Academic Edi o : Joon-Yong Chung
Recei ed: 2 May 2025
Re ised: 18 June 2025
Accep ed: 30 June 2025
Published: 2 July 2025
Ci a ion: S ani´c, J.; Šo i´c, I.;
Jo ano ic, L.; Ma i´c, I.Z.; Niki´c, P.;
Niki o i´c, M. The Role o P edic i e
Bioma ke s in Mode n P os a e Cance
Radio he apy: A Li e a u e Re iew on
Pe sonalised T ea men S a egies and
he P edic ion o Ad e se E ec s. Li e
2025,15, 1062. h ps://doi.o g/
10.3390/li e15071062
Copy igh : © 2025 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license
(h ps://c ea i ecommons.o g/
licenses/by/4.0/).
Re iew
The Role o P edic i e Bioma ke s in Mode n P os a e Cance
Radio he apy: A Li e a u e Re iew on Pe sonalised T ea men
S a egies and he P edic ion o Ad e se E ec s
Jelena S ani´c 1,2,*, I ana Šo i´c 3, Luka Jo ano ic 1, I ana Z. Ma i´c 4, P ed ag Niki´c 2,5 and Ma ina Niki o i´c 1,2
1Depa men o Radia ion Oncology, Ins i u e o Oncology and Radiology o Se bia, Pas e o a 14,
11000 Belg ade, Se bia
2Facul y o Medicine, Uni e si y o Belg ade, D . Subo i´ca S . 8, 11000 Belg ade, Se bia
3Depa men o Radiological Diagnos ics, Ins i u e o Oncology and Radiology o Se bia, Pas e o a 14,
11000 Belg ade, Se bia
4Depa men o Expe imen al Oncology, Ins i u e o Oncology and Radiology o Se bia, Pas e o a 14,
11000 Belg ade, Se bia
5Clinic o U ology, Uni e si y Clinical Cen e o Se bia, 11000 Belg ade, Se bia
*Co espondence: [email p o ec ed]; Tel.: +381-61-188-43-32
Abs ac
P os a e cance is one o he mos p e alen malignancies in men, posing a signi ican
public heal h challenge due o i s high incidence and long- e m ea men - ela ed oxici ies.
Long-li ed pa ien s o en expe ience p olonged side e ec s ha can se e ely diminish hei
quali y o li e. Despi e ad ancemen s in adio he apy echniques like IMRT and VMAT,
some pa ien s s ill expe ience acu e and la e side e ec s. Cu en ea men p o ocols do no
accoun o indi idual a iabili y in no mal- issue adiosensi i i y, highligh ing he need
o p edic i e ools and a pe sonalised ea men app oach. Gene ic ac o s and molecula
egula o s like mic oRNAs (miRNAs) con ibu e o hese a ia ions by in luencing DNA
epai , in lamma ion, and apop osis. This e iew explo es po en ial bioma ke s o a-
dio oxici y, ocusing on immune- ela ed ac o s such as IL-6 and TGF-
β
1, SNPs in luencing
adiosensi i i y, miRNAs in ol ed in adia ion esponses, and unc ional assays including
he adia ion-induced lymphocy e apop osis (RILA) es . These app oaches o e p omising
ools o iden i ying adiosensi i e pa ien s and enabling isk-adap ed adio he apy.
Keywo ds: p os a e cance ; adio oxici y; adiosensi i i y bioma ke s; pe sonalised ea men
1. In oduc ion
P os a e cance is he second mos common malignan umou , a e lung cance , and
he i h leading cause o cance dea h in men wo ldwide. A some poin in hei li es,
a ound one in eigh men may ecei e a diagnosis o his cance . Da a sugges ha p os a e
cance imposes a subs an ial public heal h bu den due o he signi ican p opo ion o olde
men in he gene al popula ion. The incidence o p os a e cance is h ee imes g ea e in
de eloped coun ies han in de eloping coun ies [1–3].
In Se bia, he e has been a con inuous inc ease in cance incidence and mo ali y, wi h
41,578 new cance cases and 19,350 new cance - ela ed dea hs in 2022. P os a e cance was
he i h mos common cance bo h in e ms o incidence and p e alence, and i anks hi d
in e ms o incidence and mo ali y among Se bian men. This un a ou able epidemiological
si ua ion, along wi h he ising numbe o new p os a e cance pa ien s, can be a ibu ed o
he lack o a na ional sc eening p og amme, limi ed media e o s o aise awa eness among
Li e 2025,15, 1062 h ps://doi.o g/10.3390/li e15071062
Li e 2025,15, 1062 2 o 21
men, and an o e all lack o su icien public in o ma ion [
4
]. The di e ences in p os a e
cance incidence e sus mo ali y a e la gely in luenced by he ex en o PSA sc eening,
which p edominan ly de ec s cance a a localised s age when ea men ou comes a e mo e
a ou able [5].
In gene al, when diagnosed on ime, mos pa ien s wi h p os a e cance ha e a long li e
expec ancy a e diagnosis. Fu he mo e, imp o ed he apeu ic al e na i es o localised
p os a e cance ha e led o highe cu e a es, wi h a ious ea men op ions achie ing
simila ou comes bu di e en oxici y p o iles. As a esul , some pa ien s may ne e
expe ience heal h issues o die om complica ions di ec ly ela ed o he p og ession
o hei disease. Howe e , many pa ien s do li e longe wi h complica ions om hei
ea men , which g ea ly a ec s hei quali y o li e. De e mining he incidence and se e i y
o he oxici y o each he apeu ic modali y is c i ical o making decisions abou app op ia e
ea men . Conside ing all ha is men ioned abo e, long- e m adia ion-induced oxici y is
eme ging as a c i ical conce n ha canno be o e looked [6,7].
2. The Mode n Radio he apy o P os a e Cance
P os a e cance is bes ea ed by a mul idisciplina y eam o specialis s, consis ing
o u ologis s, adia ion oncologis s, and medical oncologis s, who collabo a e o p o ide
comp ehensi e ca e. The ea men modali y is decided based on he s age o he disease,
his opa hological cha ac e is ics o umou s, su i al bene i s, and possible side e ec s
o each o he he apeu ic op ions. Howe e , ega dless o he s age o he disease, a pa-
ien ’s socioeconomic s a us, pe sonal p e e ences, and clinical p ac ice pa e ns a a ious
medical cen es ep esen impo an ac o s in selec ing he app op ia e he apy [
6
,
8
]. Cu -
en ea men ecommenda ions o p os a e cance , acco ding o he NCCN guidelines,
a e summa ised in Table 1and emphasise a isk-adap ed app oach, anging om ac i e
su eillance in low- isk cases o mo e-agg essi e ea men s such as su ge y, adia ion
he apy, and and ogen dep i a ion he apy in in e media e- and high- isk pa ien s [9].
Table 1. P os a e cance ea men ecommenda ions based on isk g oup (adap ed om NCCN
Guidelines, Ve sion 1.2025) [9].
Risk G oup TNM S age PSA
(ng/mL)
Gleason
Sco e/G ade G oup T ea men Op ions
Ve y low T1c <10
GS ≤6 (G ade
G oup 1), <3 posi i e
biopsy co es, PSA
densi y < 0.15
- Ac i e su eillance (p e e ed)
- Radical p os a ec omy
(selec ed cases)
- B achy he apy ( a e)
Low T1-T2a <10 GS ≤6 (G ade
G oup 1)
- Ac i e su eillance (p e e ed)
- Radical p os a ec omy
- EBRT o b achy he apy
Fa ou able
in e media e T1-T2b 10–20
GS 3 + 4 (G ade
G oup 2) OR <50%
biopsy co es posi i e
- Radical p os a ec omy ±lymph
node dissec ion
- EBRT ±sho - e m ADT (4–6 mo)
- B achy he apy ±EBRT
Un a ou able
in e media e
T2c o
≥
50% co es + o
GS 4 + 3 (G ade
G oup 3) o PSA 10–20
10–20
GS 4 + 3 (G ade
G oup 3) o mul iple
in e media e ac o s
- Radical p os a ec omy ±pel ic
LN dissec ion
- EBRT + sho - e m ADT
- EBRT + b achy he apy boos
High T3a o PSA > 20 o
GS 8 (G ade G oup 4) >20 GS 8 (G ade
G oup 4)
- EBRT + long- e m ADT (2–3 yea s)
- EBRT + b achy he apy + ADT
- Radical p os a ec omy (selec cases,
as pa o mul imodal ea men )
Li e 2025,15, 1062 3 o 21
Table 1. Con .
Risk G oup TNM S age PSA
(ng/mL)
Gleason
Sco e/G ade G oup T ea men Op ions
Ve y high
T3b-T4 o GS 9–10
(G ade G oup 5) o
>4 biopsy co es wi h
G ade G oup 4 o 5
Any GS 9–10 (G ade
G oup 5)
- EBRT + long- e m
ADT ±abi a e one
- EBRT + b achy he apy + ADT
- Radical p os a ec omy
(selec cases)
Regional (N1) Any T, N1, M0 Any Any
- EBRT + long- e m ADT
- ADT alone (non-cu a i e se ing)
- Conside abi a e one + ADT
Me as a ic
(M1) Any T, any N, M1 Any Any
- ADT + no el ho monal he apy
(abi a e one, enzalu amide,
and apalu amide)
-±Doce axel (in
high- olume disease)
- Bone-p o ec ing agen s (zoled onic
acid o denosumab)
- Pallia i e adio he apy-Lu-177
PSMA, PARP inhibi o s
(selec ed mCRPC)
GS: Gleason sco e; EBRT: ex e nal beam adia ion he apy; ADT: and ogen dep i a ion he apy; LN: lymph node;
and mCRPC: me as a ic cas a ion- esis an p os a e cance .
I is impo an o emphasise ha in he e a o pe sonalised oncology he apy, he
in oduc ion o p ecise diagnos ic echnologies, along wi h he inc easing a ailabili y o
sa e and e ec i e localised non- o minimally in asi e ea men op ions, has led o a ise
in he incidence o and clinical in e es in oligome as a ic p os a e cance . The de ini ion
o oligome as a ic p os a e cance is somewha inconsis en ; i anges om he p esence
o a single me as asis o be ween h ee and i e me as ases. Howe e , mos p ospec i e
s udies use he de ini ion o h ee o ewe me as a ic lesions wi h p ede ined loca ions [
10
].
Mo eo e , he ea men app oach o hese pa ien s is inc easingly shi ing owa ds a
mo e-agg essi e s a egy. Nume ous e ospec i e s udies ha e demons a ed ha in
he me as a ic s age o he disease, p ocedu es such as adical p os a ec omy and he
local adio he apy o me as ases can be pe o med wi h minimal isk o oxici y, and may
imp o e he apeu ic ou comes.
The managemen o oligome as a ic p os a e cance , cha ac e ised by a limi ed numbe
o me as a ic si es, emains challenging, wi h cy o educ i e su ge y and adio he apy being
he main ea men op ions. Recen esea ch sugges s ha cy o educ i e su ge y may o e
be e cance -speci ic and o e all su i al compa ed o adio he apy, al hough p og ession-
ee su i al appea s o be simila be ween he wo. Bo h ea men s ha e manageable side
e ec s, suppo ing hei use in clinical p ac ice. These indings highligh he impo ance o
pe sonalised ea men decisions and he need o u he s udies o e ine he apy o his
pa ien g oup [11].
Radio he apy, whe he used alone o in conjunc ion wi h sys emic he apy and su ge y,
plays a c ucial ole in he managemen o p os a e cance , educing he isk o local ecu -
ence and imp o ing o e all su i al. I is u ilised in he ea men o nea ly 50% o p os a e
cance pa ien s, and app oxima ely 40% o long- e m cance su i o s ha e ecei ed a-
dio he apy a some s age o hei ea men jou ney [
12
,
13
]. Depending on he ea men
goal, adia ion he apy can be classi ied as adical, pos ope a i e (adju an o sal age), o
pallia i e. In e ms o i s deli e y, adia ion he apy o p os a e cance can be adminis e ed
as ex e nal beam adia ion he apy (EBRT) o as b achy he apy (BT). In adical ea men ,
Li e 2025,15, 1062 4 o 21
adio he apy is deli e ed in one, wo, o h ee phases depending on he a ge olume:
p os a e only (one phase), p os a e and seminal esicles ( wo phases), o p os a e, seminal
esicles, and egional lymph nodes ( h ee phases). Con en ional ac iona ion (1.8–2 Gy
pe ac ion) is used, wi h o al doses anging om 72 up o 80 Gy, based on ins i u ional
p o ocols. In pos ope a i e se ings, adio he apy is usually deli e ed in a single phase wi h
64–66 Gy o he p os a e bed o up o 70 Gy o mac oscopic disease. I p ophylac ic nodal
i adia ion is indica ed, ea men may be deli e ed in wo phases [
6
,
8
,
9
]. Ex e nal beam
adia ion he apy is cu en ly one o he mos -e ec i e ea men s o localised p os a e
cance , being used in almos one- hi d o men wi h his diagnosis. When planning adio-
he apy, he isk o adia ion-induced damage o nea by heal hy issues de e mines he
dose limi s. The aim is o deli e he highes possible dose o he umou while minimising
exposu e o su ounding no mal issue. Mode n, highly p ecise echniques like in ensi y-
modula ed adia ion he apy (IMRT) and olume ic modula ed a c he apy (VMAT) a e
conside ed he gold s anda d o ea ing pa ien s wi h p os a e cance . These ad anced
adio he apy echniques enable he p ecise deli e y o high adia ion doses, up o 80 Gy,
while minimising exposu e o su ounding heal hy issue (Figu es 1and 2) [14–16].
Figu e 1. Radical p os a e cance adio he apy using he VMAT echnique: he clinical a ge
olume (CTV), ma ked in ed, was delinea ed using co- egis e ed magne ic esonance imaging (MRI),
ensu ing p ecise mapping and accu a e ea men deli e y (ma e ial om he Ins i u e o Oncology
and Radiology o Se bia).
Al hough su ounding o gans a isk, especially he bladde and ec um, a e be e
p o ec ed du ing adia ion he apy, some adia ion s ill a ec s heal hy issue. In p os a e
cance adio he apy, he mos clinically signi ican oxici ies a e hose ha lead o ea men
in e up ions, he eby p olonging he o e all cou se o he apy and ad e sely a ec ing
pa ien s’ quali y o li e. Gas oin es inal (GI) oxici y a ises om damage o he ec um
and bowel, while geni ou ina y (GU) oxici y esul s om inju y o he u e h a, bladde , o
p os a e. Gas oin es inal symp oms can ange om mild issues such as inc eased bowel
equency o mo e-se e e complica ions like ec al bleeding, anal pain, o is ula o ma ion.
Geni ou ina y oxici y may p esen as equen u ina ion, haema u ia, dysu ia, u ina y
incon inence, o u e h al s ic u e [6–8].
Li e 2025,15, 1062 5 o 21
Figu e 2. The medical linea accele a o (LINAC) o IMRT and VMAT adio he apy (ma e ial om
he Ins i u e o Oncology and Radiology o Se bia).
Consequen ly, 5–10% o pa ien s may expe ience se e e side e ec s, esul ing in
complica ions such as ib osis, nec osis, a ophy, and ascula damage. Addi ionally,
among he se ious long- e m ad e se e ec s o adio he apy a e seconda y malignancies.
Al hough seconda y cance s a e uncommon a e adio he apy o pel ic malignancies
such as p os a e cance , hey s ill ep esen a po en ially se ious la e ad e se e ec , e en in
he e a o ad anced adio he apy echniques [
17
,
18
]. Recen s udies on adia ion oxici y
ha e iden i ied mul iple ac o s ha may in luence he isk o complica ions ollowing
adio he apy. These include he speci ic adio he apy echnique used, pa ien age, smoking
and alcohol consump ion habi s, and clinical pa ame e s, such as disease s age, a his o y o
ansu e h al esec ion o he p os a e, p io abdominal o pel ic su ge ies, and he p esence
o como bidi ies [
19
–
25
]. Despi e an imp o ed unde s anding o hese con ibu ing ac o s,
indi idual adiosensi i i y emains unp edic able. Cu en adio he apy p o ocols do
no accoun o his a iabili y, highligh ing he need o eliable bioma ke s o assess
indi idual adiosensi i i y p io o ea men [18].
3. Indi idual Radiosensi i i y: The Role o Bioma ke s and P edic i e
Assays in Pe sonalising Radio he apy o P os a e Cance Pa ien s
In he e a o pe sonalised medicine, one o he main challenges in adia ion oncology
is he disco e y o bioma ke s ha e lec indi idual sensi i i y o adia ion. Since i is
es ima ed ha 80% o indi idual di e ences in adio he apy oxici y o no mal issues a e
a ibu ed o a combina ion o gene ic and epigene ic ac o s, he e is an inc easing need o
a speci ic es ha can accu a ely e lec indi idual adiosensi i i y and p edic he likeli-
hood o adio he apy- ela ed oxici y [
26
]. These bioma ke s a e essen ial o de e mining
adiosensi i i y p io o ea men and enabling indi idualised isk assessmen , which
could in u n help op imise ea men planning. Fo example, i would allow o highe
umou doses in pa ien s wi h adia ion- esis an no mal issue, while hose a g ea e
isk o se e e adia ion oxici y could be conside ed o al e na i e app oaches. These
Li e 2025,15, 1062 6 o 21
may include modi ying he adio he apy egimen (e.g., al e na i e ac iona ion schemes),
swi ching o a di e en ea men modali y (such as su ge y ins ead o adio he apy), o
in oducing pha macological he apy ea ly o manage symp oms [27,28].
Cellula damage caused by ionising adia ion igge s he ac i a ion o p o eins in-
ol ed in DNA epai , cell dea h, in lamma ion, and o he pa hophysiologic esponses,
which con ibu e o he de elopmen o adio he apy side e ec s [
29
]. These e ec s a e
classi ied as acu e, subacu e, o la e: acu e e ec s appea wi hin 1–2 weeks o ea men
due o in lamma ion o he loss o apidly di iding cells, while la e e ec s, such as ib osis,
ascula inju y, o e en seconda y cance s, may appea mon hs o yea s la e as a esul o
slowe issue esponses and esidual DNA damage [28,29].
Po en ial bioma ke s a e measu able biological indica o s ha e lec no mal phys-
iological p ocesses, pa hological changes, o esponses o en i onmen al o he apeu ic
exposu es [
29
]. In he con ex o adio he apy, bioma ke s o en de ec ed in blood o sali a
can e eal molecula e en s igge ed by ionising adia ion, such as DNA damage, in lam-
ma ion, o cell dea h pa hways. These biological ac o s a e aluable o unde s anding
indi idual adiosensi i i y, op imising ea men plans, and minimising oxici y. P edic i e
assays a e unc ional es s, o en pe o med
in i o
, ha e alua e how a pa ien ’s cells
espond o ionising adia ion. These assays commonly assess endpoin s such as clonogenic
su i al, DNA damage and epai capaci y, ch omosomal abe a ions, o adia ion-induced
apop osis. Thei p ima y objec i e is o p edic he isk o no mal- issue oxici y and aid in
he pe sonalisa ion o adio he apy. By assessing he dynamic cellula esponse o adia ion,
p edic i e assays o e di ec insigh in o an indi idual’s suscep ibili y o adia ion-induced
issue damage [27–29].
3.1. The Role o Cy okines as Po en ial Bioma ke s o Radia ion Toxici y
Cy okines play a cen al ole in he molecula esponse o ionising adia ion, ac ing as
key media o s o in lamma ion and issue damage. In lamma o y p ocesses a e inc easingly
ecognised as key modula o s o malignan umou esponses o adio he apy [
30
]. These
immuno egula o y p o eins, including in e e ons (IFNs), in e leukins (ILs), and g ow h
ac o s, acili a e communica ion be ween cells and can igge au oc ine, pa ac ine, o
endoc ine esponses [
30
]. Radia ion-induced issue inju y leads o changes in cy okine
exp ession, which closely co ela e wi h bo h acu e and la e oxici ies h ough he ac i a ion
o in lamma o y signalling pa hways. Ci cula ing cy okine le els he e o e e lec he ex en
o cellula and issue damage caused by adia ion. Because o his, cy okines a e inc easingly
ecognised as aluable bioma ke s o e alua ing no mal su ounding issue eac ions o
adio he apy. The in e play be ween p o- and an i-in lamma o y cy okines plays a key
ole in shaping he apeu ic esponse, in luencing he se e i y o adia ion-induced side
e ec s and he po en ial o umou esis ance [
31
]. In p os a e cance , in pa icula , al e ed
cy okine p o iles ha e been linked o adia ion-induced oxici y, highligh ing hei po en ial
o guiding pe sonalised ea men app oaches [30,31].
Ea ly s udies we e he i s o highligh he ole o cy okines in adia ion-induced
oxici y, showing in p eclinical and clinical lung models ha le els o IL-1, ans o ming
g ow h ac o (TGF)-
β
, and umou nec osis ac o (TNF)-
α
inc eased immedia ely a e
adia ion exposu e, while pe sis en ly ele a ed TGF-
β
was associa ed wi h a highe isk
o pulmona y ib osis [
32
]. P e ious s udies ha e epo ed ele a ed ci cula ing le els o
p oin lamma o y cy okines, including IFN-
γ
, IL-6, TNF-
α
, and IL-4, du ing he cou se o
adio he apy [
32
]. Fu he mo e, in pa ien s wi h p os a e cance , adio he apy has been
shown o induce an in lamma o y esponse, cha ac e ised by inc eased se um concen a-
ions o IL-6, IL-8, TNF-
α
, and TGF-
β
[
33
]. The s udy conduc ed by Ch is ensen e al. on a
coho o 42 pa ien s wi h p os a e cance ea ed wi h IMRT [
30
] demons a ed a signi ican
Li e 2025,15, 1062 7 o 21
ise in se um le els o IFN-
γ
and IL-6 du ing adio he apy in p os a e cance pa ien s.
Addi ionally, ele a ed le els o IL-1 and IL-2 we e linked o an inc eased isk o de eloping
geni ou ina y and gas oin es inal adio oxici y. Thei obse a ions sugges ha IL-6, IFN-
γ
, IL-1, and IL-2 may se e as key cy okine ma ke s associa ed wi h adia ion esponses,
pa icula ly in he de elopmen o acu e gas oin es inal and geni ou ina y oxici y. I has
also been shown ha he e a e di e ences in cy okine le els be ween pa ien s wi h p os a e
cance and hose wi h benign p os a e lesions o heal hy indi iduals, as well as changes in
cy okine le els ollowing adio he apy and/o and ogen he apy [
34
,
35
]. These indings
p o ide a ounda ion o u u e p ospec i e adio he apy ials aimed a alida ing he
p edic i e alue o hese cy okines, wi h he po en ial o in o m and pe sonalise pa ien
managemen du ing ea men .
Changes in p oin lamma o y cy okine le els ha e been linked no only o adia ion-
induced oxici y bu also o he umou esponse o adio he apy. Mo e-agg essi e umou
beha iou and ea men esis ance ha e been linked o ele a ed IL-6 le els. Ta ge ing IL-6
he apeu ically may imp o e ea men esul s and inc ease umou sensi i i y o adia-
ion [
36
]. Pa ien s ecei ing adia ion he apy o many di e en ypes o cance s ha e been
ound o ha e a highe p opo ion o egula o y T cells (T egs), and his inc ease is associ-
a ed wi h a poo esponse o ea men [
37
]. Howe e , he complex ole o p oin lamma o y
cy okines in adia ion he apy-induced oxici y has no ye been ully unde s ood.
In a s udy by S anojko ic e al. [
38
], he e alua ion o po en ial cy okine signa u es in
p os a e cance pa ien s e ealed signi ican ly ele a ed ci cula ing le els o IL-6 and IFN-
γ
in hose ecei ing de ini i e adio he apy compa ed o pa ien s ea ed pos ope a i ely.
This di e ence may e lec he highe adia ion dose used in he de ini i e g oup (72 Gy
s. 66 Gy in he pos ope a i e and sal age g oups, espec i ely), a ia ions in i adia ed
olumes, o ac o s such as he p esence o he p os a e and i s esponse o i adia ion. In a
coho o 44 pa ien s e alua ed a six ime poin s, bo h uni a ia e and mul i a ia e analyses,
adjus ed o ime poin and ea men ype, demons a ed a signi ican associa ion be ween
inc eased IL-6 le els du ing adio he apy and highe g ades o acu e geni ou ina y oxici y.
The indings also indica e ha empo al changes in cy okine le els du ing ea men , a he
han hei absolu e alues, may se e as mo e- eliable indica o s o adio oxici y.
A ecen s udy on p os a e cance pa ien s unde going adio he apy ound a signi ican
associa ion be ween diabe es melli us and inc eased acu e geni ou ina y oxici y [
39
]. In
addi ion, p os a e cance pa ien s who we e smoke s epo ed highe maximum a igue
le els han pa ien s who we e non-smoke s [
39
]. In e leukin-6 le els ose signi ican ly
a e he 25 h ac ion o adio he apy, and bo h IL-6 and TGF-
β
1 le els, measu ed be o e
adio he apy and a e he 25 h adio he apy ac ion, we e posi i ely co ela ed wi h
geni ou ina y oxici y g ades. Addi ionally, IL-6 and TGF-
β
1 concen a ions a e he 25 h
ac ion we e associa ed wi h a igue sco es [
39
]. I has also been shown ha p e ious
su gical in e en ions may con ibu e o he de elopmen o adia ion oxici y a si es
dis an om he su gical incision, p ima ily h ough he ac ion o TGF-
β
1 [
38
]. Al hough all
pa ien s had he same p os a e cance diagnosis, di e ences in como bidi ies and li es yle
ac o s likely in luenced hei cy okine p o iles. A s udy by Singh e al. on a coho
o 18 pa ien s wi h p os a e cance ea ed wi h IMRT demons a ed an inc ease in IL-6
and TNF-
α
concen a ions measu ed a he end o and 3 mon hs a e adio he apy wi h
an inc ease in he g ade o acu e geni ou ina y and gas oin es inal adio oxici y, while
TGF-
β
concen a ions dec eased wi h an inc ease in he g ade o acu e geni ou ina y and
gas oin es inal adio oxici y [40].
Many s udies iden i ied IL-6 as one o he mos impo an cy okines o p edic ing
no mal- issue adio oxici y e ec s, no only in p os a e cance bu also ac oss a ious o he
malignancies ea ed wi h adio he apy. In eg a ing adio he apy- ela ed ac o s, clinical
Li e 2025,15, 1062 8 o 21
indica o s, indi idual pa ien ea u es, and ci cula ing cy okine p o iles, no ably IL-6 and
TGF-
β
1, in o machine-lea ning-based p edic i e models may be bene icial o an icipa ing
un a ou able no mal issue esponses o adia ion in p os a e cance pa ien s [
38
,
39
,
41
].
The adia ion-induced cy okine p o iles a e speci ic o each cance pa ien since many
indi idual, biological, clinical, and ea men - ela ed ac o s may c ea e his pa e n [
31
].
The p ospec i e ole o cy okines in he p edic ion o no mal- issue eac ions o adio he apy
o p os a e cance needs o be u he in es iga ed on la ge homogenous coho s o
pa ien s wi h p os a e cance , ea ed wi h he same ype o adia ion he apy, wi h he
same adia ion dose schedules, dose- olume g oups, and clinicopa hological ea u es, and
using he same c i e ia o he assessmen o acu e and la e adia ion oxici y.
The oles o selec ed cy okines and hei associa ions wi h adio he apy-induced
oxici y in p os a e cance pa ien s a e summa ised in Table 2.
Table 2. Summa y o key cy okines in ol ed in adio he apy-induced oxici y in p os a e cance .
Cy okine Role Associa ion wi h Ad e se
Radio he apy E ec s
TGF-β1 (T ans o ming
G ow h Fac o Be a 1)
Modula es immune
esponses and ib osis
Ele a ed TGF-β1 le els
a e adio he apy can
con ibu e o ib osis and
oxici y in p os a e cance
pa ien s [33,39]
TNF-α(Tumou Nec osis
Fac o Alpha)
P oin lamma o y cy okine,
egula es apop osis
High TNF-αle els a e
adio he apy may be
linked o inc eased
in lamma ion and isk o
la e oxici ies [33]
IL-6 (In e leukin-6) Media es in lamma o y
esponses and issue epai
Ele a ed IL-6 can be a
ma ke o poo p ognoses,
con ibu ing o
in lamma ion and ib osis
pos -RT [30,36]
IL-1β(In e leukin-1 Be a) P omo es in lamma ion
and issue damage
Associa ed wi h
adia ion-induced ib osis
and inc eased la e oxici ies
in p os a e cance
adio he apy [39]
IFN-γ(In e e on Gamma)
Enhances immune
esponse and
egula es apop osis
Highe IFN-γle els may
co ela e wi h inc eased
lymphocy e apop osis and
lowe la e oxici y
isk [30,38]
IL-2 (In e leukin-2) S imula es T-cell ac i a ion
and p oli e a ion
Plays a key ole in immune
eco e y a e
adio he apy; al e ed le els
may in luence long- e m
oxici ies [30]
IL-8 (In e leukin-8) Chemo ac ic cy okine ha
a ac s neu ophils
Ele a ed IL-8 le els a e
adio he apy may
con ibu e o in lamma ion
and exace ba e
oxici ies [33]
Li e 2025,15, 1062 9 o 21
3.2. The RILA Assay: A Tool o S a i ying Pa ien s by Radiosensi i i y o An icipa e
Radia ion-Induced Toxici y
Va ious unc ional assays can be used o assess he adiosensi i i y o pa ien s’ cells,
such as lymphocy es o ib oblas s, in o de o p edic he isk o adia ion-induced damage
o su ounding heal hy issue. I has been shown ha he esponse o pa ien s’ lymphocy es
o adia ion de e mined by unc ional es s is ela ed o he adiosensi i i y o no mal
issue [
27
]. Local adio he apy has a di ec cy o oxic e ec on ci cula ing lymphocy es as
blood lows h ough he adia ion ield. A e exposu e o ionising adia ion, lymphocy es
die by apop osis. Howe e , di e en subpopula ions o lymphocy es, such as CD4
+
T
lymphocy es, CD8
+
T lymphocy es, B lymphocy es, and NK cells, espond di e en ly o
adia ion. S udies on lymphocy e deple ion in pa ien s consis en ly indica e ha B cells
a e he mos adiosensi i e, ollowed by T cells and NK cells. Among T cells, CD8
+
T cells
exhibi g ea e adiosensi i i y compa ed o CD4
+
T cells [
42
]. Nume ous s udies ha e
shown ha he le el o apop osis induced by he ex i o i adia ion o pa ien s’ pe iphe al
blood lymphocy es be o e adio he apy is associa ed wi h he isk o adia ion-induced
damage o no mal issues [
43
,
44
]. Speci ically, he e is a nega i e co ela ion be ween
adia ion-induced apop osis o T lymphocy es and he de elopmen o la e oxici y; pa ien s
wi h lowe le els o T cell apop osis end o expe ience mo e-se e e side e ec s compa ed
o hose wi h highe le els o apop osis [26,43,44].
A key ad ancemen in his a ea came in 1995, when esea che s in Swi ze land, led by
P o . Ozsahin and P o . C omp on, de eloped a apid assay o assess in insic adiosensi-
i i y by measu ing he adia ion-induced apop osis o CD4
+
and CD8
+
T lymphocy es.
This assay e alua ed he quan i y o pe iphe al blood lymphocy es dying by apop osis
ollowing exposu e o ionising adia ion a a dose o 8 Gy [
43
]. Then, in 2005, came he
i s p ospec i e s udy using he adia ion-induced lymphocy e apop osis (RILA) assay
and in ol ed 399 pa ien s wi h a ious cance s (p ima ily b eas , head and neck, geni-
ou ina y, and gas oin es inal) who unde wen cu a i e adio he apy [
44
]. T-lymphocy e
apop osis was assessed be o e ea men , and pa ien s we e ollowed o acu e and la e
oxici y. A e 30 mon hs, no co ela ion was ound be ween adia ion-induced apop osis
in T-lymphocy es and ea ly oxici y o su i al. Thei indings also showed ha CD8
+
T
lymphocy es unde wen highe le els o apop osis compa ed o CD4
+
T cells ollowing
adia ion exposu e. Impo an ly, hey iden i ied a s ong in e se co ela ion be ween he
RILA alue and he occu ence o la e adia ion oxici y: pa ien s wi h highe RILA sco es,
indica ing g ea e apop osis, expe ienced ewe g ade 2 and 3 la e oxici ies, while hose
wi h lowe apop osis le els we e mo e likely o su e om se e e side e ec s. O e all,
RILA alues > 16% we e signi ican ly associa ed wi h a e y low isk o g ade
≥
2 la e
oxici y. Con e sely, RILA alues below 10% we e s ongly associa ed wi h se e e la e com-
plica ions. This assay highligh ed he po en ial o T lymphocy e-based es s as p edic i e
ools o indi idual no mal- issue adiosensi i i y [
44
]. This was u he con i med in he
phase II mul icen e CO-HO-RT ial, which included 150 b eas cance pa ien s. The high
RILA sco es we e again linked o a lowe incidence o g ade 2 o highe oxici ies [
45
]. The
clinical po en ial o RILA o he p edic ion o he isk o adia ion-induced b eas ib osis
was con i med in a mul icen e F ench ial in ol ing o e 500 b eas cance pa ien s [46].
Fo o e al. [
47
] con i med a signi ican co ela ion be ween he adia ion-induced apop-
osis o CD4
+
T lymphocy es and la e geni ou ina y oxici y in 214 p os a e cance pa ien s
ea ed wi h adio he apy. A highe RILA sco e was no ably associa ed wi h a lowe isk o
la e oxici y. As a esul , esea ch ha add essed he issue o he p e alence and equency
o adia ion oxici y in pa ien s wi h p os a e cance disco e ed ha he adia ion-induced
apop osis o T cells can be u ilised o p edic gas oin es inal o geni ou ina y oxici y. The
s udy conduc ed on a coho o 50 p os a e cance pa ien s ea ed wi h 3D con o mal
Li e 2025,15, 1062 16 o 21
The added alue o his amewo k lies in he biological complemen a i y o i s com-
ponen s: ge mline gene ic a ian s (SNPs), in insic cellula adiosensi i i y (RILA), and
ea men -induced in lamma ion (cy okines). Fu u e s udies should ocus on p ospec i ely
alida ing such in eg a i e models and inco po a ing ad anced p edic i e models (e.g.,
machine lea ning) o e ine p edic ion accu acy. Es ablishing s anda dised h esholds and
ha monising assay me hodologies ac oss cen es will also be c ucial o success ul clinical
ansla ion in addi ion o epo ing unique adio oxici y e ec s.
Each o he p oposed po en ial biological p edic o s o no mal- issue adiosensi i i y
could be apidly e alua ed using blood samples: pa ien -de i ed lymphocy es o se um
and plasma, as a s a ing biological sample. SNP geno yping, low cy ome y-based RILA,
and he de e mina ion o cy okine le els by comme cially a ailable and eliable ELISA es s
a e low-cos , cos -e ec i e, and can be easily inco po a ed in o clinical se ings a e obus
esea ch s udies and clinical alida ion.
5. Conclusions
Ad ances in he ea men o localised p os a e cance ha e imp o ed su i al, shi ing
he ocus o minimising long- e m side e ec s ha can signi ican ly impac quali y o li e.
Despi e he use o mode n adio he apy echniques, some pa ien s con inue o expe ience
se e e oxici ies, highligh ing he need o p edic i e bioma ke s o guide pe sonalised ca e.
Cu en p o ocols do no ake in o accoun indi idual di e ences in adiosensi i i y. Indeed,
a p ima y goal o ansla ional esea ch in adio he apy is he iden i ica ion and alida ion
o bioma ke s ha can be used o assess he isk o acu e and la e oxici ies, as well as
o p edic an indi idual’s sensi i i y o adia ion. In eg a ing indi idual, clinical, and
biological cha ac e is ics ha a e unique o each pa ien in o ea men planning ul ima ely
allows clinicians o ailo adio he apy egimens, he eby balancing he isks and bene i s
o each pa ien .
The RILA assay has eme ged as a aluable, non-in asi e ool o p edic ing indi idual
adiosensi i i y. When in eg a ed in o clinical models along wi h o he pa ien -speci ic
ac o s, RILA helps ailo ea men s a egies ha suppo dose escala ion in pa ien s a low
isk o oxici y and guide al e na i e app oaches o hose a highe isk. Cy okines, such
as IL-6, TNF-
α
, and TGF-
β
, a e also gaining a en ion as bioma ke s o in lamma ion and
adia ion-induced issue damage. Toge he , hese bioma ke s o e p omising a enues o
op imising ea men plans, educing complica ions, and imp o ing ou comes. Gene ic a i-
a ions, such as SNPs, likely play a signi ican ole in indi idual di e ences in no mal- issue
sensi i i y o adia ion, emphasising he need o pe sonalised app oaches in adio he apy.
Mic oRNAs signi ican ly in luence p os a e cance adio he apy by modula ing adiosen-
si i i y, esis ance, and oxici y. Thei s abili y and speci ic exp ession pa e ns make
hem aluable non-in asi e bioma ke s o p edic ing ea men ou comes and side e ec s.
Ongoing esea ch will u he de ine hei ole in ad ancing pe sonalised adio he apy.
De eloping machine lea ning models o p edic bo h acu e and la e no mal- issue
eac ions o adio he apy in pa ien s wi h a ious cance s is a i al s ep owa d pe son-
alised adio he apy. Such p edic i e models should in eg a e mul iple biological ac o s
ep esen ing di e en mechanisms o adiosensi i i y: indi idual pa ien cha ac e is ics,
clinical and ea men - ela ed ac o s, RILA assay esul s, and a combina ion o po en ial
bioma ke s, such as SNPs in speci ic genes, gene o miRNA exp ession p o iles, and ci cu-
la ing cy okine pa e ns. By combining hese da a, pa ien s can be s a i ied in o subg oups
wi h a ying isks o ad e se e ec s, allowing adio he apy o be ailo ed and op imised
o each subg oup.
Li e 2025,15, 1062 17 o 21
Au ho Con ibu ions: Concep ualiza ion and d a ing: J.S.; w i ing and edi ing: I.Š.; c i ical e iew
and edi ing: L.J.; d a ing and edi ing: I.Z.M.; discussion and manusc ip e ision: P.N.; c i ical
edi ing, d a ing, and e ising: M.N. All au ho s ha e ead and ag eed o he published e sion o
he manusc ip .
Funding: This esea ch ecei ed no ex e nal unding.
Ins i u ional Re iew Boa d S a emen : E hical e iew and app o al we e wai ed o his s udy since
i is a sys ema ic e iew o published li e a u e.
In o med Consen S a emen : Pa ien consen was wai ed because no pa ien s o membe s o he
public we e in ol ed in he design, conduc o his s udy, o epo ing o his esea ch.
Da a A ailabili y S a emen : All da a gene a ed as pa o his s udy a e included in he a icle.
Con lic s o In e es : The au ho s decla e no con lic s o in e es .
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