1
0.02024 mJ MBq−1 h−1 147.2 keV Bq−1 s−1
0.08490 mJ MBq−1 h−1 HPS, S abin, da Luz [80] #
IDAC-Dose 2.1 and OpenDose [81, 82] 35.1 keV Bq−1 s−1
0.02024 mJ MBq−1 h−1 147.9 keV Bq−1 s−1
0.08532 mJ MBq−1 h−1 ICRP 107 [83]
Na ional Nuclea da a cen e , NuDa 2 ## 33.4 keV Bq−1 s−1
0.01927 mJ MBq−1 h−1 147.1 keV Bq−1 s−1
0.08484 mJ MBq−1 h−1 Konde [1]
1781Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
whe e he dose-in eg a ion pe iod
𝜏
is usually aken as in in-
i y. The ime-in eg a ed ac i i y (TIA),

A
(
S
,∞
),
hen ep e-
sen s he o al numbe o adioac i e decays ha occu in a
sou ce egion. The TIA is calcula ed om he ime in eg al
o he ime-ac i i y cu e (TAC) o he sou ce egion, whe e
he TAC is de i ed om a ime-sequence o ac i i y meas-
u emen s.
S
- alues a e de e mined analy ically o by Mon e-
Ca lo simula ions o each adionuclide and sou ce- a ge -
egion combina ion. Such da a ha e been made a ailable o
ana omical geome ies, including o gans and sphe es, wi h
uni o m dis ibu ions o ac i i y and mass densi y [79, 81,
82, 84]. Gene ally, he abso bed dose can be conside ed a
sum o sel -abso bed dose (when
T= S
, i.e. he abso bed
dose deli e ed by ac i i y esiding in he a ge egion i sel )
and c oss-abso bed dose (when
T≠ S,
he abso bed dose
con ibu ion om ac i i y loca ed in o he sou ce egions).
When he ange o pa icle emissions is much sho e han
he o gan dimensions, he AF o sel -abso bed dose is e y
nea o equal o uni y [85]. This obse a ion o ms he basis
o he es ima ion o pa ien -adjus ed
S
- alues (
Spa )
, by scal-
ing o he e e ence-model
S
- alues (
S e )
by he a io o
he e e ence-model mass
m e (
T)
o he pa ien o gan mass
mpa (
T)
, ollowing
Equa ion4 elies on he assump ion ha he di e ence
be ween he pho on AF:s o he wo masses does no con-
ibu e o a signi ican e o in
Spa
. Mo e elabo a e me hods
o he es ima ion o he pho on abso bed ac ions ha e been
p esen ed [86, 87].
Fo sou ce egions wi h high ac i i y accumula ion and
e en ion, loca ed in a su ounding wi h modes ac i i y, he
sel -abso bed dose is gene ally he dominan con ibu o o
177Lu. The sel -abso bed dose is, in u n, domina ed by he
elec on emissions, since: (i)
Δ
177Lu,e
>Δ177Lu,ph
, (ii) he
elec ons ha e sho anges in so issue and bone, and (iii)
(3)
D(
T,𝜏
)
=
∫𝜏
0

D
(
T,
)
d =
∑
s

A
(
S,𝜏
)
S
(
T← S
),
(4)
S
pa
(
T← S
)
≈
m e
(
T
)
m
pa (
T)
⋅S e
(
T← S
)
;
(
T= S
).
he sel -abso bed ac ions o he pho ons a e low o
objec s wi h dimensions ypical o many o gans [86]. The
app oxima ion o elec on local-ene gy deposi ion (LED) is
based on he assump ion ha when
T= S
(Eq.2), he AF
is equal o uni y o elec ons and ze o o pho ons, hus gi -
ing
S177Lu(
T
←
S)
≈Δ
177Lu,e
∕m
(
T)
. Table 2 shows he
sel -abso bed ene gy pe uni o TIA o 177Lu, calcula ed
as he p oduc o he mass and he sel -dose
S
- alue, based
on e e ence-model da a om one example so wa e [81].
Table2 also shows he e o in oduced i only conside ing
LED.
As no ed, o he kidney and spleen, he p oduc mass ×
S
is only 1% highe han ha based on LED. These sou ce
egions ha e con ex shapes, while o a complex sou ce
egion such as he ed ma ow (wi h a high su ace- o- ol-
ume a io), he LED dig esses om ha calcula ed om
S
- alues. The in luence o he size o sou ce/ a ge egions is
u he illus a ed in Figu e1.
As no ed, he sel -abso bed ene gy om Olinda .1,
Olinda .2.2, and IDAC-Dose 2.1 a e consis en , and o
a ge egions wi h a mass be ween 2 and 300 g, he al-
ues ag ee o wi hin 2%. The alues o Olinda .2.1 a e o
unknown easons lowe and inconsis en wi h Olinda .1
and .2.2. While he impo ance o he pho on con ibu-
ion inc eases as he dimensions o he sou ce/ a ge egion
inc ease, he e is o smalle egions an inc easing escape o
elec on ene gy. Bo h e ec s cause a di e ence wi h espec
o he LED alue. Howe e , o sou ce/ a ge egions wi h
compa ably con ex shapes and mass be ween app oxima ely
2 and 300 g (e.g., kidneys, spleen, sali a y glands, and
many umou s), he sel -abso bed dose calcula ed by LED
is wi hin 1–2% om ha using
S
- alues. Such small de ia-
ions a e o he same o de o magni ude as hose be ween
di e en se s o adionuclide o
S
- alue da a.
In p inciple, he MIRD o malism is no limi ed o a spe-
ci ic geome y. When he sou ce is loca ed in a poin in a
uni o m medium and he deposi ed ene gy sco ed in sym-
me ic shells a ound he sou ce, he
S
- alue dis ibu ion is
gene ally e med a dose-poin ke nel (DPK) [88]. Likewise,
he sou ce can be uni o mly dis ibu ed in a cen al oxel and
he ene gy sco ed in su ounding oxels o p oduce oxel
S
Table 2 Sel -abso bed ene gy
pe uni o TIA based on
S
- alues o 177Lu o he
adul male phan om om
IDAC-Dose 2.1 [81], and on
he app oxima ion o LED
using
Δ177Lu,e
om ICRP 107
(Table1)
S
- alue o sel -abso bed dose Mass
(g)
S
- alue
(mGy MBq−1 h−1)Mass ×
S
- alue
(mJ MBq−1 h−1)Ra io o
Δ177Lu,e
S(kidney
←
kidney)
422 0.204 0.0861 1.01
S(li e
←
li e )
2360 0.0376 0.0887 1.04
S(spleen
←
spleen)
228.4 0.377 0.0861 1.01
S( edma ow
←
edma ow)
1394 0.0349 0.0487 0.57
S(blood
←
blood)
1 85.3 (in 1 mL) 0.0853 1
LED:
Δ177Lu,e
N/A N/A 0.0853 1
1782 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3

- alues (VSV) [89, 90]. Fo oxel-based dosime y, he DPK
o VSV is con ol ed wi h he ac i i y dis ibu ion om a
quan i a i e SPECT image.
S
- alues can also be calcula ed
o pa ien -speci ic geome ies using oxel-based Mon e
Ca lo me hods and a CT image o de i e he issue p ope -
ies [91]. Fo 177Lu, he
S
- alue om a sou ce oxel
h
o a
a ge oxel
k
can be exp essed:
whe e
mk
is he a ge oxel mass, and he AF has been
sepa a ed in o componen s o elec ons and pho ons.
Using he LED app oxima ion o sel -abso bed dose gi es
S177Lu
(k←h)
≈Δ
177Lu,e∕
m
k
; (
k=h
). As o egion-based
dosime y desc ibed abo e, applica ion o he LED app oach
o oxel-based 177Lu dosime y is mo i a ed by he sho
elec on anges in so issue and bone, compa ed o he
oxel dimensions o he SPECT images. In addi ion, due
o he limi ed spa ial esolu ion o con empo a y SPECT
sys ems, blu ed es ima es o he eal unde lying ac i i y
dis ibu ion a e p oduced, hus limi ing he spa ial scale ha
can be accu a ely esol ed. The e o in assuming LED is in
many cases conside ably smalle han ha in oduced by he
spa ial blu ing o he ac i i y dis ibu ion [92]. F om Eq.5
and assuming LED, he sel -abso bed dose a e o oxel
k
can be calcula ed based on he oxel ac i i y olume-con-
cen a ion
[A]k
de i ed om a quan i a i e SPECT image,
acco ding o
When a oxel-wise map o he mass densi y
𝜌k
is no
a ailable, assuming a uni o m mass densi y o so issue is
(5)
S
177Lu(k←h)=1
mk
[∑
i
∈177Lu,e
EiYi𝜙e
(
k←h,Ei
)
+
∑
i
∈177Lu,ph
EiYi𝜙ph
(
k←h,Ei
)],
(6)

D
k,sel ( )=Δ
177Lu,e
[A]
k
( )
𝜌
k
.
o en su icien . Fo bony s uc u es and umou s loca ed in
hese issues, o he densi y alues a e equi ed.
Equa ion6 is applicable when he con ibu ion om
c oss-abso bed dose is low and o mid-size sou ce/ a ge
egions in so issue o bone, wi h compa a i ely con-
ex shapes. Cu e i ing o he abso bed dose a e dis-
ibu ion e sus ime can be applied a he oxel le el o
ob ain an abso bed dose map. Al e na i ely, i ing can
be applied o he mean o median abso bed dose a es
in a olume o in e es (VOI). The o me op ion allows
o isual inspec ion o he abso bed dose dis ibu ion
and he cons uc ion o dose- olume his og ams (DVHs).
Howe e , DVHs a e ecognised o be sensi i e o noise,
limi ed spa ial esolu ion, and equi es ha co- egis a-
ion is applied o he ime se ies o SPECT images which
can in oduce undesi ed in e pola ion e ec s. VOI-based
oxel dosime y basically ep esen s an al e na i e ou e
o dosime y as pe Eq.3.
Fac o s ha modi y he adiobiological esponse
Di e en ac i i y up akes and exc e ion a es can p oduce
he same abso bed dose, al hough he abso bed dose a es
di e . In EBRT and b achy he apy, he abso bed dose a e is
known as a modi ying ac o o he adiobiological e ec s,
owing o cellula epai du ing adia ion exposu e. [177Lu]
Lu-SSRT o [177Lu]Lu-PSMA he apies a e cha ac e ised
by low abso bed dose a es in compa ison o mos o he adi-
o he apy echniques. F ac iona ion is ano he ac o associ-
a ed wi h cellula epai and issue eco e y, especially o
la e- esponding issues. This is conside ed in he apies wi h
[177Lu]Lu-SSRT o [177Lu]Lu-PSMA, which a e gene ally
gi en in epea ed cycles (o ac ions), wi h a p e-de ined
cycle in e al. An addi ional modi ying ac o is nonuni o m
Fig. 1 Sel -abso bed ene gy
pe uni o TIA o 177Lu as a
unc ion o mass, based on
S
- alues o uni densi y sphe es
o IDAC-Dose 2.1, Olinda .1,
.2.1, and .2.2. The esul o
LED om ecen adionuclide
da a is also shown (dashed ho i-
zon al line) [1]. The blue band
indica es an o se o ±2% om
he alues o IDAC-Dose 2.1
1783Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
adia ion exposu e, which, owing o he sho elec on ange
o 177Lu, is cha ac e is ic o hese he apies.
The biologically e ec i e dose (
BED
), mo e ecen ly
included as a special case o he equie ec i e dose, was
in oduced in he linea -quad a ic (LQ) model o quan i y
he di e en abso bed doses equi ed o induce a gi en
adiobiological e ec [93, 94]. The
BED
akes in o accoun
he o al abso bed dose
D
, he abso bed dose a e, e ec s o
epai and ac iona ion. I is speci ic o he issue and he
conside ed adiobiologic endpoin o which he LQ-model
pa ame e
𝛼∕𝛽
was de i ed. The
BED
is o mula ed as a
double in eg al ha speci ies he in e ac ion o he a e o
issue-damage induc ion due o adia ion exposu e and he
a e o epai . Fo a single adionuclide- he apy adminis a-
ion and assuming a mono-exponen ial washou , his double
in eg al e alua es o [95]
whe e
𝜆
is he a e cons an linked o he e ec i e hal -li e o
he adiopha maceu ical in he issue
(
𝜆= ln2∕T
e )
, and
𝜇
is
he epai cons an , assuming a mono-exponen ially dec eas-
ing a e o epai . The BED exp ession has been ex ended
o he MIRD schema and applied o o gans a isk such as
he ed ma ow and kidneys [58, 59]. BED exp essions we e
de i ed o ac iona ed ea men s, which o ac ions sepa-
a ed by long ime in e als wi h espec o he e ec i e hal -
li e esul in he sum o he BED om each ac ion [96, 97].
Quan i ica ion o 177Lu ac i i y
Calib a ion o  heac i i y me e
P io o deli e y o any ea men , he ac i i y me e, also
called dose calib a o , should be co ec ly calib a ed o he
con aine s used o dispensing he ac i i y. I needs o be
assu ed ha he measu ed ac i i y is aceable o a p ima y
s anda d. This can be achie ed by calib a ion o he ac i i y
me e dialse ings owa ds a 177Lu sou ce ha is accompa-
nied by an ac i i y s a emen wi h aceabili y o a s anda d
me ology labo a o y [98]. The s abili y o he ac i i y me e
esponse also needs o be moni o ed.
Quan i a i e SPECT/CT imaging
177Lu is one o he bes -cha ac e ised adionuclides wi h
ega ds o image-based ac i i y quan i ica ion. Whils ea ly
dosime y s udies we e p edominan ly based on plana
gamma-came a images, SPECT imaging is o many appli-
ca ions now conside ed he me hod o choice [99, 100].
Quan i a i e SPECT/CT is desc ibed in MIRD pamphle
(7)
BED =
D⋅
(
1+D
𝛼∕𝛽
⋅
𝜆
𝜆+𝜇
)
23 [101] and he EANM/MIRD guideline o quan i a i e
177Lu SPECT [102]. The in en ion in he ollowing is o
summa ise he p ac ical s eps mos ele an o dosime y o
177Lu-labelled compounds.
Came a calib a ion ac o
Came a calib a ion e e s o he p ocess used o con e he
coun s measu ed by he SPECT came a o ac i i y. The cali-
b a ion ac o is de e mined by imaging a sou ce o known
ac i i y, o ac i i y concen a ion, in a e e ence geome y,
using he same SPECT sys em and acquisi ion se ings as
used o pa ien imaging. Cu en ly, he sou ce geome y
and imaging pa ame e s a e no s anda dised, and di e en
app oaches ha e been epo ed o 177Lu [100, 103–108].
O he me hods p oposed, a la ge phan om, simila o ha
used o PET image calib a ion, is conside ed he mos
obus calib a ion geome y. The SPECT calib a ion ac o
Qsp
is de i ed om he omog aphic image, econs uc ed
using he same p o ocol as used o pa ien imaging.
Qsp
is de ined as he econs uc ed coun a e pe ac i i y (cps/
MBq), acco ding o
whe e
Ccal
is he coun a e in a VOI, calcula ed as he o al
coun s in he VOI di ided by he acquisi ion ime-in e al.
The denomina o
Acal
is he p oduc o he ac i i y concen a-
ion in he phan om and he olume o he VOI. Some com-
me cial sys ems ha e in oduced quan i a i e econs uc ion
algo i hms ha p oduce images in he uni o ac i i y, o ac i -
i y concen a ion, ins ead o coun s. Calib a ion o such sys-
ems is s ill based on physical measu emen s, and he calib a-
ion ac o equi es e i ica ion. Calib a ion ac o s may also
a y o e ime, depending on he s abili y o he sys em o i
he came a is e- uned, and epea ed moni o ing is ad ised.
Coun a e pe o mance
E ec s o pulse pile-up and dead ime should be conside ed
when imaging du ing he apies wi h [177Lu]Lu-SSRT o
[177Lu]Lu-PSMA i he coun a e is expec ed o be high
a pa ien imaging. Such e ec s ende he came a sys em
o espond nonlinea ly o he ac i i y in he ield-o - iew
(FOV) [102, 109]. Cha ac e isa ion o he coun - a e pe o -
mance is made by imaging o a ange o ac i i ies, co e ing
he maximum ac i i y likely o be encoun e ed in he pa ien .
The geome y needs o be chosen such ha he amoun o
sca e is simila o ha o pa ien imaging, o example by
using a sou ce wi hin a la ge cylind ical phan om. The mag-
ni ude o he dead- ime e ec depends on he o al coun a e
inciden ac oss he en i e ene gy ange. The e o e, i is also
(8)
Q
sp =
C
cal
A
cal
,
1784 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
dependen on he sca e ed e en s inciden on he de ec o .
As sca e and coun a e can a y a di e en p ojec ion
angles, dead ime e ec s will also a y wi h he p ojec ion
angle [101]. A dead- ime co ec ion ac o has been de el-
oped o 131I SPECT, which is based on he mean coun
a e o e all p ojec ions [110]. Following he cu en s anda d
adminis a ion p o ocol o 7.4 GBq o 177Lu pe cycle and
ecognising ha he e is an ini ial componen o as u ina y
exc e ion o [177Lu]Lu-SSRT and [177Lu]Lu-PSMA, dead
ime e ec s a e gene ally only o conce n wi hin he i s
hou s a e adminis a ion and less o kidney and umou
dosime y [109]. Fo highe ac i i y adminis a ions, co ec-
ion o coun - a e pe o mance may be necessa y.
Co ec ion o  hepa ial‑ olume e ec (PVE)
The PVE is ele an in mos cases o 177Lu dosime y. I
is essen ially a esul o he limi ed spa ial esolu ion o
SPECT sys ems, which p oduces a blu ed e sion o he
unde lying ac i i y dis ibu ion. Assessmen o PVEs can
be made by phan om s udies o a se o inse s co e ing a
ange o clinically ele an olumes. The same pa ame e s
o image acquisi ion and econs uc ion as used in pa ien
s udiesa e applied. The eco e y coe icien
R( )
o an inse
o olume
is calcula ed acco ding o
whe e
CR( )
is he coun a e measu ed in a VOI o olume
, and
AR( )
is he 177Lu ac i i y con ained in he inse a
he ime o measu emen . Al e na i ely, Eq.9 can be o -
mula ed in e ms o ac i i y concen a ion and coun a e
concen a ion. Commonly, sphe ical inse s a e used o
de e mine eco e y coe icien s [72]. I may also be app o-
p ia e o cha ac e ise he eco e y cu e using nonsphe i-
cal objec s, o wi h di e en sou ce- o-backg ound con as
a ios. Fo kidney-shaped objec s, eco e y coe icien s ha e
been measu ed using 3D-p in ed objec s o Mon e Ca lo
simula ed images [106, 111, 112]. Fo PET/CT, a numbe
o image-based co ec ion me hods ha e been de eloped ha
may also be applicable o 177Lu dosime y [113].
Pa ien image acquisi ion andimage p ocessing
I is ecommended o use he same SPECT/CT sys em o
he en i e y o he dosime y s udy. Medium ene gy collima-
o s a e ecommended o 177Lu imaging o mos sys ems.
Al hough 177Lu has wo pho o peaks (113 and 208 keV),
commonly only he 208 keV pho opeak is used o quan i a-
i e imaging wi h NaI-based gamma came as, as his peak
con ains conside ably less sca e han he 113 keV win-
dow [102]. Fo sys ems based on CZT c ys als, he 208 keV
(9)
R
( )=
C
R
( )
Qs
p
⋅A
R
( )
,
peak may be ou side he spec al ange, and he use o he
113 keV peak has been in es iga ed [114]. On NaI-based
came as, an ene gy window o 15 o 20% is common o he
208 keV peak, and when he iple-ene gy window (TEW)
sca e co ec ion is employed, wo addi ional, na ow sca -
e windows a e se adjacen o he main window. The cam-
e a should be se o au oma ic con ou ing and p ojec ions
acqui ed in a 128 × 128 ma ix o highe (zoom ac o =
1). I e a i e omog aphic econs uc ion is s ongly ecom-
mended, including CT-based co ec ions o a enua ion,
sca e , and, when a ailable, collima o - esponse modelling
(also e med esolu ion eco e y). The numbe o p ojec-
ions and ime pe p ojec ion should be chosen based on he
expec ed signal- o-noise a io o he VOI coun s, which is
go e ned by he amoun o ac i i y in he pa ien , he cam-
e a sys em sensi i i y, he ma ix size, and he noise p opa-
ga ion o he omog aphic econs uc ion. Be ween 60 and
120p ojec ion angles a e gene ally ecommended, al hough,
o es ima ion o he ac i i y concen a ion in cen ally
loca ed,high-up ake issues, he numbe o p ojec ions can
po en ially be educed [115]. Scan imes a y widely bu a e
ypically in he o de o 30–40 s pe p ojec ion [116] and can
be adjus ed be ween ea ly and la e imaging ime poin s. Fo
[177Lu]Lu-PSMA he apies, mul iple-FOV SPECT/CT may
be equi ed o co e he en i e ex en o he disease. Fo his
eason, sho e imes pe p ojec ion ha e been in es iga ed
[115], possibly opening o nea whole-body SPECT imag-
ing. The numbe o upda es (i e a ions
×
subse s) should be
highe o quan i a i e imaging han o diagnos ics, as he
main pu pose is o ob ain a eliable es ima e o he ac i i y
in sou ce egions. The econs uc ion p o ocol o ac i i y
quan i ica ion should be op imized o ensu e con e gence
o he VOI coun a e [102, 106]. As a i s app oach, he
phan om used o eco e y measu emen s can be used o
examine he a e o con e gence. The applica ion o pos -
econs uc ion il e ing is no ecommended o quan i a i e
imaging, as his will a ec he eco e y and hus he quan-
i a i e accu acy.
Image analysis o ac i i y quan i ica ion andabso bed
dose calcula ion
Quan i ica ion o he ac i i y A
(
S
,
)
in a sou ce egion a
ime
pos adminis a ion is made based on he o al coun
a e
C( VOI, )
measu ed wi hin a VOI o olume
VOI
o e
he sou ce egion, acco ding o
A obus and consis en segmen a ion s a egy needs o be
main ained o VOI delinea ion. Fu he mo e, he segmen-
a ion me hod needs o be applicable o all imaging ime
(10)
A(
S,
)
=
C(
VOI
, )
Q
sp
⋅R
(
VOI).
1785Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
poin s and ac oss pa ien s. The p ac ical implemen a ion o
SPECT image segmen a ion depends pa ly on he image
da a a ailable. Fo hyb id SPECT/CT sys ems, VOI delinea-
ion o o gans is p e e ably made using CT in o ma ion. Due
o o gan mo ion be ween he CT and SPECT acquisi ions,
he VOI posi ions may equi e adjus men o he SPECT
da a se . Fo umou s, VOI delinea ion on a low-con as CT
is o en challenging, and a co- egis e ed con as -enhanced
CT o he SPECT image may hen be use ul. Techniques
used o SPECT image segmen a ion include manual ope a-
o delinea ion, ixed-pe cen age h esholds [72], adap i e o
au oma ed h esholding [117, 118], g adien -based su ace
adap ion [119], and me hods based on con olu ional neu-
al ne wo ks [120]. Fixed h esholding on SPECT images
is commonly a ailable in comme cial sys ems bu has he
disad an age o being highly sensi i e o local con as and
noise [121]. The es ima ion o he mass o he a ge egion
m(
T)
can be made om segmen a ion in PET, CT, o MRI
images, o , depending on he segmen a ion s a egy, based
on he same VOI as applied o he SPECT images.
The abso bed dose can be epo ed o whole o gans,
umou s, o pa s o hese, al hough he limi a ions associ-
a ed wi h spa ial esolu ion and noise need o be espec ed.
Segmen a ion o pa s o la ge o gans, such as he li e ,
may be use ul o assess egional di e ences in abso bed
dose i he e a e p onounced clus e s wi h di e en ac i i y
concen a ions.
Plana image‑based ac i i y quan i ica ion
Al hough plana imaging is known o su e om supe -
posi ion o ac i i y in issues ha lie abo e o below he
sou ce egion o be analysed, he e a e s ill applica ions
wi hin 177Lu dosime y. These include es ima ion o he
o al-body TAC o issues whe e he c oss-abso bed dose
om he pho ons emi ed by 177Lu is impo an , as may
be he case o bone-ma ow. O he applica ions include
dosime y o sali a y, lac imal and pi ui a y glands. Plana
image-based ac i i y quan i ica ion has been desc ibed in
MIRD Pamphle 16 [122], and he in en ion is o summa ise
he me hodological aspec s mos ele an o dosime y o
177Lu-labelled compounds.
Came a calib a ion ac o
Ea lie me hods o plana image-based ac i i y quan i ica-
ion we e based on pa ien acquisi ion ea ly a e admin-
is a ion be o e he pa ien had oided. A con e sion ac-
o was calcula ed om he image coun s o e he whole
body di ided by he adminis e ed ac i i y. This con e sion
ac o was hen assumed o ake all physical e ec s in o
accoun , i.e. bo h he sys em sensi i i y and e ec s o pho on
a enua ion and sca e ing, hus neglec ing he a ia ion in
hese phenomena ac oss he pa ien body.
A p e e able me hod is o de e mine he calib a ion ac o
sepa a ely and hen apply co ec ions o a enua ion and
sca e . The plana calib a ion ac o ,
Qpl
, ep esen s he
coun a e ob ained pe uni o ac i i y o a sou ce placed
in he ai , de e mined by plana image acquisi ion o 177Lu
wi h a known amoun o ac i i y [123, 124]. To de e mine
Qpl
, a egion-o -in e es (ROI) is delinea ed a ound he
sou ce, wi h a ma gin o ake he esolu ion-induced spill-ou
in o accoun , and he sum o he ROI coun s is di ided by he
acquisi ion ime in e al and he sou ce ac i i y. The ime
in e al should ep esen he ime ha a pa icula pixel is in
he came a FOV a pa ien imaging, and when whole-body
scanning is used, he calib a ion measu emen may need o
be made in scan mode, depending on how he acquisi ion
ime is epo ed in he DICOM heade . Fo dual-head cam-
e as, calib a ion image acquisi ion needs o be made o bo h
came a heads, and when applicable, he geome ic mean o
he coun s aken. A long backg ound scan can also be made
o assess he impac o impe ec nonuni o mi y co ec ion
and examine he backg ound coun a e. P e e ably, sca e
co ec ion should be applied be o e he de e mina ion o he
ROI coun a e.
Pa ien image acquisi ion, image p ocessing, andanalysis
Rega ding he collima o and ene gy window se ings, he
same ecommenda ions apply o plana as o SPECT image
acquisi ion. The ma ix size is o en 1024 × 256, co e ing
he pa ien ’s leng h. The couch eloci y is adjus ed o he
expec ed coun a e a pa ien imaging and may a y o he
di e en ime poin s a e adminis a ion.
The conjuga e- iew me hod is he mos commonly used
me hod o ac i i y quan i ica ion om an e io -pos e io
plana images [122, 125, 126]. The ac i i y in a sou ce
egion is calcula ed acco ding o
whe e
CA( )
and
CP( )
a e he coun a es in ROIs delinea ed
o e he sou ce egion in he an e io and pos e io images,
espec i ely. The a enua ion co ec ion
a(𝜇,L)
is gi en by
exp(
𝜇⋅L
∕
2
)
, whe e
L
is he pa ien hickness a he sou ce-
egion loca ion, and
𝜇
is he a enua ion coe icien o he
208-keV emission (assuming ha he ene gy window is se
o e his pho opeak). An addi ional ac o is some imes used
in Eq.11 o co ec sel -a enua ion in he sou ce egion
[122, 125, 126]. Howe e , his ac o becomes nea uni y
o 177Lu, and i can hus be omi ed. The simples me hod
o a enua ion and sca e co ec ion is o use an e ec i e,
o b oad-beam a enua ion coe icien ,
𝜇e
. The alue o
𝜇e
(11)
A�
S,
�
=
√
CA( )⋅CP( )⋅a(𝜇,L)⋅
1
Q
pl
,
1786 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
ma ow

ARM
, bone

Abone
, o he o gans wi h high-ac i i y
up ake

Ah
, and he emainde o he body

ARoB
acco ding o
wi h hei co esponding
S
- alues. Ac i i y in he ed ma -
ow consis s o ac i i y bound o ed-ma ow cells, and
blood pe using h ough ma ow space and he ex acellu-
la luid. Assuming he adminis e ed compound does no
speci ically bind o ed ma ow cells, hen he ac i i y and
TIA concen a ions can be de i ed om blood samples by
he assump ion ha
[
A
RM]
=
[
A
BL]
⋅
RMBLR
, wi h
RMBLR
ep esen ing he ac i i y concen a ion in ed ma ow
o e blood (BL). The blood-based me hod o calcula ing
he sel -abso bed dose o ed ma ow, i.e., he i s e m in
Eq.12, hen ollows om:
whe e
mRM, e
is he ed-ma ow mass in he e e ence phan-
om o he
S
- alue (Table4). The ac o
RMBLR
is gen-
e ally conside ed o be 1, bo h o [177Lu]Lu-SSRT and
o [177Lu]Lu-PSMA. Image-based es ima ion o he ed
ma ow TAC has been made om se ial imaging by plana
whole-body scans [37, 38], hyb id plana -SPECT/CT [39],
o SPECT/CT [40]. Wi h se ial SPECT/CT, he ac i i y con-
cen a ion is o en de e mined om VOIs o e he lumba
e eb ae due o hei ela i ely la ge olume and loca ion
away om high-up ake egions ha may o he wise con ib-
u e wi h misplaced coun s due o limi ed spa ial esolu ion
and sca e .
The abso bed dose o blood has been used o in es iga e
co ela ions o he exp ession o bioma ke s o DNA dam-
age [41]. The mean abso bed dose o blood,
DBL
, is hen
calcula ed by summa ion o he sel -dose and he γ- ay c oss
dose om he o al body (TB), acco ding o
The
S
- alue o 1 mL blood has been de e mined o
177Lu om he assump ion o LED, gi ing
S(BL
←
BL)
=
(12)
D
RM =

ARM ⋅S(RM ←RM)+

Abone ⋅S(RM ←bone
)
+∑
h

Ah⋅S(RM ←h)+

ARoB ⋅S(RM ←RoB),
(13)
D
(RM ←RM)=
[
A
BL]
⋅RMBLR ⋅m
RM, e
⋅S(RM ←RM)
,
(14)
DBL
=
[

A
BL]
⋅S(BL ←BL)+
A
TB
⋅S
𝛾
(BL ←TB)
.
85.3
Gy∕(GBqh∕mL)
, see Table2 [41]. The uni o
[
A
BL]
should hus be
GBqh∕mL
. The
S
- alue o o al-body o
γ- ays was ob ained as
S𝛾
(BL ←TB)=S
𝛾
(TB ←TB)∕M
2∕3
TB
,
whe e
M
is he body weigh and
S𝛾(TB
←
TB)
= 0.00185
Gy∕(GBqh)
o 177Lu [41, 45].
Speci ic up ake in he skele on is o conce n o pa ien s
wi h bone me as ases, which is gene ally obse ed in end-
s age p os a e cance [74]. In such si ua ions, image-based
dosime y is equi ed o calcula e he ed ma ow abso bed
dose dis ibu ion. La ge olumes o skele al lesions will
also in luence he ed ma ow dis ibu ion in ma ow space,
which may be conside ed o dosime y o [177Lu]Lu-
PSMA [175] and [177Lu]Lu-SSRT he apies [178]. Fu -
he mo e, any ee lu e ium ions in he injec ed d ug will
bind o he skele on (60% o he ac i i y) and be deposi ed
in he li e (10%) [179], which can be p e en ed by he
addi ion o DTPA be o e adiopha maceu ical adminis a-
ion [180].
S
- alues o 177Lu a e based on he dis ibu ion o ed
ma ow in an a e age popula ion, ollowing ICRP 89 [160].
Table4 lis s sel -dose
S
- alues o wo da a se s. The di e -
ence in hese models mos ly ela es o he ed-ma ow mass:
IDAC-Dose 2.1 is based on da a om ICRP 133 [84], whe e
he ed ma ow also con ains blood (4% o he o al blood
olume o he e e ence phan om).
Recommenda ions o dosime y
Measu emen o he ac i i y concen a ion in he blood
emains he mos common me hod o ed-ma ow dosim-
e y. Sampling ime poin s should be chosen o cap u e
bo h he ea ly TAC peak and he slowe washou phase.
An example sampling schedule is di ec ly a e adminis a-
ion, 10 min, 30 min, 60 min, 90 min, 120 min, 360 min,
24 h, and one la e ime-poin . Image-based es ima ion
o he ed-ma ow TAC can also be made using sequen-
ial plana o SPECT/CT whole-body imaging [175, 178].
Typically, 2 o 3 ime-poin s a e acqui ed up o 48 h, and
a leas one la e ime poin o ollow he slowe com-
ponen . Fo SPECT/CT-based me hods, i is ad isable o
a oid o adjus o spill-in o coun s om egions wi h
skele al me as ases [178].
Dosime y o  hesali a y, lac imal, andpi ui a y
glands
Summa y o a ailable dosime y da a
Abso bed doses o sali a y and lac imal glands ollowing
[177Lu]Lu-PSMA he apy a e summa ised in Appendix1,
Table6, and images acqui ed p io o, anddu ing he apy
wi h[177Lu]Lu-PSMA a e shown in Fig.4.As wi h o he
Table 4 Da a o ed ma ow, including he mass and sel -dose
S
- al-
ues o 177Lu, acco ding o Olinda 2.1 and IDAC-Dose 2.1
Mass (g)
S(RM
←
RM)
(mGy MBq−1 h−1)
Male Female Male Female
Olinda . 2.1 1170 0.0414 900 0.0537
IDAC-Dose 2.1 1394 0.0349 1064 0.0457
1793Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3

issues, a la ge in e -pa ien a iabili y is obse ed. Fo
sali a y glands, he abso bed doses ange be ween 0.5 and
1.9 Gy/GBq. S udies ha included dosime y o mo e
han one cycle demons a ed a modes a ia ion be ween
cycles [12, 23]. Fo lac imal glands, he abso bed doses
ange be ween 0.4 and 3.8 Gy/GBq. One s udy epo ed a
mean abso bed dose o 16 ± 4 Gy pe he apy cycle, each
o 5.5 GBq [177Lu]Lu-PSMA-617, which was almos 4
imes highe han he abso bed dose o he sali a y glands
[67]. The lac imal glands can po en ially be conside ed he
main o gan a isk in he apy wi h 177Lu-PSMA, al hough
p esen ly, no signi ican conce n o xe oph halmia has
been epo ed [23].
The pi ui a y gland has a high exp ession o SSRs
(Fig.5).Abso bed doses o he pi ui a y gland ollowing
[177Lu]Lu-SSRT he apy ha e been in es iga ed by plana
image quan i ica ion wi h epo ed mean abso bed doses o
0.89 Gy/GBq ( ange 0.46–1.8 Gy/GBq) [69]. Radiobiologi-
cal modelling was used o compa e ole ance le els de i ed
om EBRT, a i ing a an EQD2 o 3.5 Gy (1.7–7.7 Gy)
pe 7.4 GBq cycle.
Me hodological aspec s
Fo he h ee pai s o sali a y glands, he pa o ids ha e
ypical dimensions smalle han 5 cm in all di ec ions,
submandibula and sublingual glands ha e ypical dimen-
sions smalle han 4 cm and 2 cm, espec i ely [181]. The
o al mass o he h ee pai s o sali a y glands is o he
ICRP 110 e e ence adul male 85 g [182]. Howe e , a la ge
in e -pa ien a ia ion in he sali a y gland olume has been
obse ed [183, 184].
Indi idual mass es ima ion o sali a y glands o
[177Lu]Lu-PSMA dosime y is gene ally only made o
he pa o id and submandibula glands. Repo ed anges
a e 31–43 g o bo h se s o glands [12]. Ano he s udy
epo ed masses o 71 g o pa o id and 28 g o subman-
dibula glands [23]. The mass o lac imal glands has been
es ima ed o be app oxima ely 1.4 g o bo h glands [67,
185]. The ICRP 89 pi ui a y gland mass is gi en as 0.6
g, while mo e ecen olume y has epo ed alues o
app oxima ely 0.4 cm3 o indi iduals aged 50 yea s o
mo e [186].
Ac i i y quan i ica ion o sali a y, lac imal, and
pi ui a y glands du ing [177Lu]Lu-PSMA o [177Lu]
Lu-SSRT he apies was mos ly based on plana imag-
ing [12, 18, 23, 54, 67, 69, 176, 187, 188]. In he di -
e en imaging p o ocols employed, h ee o nine plana
whole-body images we e acqui ed be ween 0.5 and 192
h a e adminis a ion. Ac i i y quan i ica ion was ca -
ied ou by di ec delinea ion on plana images wi h o
wi hou backg ound co ec ion. Th ee s udies o [177Lu]
Lu-PSMA employed a hyb id imaging me hod (4 plana
images up o 120 h + 1 SPECT/CT image a 24 h) [21]
o only SPECT/CT images [22, 74]. No gene al end
could be obse ed when compa ing abso bed doses cal-
cula ed based on plana images only, a hyb id me hod,
o SPECT/CT images only.
Al hough he use o plana -based ac i i y quan i-
ica ion is ecognised o su e om he supe posi ion
o ac i i y loca ed in di e en issues, o sali a y and
lac imal glands he coun con ibu ion om o e lapping
issues can be expec ed o be modes a la e ime poin s.
Howe e , a ea ly ime poin s (<3 h) ac i i y in la ge
blood essels may in e e e wi h he ac i i y es ima e.
Due o he small dimensions o hese glands (<30 mL),
he PVEs a e la ge. In one s udy based on 3 SPECT/CT
images, VOIs ha included a 1- o 2-cm ma gin we e
applied o quan i y ac i i y in sali a y and lac imal
glands [74]. Gi en he low concen a ion a la e ime
poin s o [177Lu]Lu-PSMA in supe imposed issues, pla-
na imaging can po en ially yield su icien ly accu a e
ac i i y es ima es wi hin he sali a y and lac imal glands.
Howe e , his would need con i ma ion by compa ison
o SPECT/CT. Plana -based ac i i y quan i ica ion o
he pi ui a y gland in [177Lu]Lu-SSRT he apy is ham-
pe ed by possible ac i i y up ake in he nasal mucosa, and
SPECT/CT is ecommended.
TACs o [177Lu]Lu-PSMA wi hin he sali a y and
lac imal glands exhibi an inc ease up o app oxima ely
24 h pos -adminis a ion and a cons an a e o wash-
ou beyond his poin [188]. Conce ning he choice o
he imaging ime poin s, one s udy [67] compa ed he
abso bed dose o sali a y glands and lac imal glands
when using 4 imaging ime poin s up o 72 h o when
using an addi ional ime poin a 168 h. Resul s indica ed
ha abso bed doses we e o e es ima ed when omi ing
he las ime poin by 20% o sali a y glands and by 10%
o lac imal glands.
Mos o he epo ed abso bed dose alues ha e been cal-
cula ed based on
S
- alues o uni densi y sphe es. Fo sali-
a y glands, he
S
- alue was adjus ed o he pa ien -speci ic
gland mass, measu ed using CT [18, 23], o was se o 85
g [67] co esponding o he mass gi en in ICRP 110 [182].
Lac imal glands a e no always easily delineable in CT
images, al hough his echnique was used wi h a mean alue
o 0.8 g in a coho o 18 pa ien s [23]. Accu a e olume y
o he pi ui a y gland would likely equi e high- esolu ion
MR imaging, and he e o e indi idual mass es ima ion is
challenging.
The ICRP 110 e e ence compu e models include
he sali a y glands [182], and
S
- alues o 177Lu a e
included in OpenDose [82], IDAC-Dose 2.1 [81], as well
as Olinda .2.1 (Table5). Fo compa ison, he
S
- alue
calcula ed based on he LED app oach is also included
in Table5.
1794 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
As no ed, he di e ences be ween he alues in Table5
a e modes and a e p obably mainly ela ed o di e -
ences in he mass, he geome ical ep esen a ion o hese
small egions, and possibly he adionuclide da a used.
Fo example, al hough IDAC-Dose 2.1 and OpenDose a e
based on he same compu e phan oms om ICRP 110 and
he same adionuclide da a om ICRP 107, he
S
- alues
o sali a y and pi ui a y glands di e , likely due o di -
e en oxel sizes ha a ec he mass used o calcula ion
[82]. Fo abso bed dose calcula ion, any o hese alues
may be used. When applicable, app op ia e mass scaling
should be applied acco ding o he mass o he pa ien ’s
glands (Eq.4).
Lac imal glands a e no included in he ICRP110 phan-
om, and p ecompu ed
S
- alues a e no a ailable. The e o e,
S
- alues o uni densi y sphe es o he LED app oach mus
be used. In he absence o ana omical imaging, a mass o 1.4
g may be used, p e e ably also including a ele an ange o
masses o ob ain an es ima e o he s anda d unce ain y in
he abso bed dose. The
S
- alue o a uni densi y sphe e wi h
mass 1.4 g was used ea lie [67], which co esponded o he
a e age alue o wo o he s udies [185, 189].
The pi ui a y gland is included as a a ge egion in Open-
Dose, which is hus he ecommended
S
- alue. The LED
app oach gi es a alue which is 6% highe han he
S
- alue
in OpenDose, p obably due o he escape o elec on ene gy
o his small sou ce egion.
Recommenda ions o dosime y
Dosime y o sali a y, lac imal, and pi ui a y glands
p esen s new and challenging asks o physicis s and
physicians in ol ed in [177Lu]Lu-SSRT and [177Lu]Lu-
PSMA he apies. The challenge is mos ly ela ed o he
small olume o hese glands, which makes he pa ien -spe-
ci ic mass es ima ion di icul . Fo lac imal and pi ui a y
glands, dosime y can be made assuming a s anda d mass
ha should p e e ably be a ied ac oss a ealis ic ange
o ob ain an es ima e o he unce ain y in oduced by he
mass assump ion. Ano he challenge is he lack o s udies
ha include sequen ial SPECT/CT o e hese glands. Thus,
o da e, he e is no s anda dised app oach o dosime y
o hese glands. Howe e , SPECT/CT-based dosime y is
encou aged as i is expec ed o p o ide impo an dosim-
e y da a and a be e unde s anding o he le els o he
abso bed doses deli e ed.
Dosime y o  umou s
Summa y o a ailable dosime y da a
Dosime y esul s o umou s in [177Lu]Lu-SSRT he apy
a e summa ised in Appendix2, Table7 [40, 72, 99, 171,
190–194]. Fo [177Lu]Lu-DOTA-TATE, a ecen summa y
is also a ailable [36]. A wide ange o umou -abso bed
doses ha e been epo ed, be ween 0.1 and 32 Gy/GBq.
Fo s udies ha included dosime y in each cycle, i was
no ed ha he umou abso bed doses dec eased be ween
cycles [73, 99, 195]. One s udy obse ed a signi ican ly
mo e p onounced dec ease o g ade 2 han g ade 1 NETs
[195], while ano he obse ed a dec ease o panc ea ic bu
no small-in es inal NETs [73]. E ec i e hal -li es we e
epo ed o a ew s udies and anged be ween app oxima ely
50 and 120 h, wi h sho e hal -li es obse ed o g ade 2
han o g ade 1 NETs [171, 192, 195].
Table8 summa ises dosime y s udies o [177Lu]Lu-
PSMA [12, 23, 74, 176, 187]. The mean alues o epo ed
umou abso bed doses lie be ween app oxima ely 1 and 8
Gy/GBq, wi h a end o highe abso bed doses o bone
me as ases. The epo ed s anda d de ia ions ha e nea ly
equal magni ude as he mean, indica ing a la ge a ia ion
be ween pa ien s, umou s, and cycles. A end o dec easing
Table 5 Sel -dose
S
- alues o
sali a y, lac imal, and pi ui a y
glands, and uni densi y sphe es,
ob ained om Olinda .2.1,
IDAC-Dose 2.1, and OpenDose.
S
- alues o LED ha e been
calcula ed based on
Δ177Lu,e
om ICRP 107 (Table1)
di ided by he mass. Masses a e
e ie ed om ICRP89 [160]
excep o lac imal glands [67].
In hei calcula ion p ocess,
IDAC-Dose 2.1 and OpenDose
used sligh ly modi ied o gan
masses om ICRP 89, as
indica ed in b acke s
Mass (g)
ICRP 89
S
- alue
(mGy MBq−1 h−1)Uni -densi y sphe e
S
- alue
(mGy MBq−1 h−1)
Olinda 2.1 IDAC-Dose 2.1 OpenDose IDAC-Dose 2.1 LED
Sali a y glands (male) 85 1.00 0.947
(88.98 g) 0.994
(84.969 g) 1.01 1.00
Sali a y glands ( emale) 70 1.22 1.17
(72.15 g) 1.20
(70.004 g) 1.23 1.22
Lac imal glands N/A N/A N/A N/A 60.0
(1.4 g) 60.9
(1.4 g)
Pi ui a y gland (male) 0.6 N/A 127
(0.628 g) 133
(0.602 g) 137 142
Pi ui a y gland ( emale) 0.6 N/A 129
(0.618 g) 134
(0.597 g) 137 142
1795Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
abso bed doses o e cycles was obse ed [23]. In addi ion
o indi idual-lesion dosime y, SPECT/CT oxel dosime y
has been used o de e mine a whole-body umou abso bed
dose, calcula ed as he mean abso bed dose ac oss all lesions
ecei ing 5 Gy o mo e [74].
Me hodological aspec s
Whils ea ly s udies used plana -based ac i i y quan i ica ion
o [177Lu]Lu-SSRT, he e is a gene al ansi ion owa ds
sequen ial SPECT/CT o hyb id plana -SPECT/CT p o o-
cols. Fo [177Lu]Lu-PSMA, plana image-based ac i i y
quan i ica ion is s ill employed, possibly due o he la ge
imaging FOV equi ed o co e he en i e ex en o disease.
Fo [177Lu]Lu-SSRT, a compa a i e s udy o di e en
me hods o ac i i y quan i ica ion in he same coho o
pa ien s epo ed umou abso bed doses o 2.6 ± 1.5 Gy/
GBq when using SPECT/CT only, 3.1 ± 2.2 Gy/GBq using
a hyb id plana -SPECT/CT app oach, and 5.3 ± 6.3 Gy/
GBq using plana quan i ica ion [191]. Median and anges
we e ela i ely compa able be ween SPECT/CT and hyb id
plana -SPECT/CT bu we e conside ably highe when only
employing plana imaging. SPECT/CT-based ac i i y quan-
i ica ion will enable s anda disa ion, al houghdi e en
i e a i e econs uc ion me hods and hei pa ame e s may
s ill yield a a iable accu acy. Fo [177Lu]Lu-PSMA, using
se e al FOV o he SPECT acquisi ions is an a ac i e
al e na i e [74], al hough pe o ming sequen ial scanning o
each cycle may be conside ed demanding in e ms o pa ien
com o . Dosime y me hods based on simpli ied acquisi ion
p o ocols a e eme ging [140]. Explici eco e y co ec ion,
using p io phan om imaging o sphe ical inse s o de e -
mina ion o he eco e y coe icien s, has been applied [12,
72, 192, 193, 195] and is a necessa y equi emen o ob ain
accu a e umou abso bed dose es ima es om SPECT/CT.
Be ween h ee and i e image acquisi ions ha e gene ally
been included, whe e he iming o he las acquisi ion has
a ied be ween 72 (3 d) and 168 h (7 d). To ou knowledge,
an explici compa ison o he impac o a la e acquisi ion
ime has no been made o umou dosime y. Howe e ,
he long biological hal -li e o umou s wa an s a la e ime
poin . Mos s udies used
S
- alues o uni densi y sphe es,
bu he LED app oach o oxel-based Mon e Ca lo we e
also used. The lesion mass was de e mined by delinea ion
in diagnos ic CT, SPECT/CT, o PET/CT.
Recommenda ions o dosime y
Tumou dosime y equi es SPECT/CT o ac i i y quan i i-
ca ion, p e e ably using sequen ial SPECT/CT, o o he wise
a hyb id plana -SPECT/CT app oach. Fo he la e , only
umou s ha a e no o e lapped wi h o he issues wi h a
p onounced ac i i y accumula ion can be included [192].
Applica ion o explici eco e y co ec ion is a p e- equi-
si e, hen aking he segmen a ion me hod and me hod o
olume y in o accoun . The iming o image acquisi ions
is simila o hose ecommended o kidney dosime y. The
long biological hal - ime o he umou e en ion emphasises
he need o a la e acquisi ion ime poin , see Figu e2.
Discussion
No able ad ances ha e been made in he ield o adionu-
clide he apy wi h he in oduc ion o new a ge ing mol-
ecules, adionuclides, equipmen , echnology, and me hods
o ac i i y quan i ica ion and dosime y. In pa allel, he a-
nos ic app oaches a e expanding and he e idence o dose-
e ec co ela ions inc easing [36, 74, 176, 196–198]. The
adionuclide 177Lu has excellen cha ac e is ics o he a-
peu ic imaging and a hal -li e ha sui s he pha macoki-
ne ics o many adio he apeu ic compounds. These aspec s
o e ad an ages o he anos ics and gi e he ounda ion o
pe sonalised, dosime y-guided he apy based on [177Lu]
Lu-SSRT and [177Lu]Lu-PSMA.
The abso bed dose ole ance o adiosensi i e o gans
and he umou abso bed doses equi ed o ea men e i-
cacy a e no ye es ablished. O gans a isk o he apy wi h
[177Lu]Lu-SSRT a e conside ed o be he kidneys, bone
ma ow, and possibly he pi ui a y gland. Fo [177Lu]Lu-
PSMA he apy, he p ima y o gans a isk a e he pa o id
and lac imal glands and bone ma ow. The adiobiological
eac ions o he bone ma ow and pa o id glands a e mani-
es ed bo h ea ly and la e, while kidneys and pi ui a y gland
a e gene ally ega ded as la e- esponding issues. Se e al
s udies ha e add essed dose-e ec in es iga ions o he a-
pies wi h [177Lu]Lu-SSRT and [177Lu]Lu-PSMA. Rela-
ionships be ween umou diame e o olume educ ion and
he abso bed dose e alua ed a he ime o bes esponse
we e obse ed in [177Lu]Lu-SSRT he apy o NET [72,
73]. Fo [177Lu]Lu-PSMA, a signi ican ly highe abso bed
dose was obse ed o PSA- esponde s e sus non espond-
e s when he mean abso bed dose was calcula ed ac oss all
me as ases [74]. Fo [177Lu]Lu-SSRT he apy o NETs,
dosime y-guided ials ha e been unde aken wi h he aim
o deli e ing a high umou abso bed dose whils espec -
ing he abso bed dose o BED ole ance o he kidneys [32,
40, 55, 152, 199]. Modi ica ions o he s anda d ea men
p o ocol ha e included ailo ing o he numbe o 7.4 GBq
ea men cycles o he indi idual pa ien o modula ion o
he adminis e ed ac i i y pe cycle.
1796 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
La ge in a- and in e -pa ien a iabili ies in abso bed
doses deli e ed du ing he apies wi h [177Lu]Lu-SSRT
and [177Lu]Lu-PSMA ha e been demons a ed in se e al
s udies, bo h ega ding umou s and no mal o gans [36,
140]. The obse ed a iabili y may pa ly be he di e si y
o dosime y me hods and p o ocols applied a di e en cen-
es, depending on expe ience, esou ces, and echnology
[135, 200, 201]. Howe e , he e is now an expanding in e es
in pe sonalised dosime y, and se e al ini ia i es ha e been
aken o imp o e aceabili y in abso bed-dose es ima es,
unce ain y assessmen , and consis ency ac oss cen es [82,
102, 138, 202]. Mo e p o ound easons o he obse ed
abso bed dose a iabili y a e he in insic cha ac e is ics o
he pa ien s, which go e n he adiopha maceu ical up ake
and washou o umou s and no mal o gans. As a conse-
quence, he adminis a ion o he same amoun o ac i i y
o all pa ien s leads o a wide ange o abso bed doses o
umou s and c i ical o gans. Gi en ha he he apeu ic e ec
is induced by ionising adia ion, i is expec ed ha pe son-
aliza ion, including dosime y, will lead o an imp o ed isk-
e sus-bene i balance.
The p ac ical implemen a ion o dosime y equi es imag-
ing a se e al ime poin s a e adminis a ion. Fo mos o
he issues o dosime y in e es in he apy wi h [177Lu]
Lu-SSRT and [177Lu]Lu-PSMA, we ind ha h ee acqui-
si ions, well sepa a ed in ime, a e su icien o cap u e
he pha macokine ics. Gene ally, he las image should
be acqui ed a a ime beyond he e ec i e hal -li e o he
Fig. 5 [68Ga]Ga-DOTA-TATE PET/CT o he head-and-neck egion o a NET pa ien . A ows indica e he adiopha maceu ical up ake in he
pi ui a y egion
Fig. 4 An e io maximum-
in ensi y p ojec ion o p e- he -
apy [68Ga]Ga-PSMA PET/CT
(le ) and [177Lu]Lu-PSMA-
he apy gamma came a image
( igh ) in a pa ien ea ed o
me as a ic p os a e cance .
La ge up ake can be obse ed in
he di e en sali a y glands and
in lac imal glands
1797Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
pa icula issue, and especially o umou s, his ex ends o
many days a e adminis a ion. Fo issues whe e he ypi-
cal pha macokine ics is well known om p e ious pa ien
coho s, p oposals ha e been made o using a lowe num-
be o e en a single acquisi ion ime poin o dosime y
[139–141]. The use o p e- he apeu ic 68Ga-PET/CT and i s
co ela ion o [177Lu]Lu-PSMA dosime y o umou s and
pa o id glands ha e also been in es iga ed [74]. Al hough
ecognising ha such app oaches o simpli ying he dosim-
e y p o ocol need ca e ul c oss- alida ion, hey o e ad an-
ages in e ms o b oadening he clinical use o dosime y.
In addi ion, pha macokine ic modelling may assis in u u e
dose planning [203, 204], as well as AI-based image seg-
men a ion me hods [120].
The apies wi h [177Lu]Lu-SSRT and [177Lu]Lu-PSMA
a e o be en isaged in an o e all amewo k o p ecision
medicine, in ol ing imaging, clinical da a, gene ics, dosim-
e y, and adiobiology. As wi h o he bioma ke s, dosime y
da a do no ep esen he only p edic i e pa ame e , bu i
is ega ded as one among o he s ha need o be aken in o
accoun . 177Lu is well sui ed o imaging and dosime y-
guided ea men schedules and can achie e he p e equisi es
o mul icen e compa abili y. In addi ion, om a adia ion
p o ec ion poin o iew, he e a e legisla i e obliga ions
o pe o ming dosime y o he apeu ic nuclea medicine
[205].
Conclusions
The e is a g owing body o da a on abso bed doses o o gans
and umou s in ea men s wi h [177Lu]Lu-SSRT and
[177Lu]Lu-PSMA. Toge he , such da a p o ide an imp o ed
unde s anding o hese he apies and may, in he long un,
lead o he de elopmen o dosime y-guided ea men p o-
ocols. The me hods ou lined in his epo a e no p esc ip-
i e bu aim o ha monise da a collec ion be ween cen es
in o de o ob ain compa able da a. The me hods should be
wi hin each o all cance cen es ha o e he apy wi h
177Lu-labelled compounds.
Appendix1
Table 6
Table 6 Summa y o dosime y da a o sali a y and lac imal glands in [177Lu]Lu-PSMA ea men o me as a ic cas a ion- esis an p os a e cance
Fi s au ho (yea ) Ligand # pa s Me hod o ac i i y quan i-
ica ion Me hod o AD calcula ion AD pe uni o adminis e ed
ac i i y (Gy/GBq) (Mean
± SD)
Mass (g) (mean ± SD)
[ ange] No. o conside ed
cycles Re .
Delke (2016) PSMA-617 5 Plana : 1 h, 24 h, 48 h, 72 h Sphe e S- alues Sali a y: 1.4 ± 0.5 38 ± 5 [31–43] 2 [12]
Kabasakal (2015) PSMA-617 7 Plana : 4 h, 24 h, 48 h,
120 h Sphe e S- alues
Mass om CT delinea ion Pa o id: 1.17 ± 0.31 - 1 (P e- he apeu ic
ace adm.) [18]
K a ochwil (2016) PSMA-617 4 Plana : 0.5 h, 3 h, 20 h, 44
h, 5−8 days Sphe e S- alues
Mass om PET/CT deline-
a ion
Pa o id: 1.28 ± 0.40
Submandibula : 1.48 ± 0.37 - 2 [54]
Baum (2016) PSMA I&T 30 Plana : 5 ime-poin s 0.5 h
o 118 h
SPECT/CT: be ween 45 h
and 118 h
Olinda .1 Pa o id: 1.3 ± 2.3, max: 9.5 - 1 [187]
1798 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3

AD, abso bed dose; VDK, oxel dose ke nel
Table 6 (con inued)
Fi s au ho (yea ) Ligand # pa s Me hod o ac i i y quan i-
ica ion Me hod o AD calcula ion AD pe uni o adminis e ed
ac i i y (Gy/GBq) (Mean
± SD)
Mass (g) (mean ± SD)
[ ange] No. o conside ed
cycles Re .
Sca pa (2017) PSMA-617 10 Hyb id ( o abdomen):
Plana : 0.5 h, 4 h, 24 h, 72
h, 96 h
SPECT/CT: 24 h
Sphe e S- alues
Mass om PET/CT deline-
a ion
Pa o id: 0.56 ± 0.25, max:
1.040
Submandibula : 0.50 ±
0.15, max: 0.660
Lac imal: 1.01 ± 0.69,
max: 2.7
Volumes: Pa o id: 24.98
mL, max: 34 mL
Submandibula : 8.63 mL,
max:10.35 mL
1 [206]
Hohbe g (2016) DKFZ-
PSMA-617 9 Plana : 0.5 h, 24 h, 48 h, 72
h, 168 h Olinda .1 ( AFs o
hy oid wi h mass
adjus men )
Fo lac imal: sphe e
S- alues
Fixed masses o sali a y
and lac imal
Sali a y (pa o id + subman-
dibula ): 0.72 ± 0.14,
max: 0.898
Lac imal: 2.82 ± 0.76,
max: 4.04
Sali a y: 85
Lac imal: 1.4 1 [67]
Fendle (2017) PSMA-617 10 SPECT/CT: 24 h, 48 h, 72 h No de ails Sali a y: 1.0 ± 0.6 - 2 [22]
Kabasakal (2017) PSMA-617 6 Hyb id: Plana : 4 h, 24 h,
48 h, 120 h
SPECT/CT: 24 h
Sphe e S- alues
Mass om CT delinea ion Pa o id: 1.9 ± 1.19 - 1 [21]
Okamo o (2017) PSMA I&T 18 Plana : 30–120 min, 24 h,
48 h, 72 h, 6–8 days Sphe e S- alues
Mass om PET/CT deline-
a ion
Pa o id: 0.55 ± 0.14, max:
0.84
Submandibula : 0.64 ± 0.40,
max: 1.70
Lac imal: 3.8 ±1.4, max:
7.03
Fo one gland:
Pa o id: 19.1 ± 5.7
[8.0–35.6]
Submandibula : 8.2 ± 1.9
[4.2–14.3]
Lac imal: 0.45 ± 0.12
[0.25–0.78]
F om 1 o 4 [23]
Yada (2017) DKFZ-
PSMA-617 26 Plana : 0.5 h, 3.5 h, 24 h, 48
h, 72 h, 96 h, 120 h, 144
h, 168 h
Sphe e S- alues
Mass om SPECT/CT
delinea ion
Pa o id: 1.31 ± 0.22
Submandibula : 1.11 ± 0.39
Sali a y glands (Pa o id +
Submandibula ): 1.24 ±
0.27, max: 1.85
- 1 [188]
Viole (2019) PSMA-617 30 SPECT/CT: 1 h, 24 h, 96 h 2 me hods: Voxel-based,
VDK
Sphe e S- alues (mass om
PET/CT delinea ion)
Pa o id: 0.58 ± 0.43, max:
1.87
Submandibula : 0.44 ±
0.36, max: 1.75
Lac imal: 0.36 ± 0.18,
max: 0.81
- 1 [74]
1799Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
Appendix2
Tables 7, 8
Table 7 Summa y o dosime y da a o neu odendoc ine umou s ea ed wi h [177Lu]Lu-DOTA-TATE, excep whe e explici ly s a ed o he wise
Fi s au ho (yea ) # pa s Me hod o ac i i y
quan i ica ion E ec i e hal -li e wash-
ou (h) Me hod o AD calcula-
ion AD pe uni adminis e ed
ac i i y (Gy/GBq) Re .
Weh mann (2007) 61 Plana : close o adm., 3 h,
20 h, 44 h, 68 h Mean ± SD: 75.5 ± 20.9 Sphe e S- alue. Volume/
mass om CT delinea ionMean ± SD: 9.7 ± 11 [171]
Weh mann (2007)
[177Lu]Lu-DOTA-
NOC
8 As abo e Mean ± SD: 66.7 ± 16.6 As abo e Mean ± SD: 7.5 ± 8.3
Ga ka ij (2010) 7 Hyb id: Plana : 1 h, 24 h,
96 h, 168 h
SPECT/CT: 24 h o 96 h
- LED, olume/mass om
SPECT/CT delinea ion,
mass om CT
Median ( ange): 6.7
(0.1–20) [99]
Jackson (2013) 17 SPECT/CT: 4 h, 24 h,
and 72 h - Voxel-based, DPK AD pe cycle: 21.4 ± 9.7
Gy (6.6–10.2 GBq pe
cycle)
[190]
Ilan (2015) 24 SPECT/CT: 24 h, 96 h,
and 168 h - Sphe e S- alue, olume/
mass om SPECT/CT
delinea ion
Median ( ange): 6.8
(1.3–23) ( o i s cycle) [72]
Kupi z (2017) 16 Plana and SPECT/CT:
be ween 4 h and 168 h,
all pa s 4 h, 24 h, and
72 h
- Sphe e S- alues. Volume/
mass om CT delinea ionPlana : mean ± SD: 5.3
± 6.3
Median ( ange): 3.1
(0.18–25)
Hyb id plana -SPECT/CT:
mean ± SD: 3.1 ± 2.2
Median ( ange): 2.7
(0.20–7.9)
SPECT/CT: mean ± SD:
2.6 ± 1.5
Median ( ange): 2.7
(0.16–5.4)
[191]
Ro h (2018) 6 Plana and SPECT/CT: 1
h, 24 h, 96 h, 168 h F om SPECT/CT:
Mean: 96 h
Range: 84 h – 117 h
LED, olume om
SPECT/CT delinea ion,
mass om CT
Hyb id plana -SPECT/
CT: mean: 3.6
SPECT/CT: mean: 3.9
Range: 1.3–7.3
[192]
Jahn (2019) 25 SPECT/CT: 24 h, 96 h,
and 168 h - Sphe e S- alues.
Volume/mass om
SPECT/CT delinea ion
Mean: 4.7
Median ( ange): 3.8
(1.3–15.5)
[193]
Rudisile (2019) 35 SPECT/CT: 24 h, 48 h,
and 72 h - Sphe e S- alues.
Volume/mass om
SPECT/CT delinea ion
Mean ± SD: 2.3 ± 1.83 [194]
Del P e e (2019) 34 SPECT/CT: 4 h, 24 h,
and 72 h - Ac i i y concen a ion,
small VOI in high-
up ake egion. Sphe e
S- alue
Median ( ange): 4.4
(0.1–32.0) [40]
Jahn (2021) 48 SPECT/CT: 24 h, 96 h,
and 168 h - Sphe e S- alues.
Volume/mass om
SPECT/CT delinea ion
Medians o cycles 1, 2,
3, 4, 5,
≥
6 ( e ie ed
om g aph)
Panc ea ic (P): 6.6, 3.9,
2.8, 2.7, 2.6, 1.8
Small-in es ine (SI): 4.6,
4.9, 4.1, 3.4, 4.1, 2.8
Range all cycles, g ade P
and SI: 0.7–23
[73]
1800 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
Table 7 (Con inued)
Fi s au ho (yea ) # pa s Me hod o ac i i y
quan i ica ion E ec i e hal -li e wash-
ou (h) Me hod o AD calcula-
ion AD pe uni adminis e ed
ac i i y (Gy/GBq) Re .
Ro h (2021) 41 Hyb id: Plana : 1 h,
24 h, 96 h, 168
hSPECT/CT: 24 h
G ade 1 mean: 103 h, CI:
96–109 h
G ade 2 mean: 81 h, CI:
73–90 h
Voxel-based Mon e
Ca lo, olume om
SPECT/CT delinea ion,
mass om CT
Medians o cycles 1, 2,
3, 4, 5,
≥
6
G ade 1: 4.4, 4.4, 4.1,
3.5, 3.8, 3.2
G ade 2: 3.6, 3.1, 2, 1.6,
1.1, 0.8
Range all cycles, g ade 1
and 2: 0.3–10
[195]
AD, abso bed dose; DPK, dose-poin ke nel; CI, con idence in e al
Table 8 Summa y o dosime y da a o umou s in [177Lu]Lu-PSMA ea men o me as a ic cas a ion- esis an p os a e cance
AD, abso bed dose
Fi s au ho (yea ) Ligand # pa s Me hod o ac i i y quan-
i ica ion E ec i e
hal -li e
washou
(h)
Me hod o AD calcula-
ion AD pe uni adminis e ed
ac i i y (Gy/GBq) (mean
± SD)
Re .
Delke (2016) PSMA-617 5 SPECT/CT: 1 h, 24 h, 48 h,
and 72 h -Sphe e S- alues. Mass
om SPECT/CT deline-
a ion
Bone me as ases: 5.3 ±
3.7
Lymph node me as ases:
4.2 ± 5.3
So issue me as ases: 2.1
± 0.8
[12]
Baum (2016) PSMA I&T 30 Plana : 5 ime poin s
0.5–118 h Median
( ange):
51
(14–160)
Olinda .1 Median ( ange): 3.3
(0.03–78) [187]
Sca pa (2017) PSMA-617 10 Plana : 0.5 h, 4 h, 24 h, 72
h, and 96 h -Sphe e S- alues. Mass
om
68Ga-PET/CT delinea-
ion.
All: 2.8 ± 0.5 ( ange
1.1–7.2)
Bone me as ases: 3.40 ±
1.94
Lymph node me as ases:
2.55 ± 0.42
Visce al lesions: 2.43 ±
0.78
[176]
Okamo o (2017) PSMA I&T 18 Plana : 1 h, 24 h, 6–8 days,
some p s 48 and 72 h -Sphe e S- alues. Mass
om
CT delinea ion.
All: 3.2 ± 2.6 ( ange
0.22–12)
Bone me as ases: 3.40 ±
2.7
Lymph node me as ases:
3.2 ± 2.2
Li e me as ases: 1.2 ±
0.67
Lung me as ases: 1.75 ±
0.92
[23]
Viole (2019) PSMA-617 30 SPECT/CT (2- o 3-bed-
posi ions) 4 h, 24 h, and
96 h
-Voxel-based, DPK. Mean
AD ac oss all lesions
ecei ing > 5 Gy.
Bone me as ases: 5.28 ±
2.46
Lymph node me as ases:
3.91 ± 3.93
[74]
1801Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3
Abb e ia ions PSMA:P os a e-speci ic memb ane an igen; [177Lu]
Lu-PSMA:177Lu-labelled small-molecule PSMA- a ge ing ligands;
SSR:Soma os a in- ecep o ; [177Lu]Lu-SSRT:177Lu-labelled soma-
os a in- ecep o a ge ing ligands; BED:Biologically e ec i e dose;
EBRT:Ex e nal-beam adio he apy; TIA:Time-in eg a ed ac i i y;
TAC :Time-ac i i y cu e; TEW:T iple-ene gy window; FOV:Field o
iew; ROI:Region o in e es ; VOI:Volume o in e es ; PVE:Pa ial-
olume e ec ; AF:Abso bed ac ion
Acknowledgemen s The guidelines we e b ough o he a en ion o
he ele an EANM Commi ees and he Na ional Socie ies o Nuclea
Medicine. The commen s and sugges ions om he EANM Radia ion
P o ec ion Commi ee and he F ench and B i ish Na ional Socie ies
a e highly app ecia ed and ha e been conside ed o his guideline.
Funding Open access unding p o ided by Lund Uni e si y.Eco-
nomic suppo wasg an ed by he Swedish Cance Socie y (180747,
211754Pj01H) andM s. Be a Kamp ad’s Founda ion (BKS-2020-13)
(Sjög een Gleisne ).
Decla a ions
E hics app o al All p ocedu es pe o med in s udies in ol ing human
pa icipan s we e in acco dance wi h he e hical s anda ds o he ins i-
u ional and/o na ional esea ch commi ee and wi h he p inciples o
he 1964 Decla a ion o Helsinki and i s la e amendmen s o compa-
able e hical s anda ds. This a icle does no desc ibe any s udies wi h
animals pe o med by any o he au ho s.
Open Access This a icle is licensed unde a C ea i e Commons A i-
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1802 Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
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Au ho s and A ilia ions
Ka a inaSjög eenGleisne 1 · NicolasChouin2· PabloMinguezGabina3,4· F ancescoCicone5,6· Sil anoGnesin7·
Ca olineS okke8,9· Ma kKonijnenbe g10,11· Ma aC emonesi12· F ede ikA.Ve bu g10· Pe e Be nha d 13,14·
U aEbe lein15· Jona hanGea 16
1 Medical Radia ion Physics, Clinical Sciences Lund, Lund
Uni e si y, Lund, Sweden
2 Uni e si é de Nan es, CNRS, Inse m, Oni is, CRCINA,
Nan es, F ance
3 Depa men o Medical Physics andRadia ion P o ec ion,
Gu u ze a-C uces Uni e si y Hospi al/Bioc uces Heal h
Resea ch Ins i u e, Ba akaldo, Spain
4 Depa men o Applied Physics, Facul y o Enginee ing,
UPV/EHU, Bilbao, Spain
5 Depa men o Expe imen al andClinical Medicine,
Neu oscience Resea ch Cen e, PET/RM Uni , “Magna
G aecia” Uni e si y o Ca anza o, Ca anza o, I aly
6 Nuclea Medicine Uni , Uni e si y Hospi al “Ma e Domini,
Ca anza o, I aly
7 Ins i u e o Radia ion Physics, Lausanne Uni e si y Hospi al,
Uni e si y o Lausanne, Lausanne, Swi ze land
8 Di ision o Radiology andNuclea Medicine, Oslo
Uni e si y Hospi al, Oslo, No way
9 Depa men o Physics, Uni e si y o Oslo, Oslo, No way
10 Depa men o Radiology andNuclea Medicine, E asmus
Medical Cen e , Ro e dam, heNe he lands
11 Depa men o Medical Imaging, Radboud Uni e si y
Medical Cen e , Nijmegen, heNe he lands
12 Radia ion Resea ch Uni , Depa men o Medical Imaging
andRadia ion Sciences, Is i u o Eu opeo di Oncologia,
IRCCS, Milan, I aly
13 Depa men o Medical Radia ion Sciences, Ins i u e
o Clinical Sciences, Sahlg enska Academy, Go henbu g
Uni e si y, Go henbu g, Sweden
14 Depa men o Medical Physics andBiomedical Enginee ing,
Sahlg enska Uni e si y Hospi al, Go henbu g, Sweden
15 Depa men o Nuclea Medicine, Uni e si y Hospi al
Wü zbu g, Wü zbu g, Ge many
16 Join depa men o Physics, Royal Ma sden NHSFT
andIns i u e o Cance Resea ch, Su on, UK
1809Eu opean Jou nal o Nuclea Medicine and Molecula Imaging (2022) 49:1778–1809
1 3