JMIR P ep in s Sacco e al
An in e disciplina y ecosys em o he psychosocial
and beha iou al managemen o Ca dio oxici y in
elde ly b eas cance pa ien : a p ospec i e clinical
s udy
Gaia Giulia Angela Sacco, Ke i Mazzocco, Anas asia Cons an inidou, And i
Papakons an inou, Da ide Mau i, G igo ios Kallia akis, Manolis Tsiknakis, Domen
Ribnika , Do o hea Tsekou a, Valan is Aida inis, Ke amida Kalliopi,
Oikonomopoulou Panagio a, A hos An oniades, Fede ica Rizzi, Geo gia
Ka anasiou, Anca Bucu , Elsa Pacella, Daniela Ca dinale, Ca lo Cipolla, Elisabe a
Munzone, Dimi is Fo iadis, Giuseppe Cu igliano, Gab iella P a e oni
Submi ed o: JMIR Resea ch P o ocols
on: June 20, 2024
Disclaime : © The au ho s. All igh s ese ed. This is a p i ileged documen cu en ly unde pee - e iew/communi y
e iew. Au ho s ha e p o ided JMIR Publica ions wi h an exclusi e license o publish his p ep in on i 's websi e o
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h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
Table o Con en s
O iginal Manusc ip ....................................................................................................................................................................... 5
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
An in e disciplina y ecosys em o he psychosocial and beha iou al
managemen o Ca dio oxici y in elde ly b eas cance pa ien : a
p ospec i e clinical s udy
Gaia Giulia Angela Sacco1*; Ke i Mazzocco1, 2*; Anas asia Cons an inidou3; And i Papakons an inou4; Da ide
Mau i5; G igo ios Kallia akis6; Manolis Tsiknakis7; Domen Ribnika 8; Do o hea Tsekou a9; Valan is Aida inis9;
Ke amida Kalliopi10; Oikonomopoulou Panagio a10; A hos An oniades11; Fede ica Rizzi12; Geo gia Ka anasiou13;
Anca Bucu 14; Elsa Pacella15; Daniela Ca dinale1; Ca lo Cipolla1; Elisabe a Munzone1; Dimi is Fo iadis13; Giuseppe
Cu igliano1, 2; Gab iella P a e oni1, 2
1Is i u o Eu opeo di Oncologia IRCCS Milano IT
2Depa men o Oncology and Hema o-oncology, Uni e si y o Milan Milan IT
3Medical Oncology Depa men , Bank o Cyp us Oncology Cen e Nicosia CY
4Oncology-Pa hology Dep ., Ka olinska Ins i u e - Cance Cen e Ka olinska (CCK) Solna SE
5Medical oncology depa men , Gene al Hospi al o Lamia Lamia GR
6Compu a ion, Compu a ional BioMedicine Labo a o y (CBML), Founda ion o Resea ch and Technology-Hellas (FORTH) He aklion GR
7Depa men o Elec ical & Compu e Enginee ing, Hellenic Medi e anean Uni e si y (HMU) Chania GR
8Medical Oncology Depa men , Ins i u e o Oncology Ljubljana Ljubljana SI
92nd Depa men o Su ge y, A e aieio Uni e si y Hospi al, Na ional and Kapodis ian Uni e si y o A hens A hens GR
102nd Depa men o Ca diology, A ikon Uni e si y Hospi al, Na ional and Kapodis ian Uni e si y o A hens A hens GR
11S emble, S emble Ven u es LTD Ge masogeia CY
12IMS - Is i u o di Managemen Sani a io B esso IT
13Depa men o Ma e ials Science and Enginee ing, UOI - Uni e si y o Ioannina Ioannina GR
14Philips Resea ch Eu ope Eindho en NL
15ESC, Eu opean Socie y o Ca diology Sophia An ipolis FR
* hese au ho s con ibu ed equally
Abs ac
Backg ound: O e 50% o newly diagnosed b eas cance pa ien s a e 65+ yea s old. Due o age- ela ed ac o s and he p esence
o como bidi ies, hese pa ien s a e pa icula ly ulne able o de eloping ca diac oxici y associa ed wi h cance ea men s,
which may lead o subop imal in e en ions and unde ea men , esul ing in poo e heal h ou comes, Quali y o Li e (QoL)
de e io a ion and inc eased heal hca e cos s. Gi en he unde ep esen a ion o elde ly b eas cance pa ien s in clinical ials and
he inc easing ecogni ion o psycho-social and beha iou al ac o s’ impac on ca dio ascula (CV) disease onse , b oade and
in e disciplina y s udies a e equi ed o de elop new and inno a i e bes p ac ices o his clinical popula ion.
Objec i e: Using an inno a i e eHeal h app oach combining he CARDIOCARE (CARDIOCARE – “An In e disciplina y
App oach o he Managemen o he Elde ly Mul imo bid Pa ien wi h B eas Cance The apy Induced Ca diac Toxici y” –
G an Ag eemen 945175) Mobile App and echnologically ad anced wea able de ices (i.e., he Ga min Venu SQ wa ch and he
Pola h10), he CARDIOCARE p ospec i e s udy pu sues a wo old aim: 1) es ing he e ec i eness o he CARDIOCARE
mobile App o moni o and assess elde ly b eas cance pa ien s’ in insic capaci y and QoL and e alua ing CARDIOCARE
eHeal h in e en ions e ec i eness on hese pa ame e s 2) de eloping a holis ic, pa ien -cen ed isk p edic ion model, speci ic
o he de ec ion o ca dio oxici y be o e i clinically eme ges.
Me hods: The s udy is p ospec i e and mul icen ic and in ol es six clinical and i e echnical pa ne s ac oss Eu ope. Se en
hund ed i y elde ly b eas cance pa ien s (? 60yea s old) a e andomised in o ei he he in e en ion g oup o he con ol a m,
wi h only pa ien s in he o me ecei ing access o eHeal h psychological, beha iou al, and unc ional in e en ions
implemen ed on he CARDIOCARE eHeal Hea App. Pa ien s will be ec ui ed in he six clinical cen es and will unde go
clinical p ocedu es o collec mul i-modal da a including clinical da a, ca diac imaging, biochemical and psychological
bioma ke s and omics, in insic capaci y, and QoL indica o s, measu ed a baseline (T0) and e e y h ee mon hs, up o 12 mon hs
(T5).
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
Resul s: CARDIOCARE is a p ojec unded by Ho izon 2020 and en ollmen (WP4) s a ed in May 2023. Rec ui men and i s
da a analysis a e cu en ly unde way.
Conclusions: The CARDIOCARE p ospec i e s udy will con ibu e o de eloping new bes p ac ice guidelines o managing
elde ly mul imo bid b eas cance pa ien s while p ese ing hei in insic capaci y and imp o ing hei QoL. Fu he mo e, he
CARDIOCARE Mobile App and he wea able de ices will allow clinicians o iden i y ajec o ies ac oss he ca dio oxici y
disease con inuum and hus in e ene in a p e en a i e way on highe - isk pa ien s. Such a heal hca e app oach will also bene i
he heal hca e sys em, which cu en ly spends almos 40% o i s esou ces on pa ien s o e 60, wi h long- e m ca e and hospi al
admissions being he p ima y cos d i e s. Clinical T ial: NCT06334445
(JMIR P ep in s 20/06/2024:63455)
DOI: h ps://doi.o g/10.2196/p ep in s.63455
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h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
O iginal Manusc ip
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
An in e disciplina y ecosys em o he psychosocial and beha iou al managemen o
Ca dio oxici y in elde ly b eas cance pa ien : a p ospec i e clinical s udy
Au ho s: Gaia Giulia Angela Sacco1, Ke i Mazzocco1,2, Anas asia Cons an inidou3, And i
Papakons an inou4, Da ide Mau i5, G igo ios Kallia akis6, Manolis Tsiknakis7, Domen Ribnika 8,
Do o hea Tsekou a9, Valan is Aida inis9, Ke amida Kalliopi10, Oikonomopoulou Panagio a10, A hos
An oniades11, Fede ica Rizzi12, Anca Bucu 14, Elsa Pacella15, Geo gia Ka anasiou13, Daniela
Ca dinale1, Ca lo Cipolla1, Elisabe a Munzone1, Dimi is Fo iadis13, Giuseppe Cu igliano1,2,
Gab iella P a e oni1,2
A ilia ions:
1 Eu opean Ins i u e o Oncology, IRCCS, Milano, I aly
2 Depa men o Oncology and Hema o-oncology, Uni e si y o Milan, I aly
3 Medical Oncology Depa men , Bank o Cyp us Oncology Cen e, Nicosia, Cyp us
4 Oncology-Pa hology Dep ., Ka olinska Ins i u e - Cance Cen e Ka olinska (CCK), Solna,
Sweden
5 Medical oncology depa men , Gene al Hospi al o Lamia, Lamia, G eece
6 Compu a ion, Compu a ional BioMedicine Labo a o y (CBML), Founda ion o Resea ch and
Technology-Hellas (FORTH), He aklion, G eece
7 Depa men o Elec ical & Compu e Enginee ing, Hellenic Medi e anean Uni e si y (HMU),
G eece
8 Medical Oncology Depa men , Ins i u e o Oncology Ljubljana, Ljubljana, Slo enia
9 2nd Depa men o Su ge y, A e aieio Uni e si y Hospi al, Na ional and Kapodis ian Uni e si y o
A hens, A hens, G eece
10 2nd Depa men o Ca diology, A ikon Uni e si y Hospi al, Na ional and Kapodis ian Uni e si y
o A hens, A hens, G eece
11S emble, S emble Ven u es LTD, Ge masogeia, Cyp us
12 IMS - Is i u o di Managemen Sani a io, B esso, I aly
13 Depa men o Ma e ials Science and Enginee ing, UOI - Uni e si y o Ioannina, Ioannina,
G eece
14 Philips=Resea ch Eu ope, Eindho en, The Ne he lands
15ESC, Eu opean Socie y o Ca diology, Sophia An ipolis, F ance
Co esponding au ho :
Gaia Giulia Angela Sacco
Eu opean Ins i u e o Oncology, IRCCS, Milano, I aly
Mobile: +393392057169
e-mail: [email protected]
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
AN INTERDISCIPLINARY ECOSYSTEM FOR THE PSYCHOSOCIAL AND BEHAVIOURAL
MANAGEMENT OF CARDIOTOXICITY IN ELDERLY BREAST CANCER PATIENT: A PROSPECTIVE
CLINICAL STUDY
ABSTRACT
Backg ound: O e 50% o newly diagnosed b eas cance pa ien s a e 65+ yea s old. Due o
age- ela ed ac o s and he p esence o como bidi ies, hese pa ien s a e pa icula ly
ulne able o de eloping ca diac oxici y associa ed wi h cance ea men s, which may lead o
subop imal in e en ions and unde ea men , esul ing in poo e heal h ou comes, Quali y o
Li e (QoL) de e io a ion and inc eased heal hca e cos s. Gi en he unde ep esen a ion o
elde ly b eas cance pa ien s in clinical ials and he inc easing ecogni ion o psycho-social
and beha iou al ac o s’ impac on ca dio ascula (CV) disease onse , b oade and
in e disciplina y s udies a e equi ed o de elop new and inno a i e bes p ac ices o his
clinical popula ion.
Objec i es: Using an inno a i e eHeal h app oach combining he CARDIOCARE (CARDIOCARE –
“An In e disciplina y App oach o he Managemen o he Elde ly Mul imo bid Pa ien wi h
B eas Cance The apy Induced Ca diac Toxici y” – G an Ag eemen 945175) Mobile App and
echnologically ad anced wea able de ices (i.e., he Ga min Venu SQ wa ch and he Pola h10),
he CARDIOCARE p ospec i e s udy pu sues a wo old aim: 1) es ing he e ec i eness o he
CARDIOCARE mobile App o moni o and assess elde ly b eas cance pa ien s’ in insic
capaci y and QoL and e alua ing CARDIOCARE eHeal h in e en ions e ec i eness on hese
pa ame e s 2) de eloping a holis ic, pa ien -cen ed isk p edic ion model, speci ic o he
de ec ion o ca dio oxici y be o e i clinically eme ges.
Me hods: The s udy is p ospec i e and mul icen ic and in ol es six clinical and i e echnical
pa ne s ac oss Eu ope. Se en hund ed i y elde ly b eas cance pa ien s (≥ 60yea s old) a e
andomised in o ei he he in e en ion g oup o he con ol a m, wi h only pa ien s in he
o me ecei ing access o eHeal h psychological, beha iou al, and unc ional in e en ions
implemen ed on he CARDIOCARE eHeal Hea App. Pa ien s will be ec ui ed in he six clinical
cen es and will unde go clinical p ocedu es o collec mul i-modal da a including clinical da a,
ca diac imaging, biochemical and psychological bioma ke s and omics, in insic capaci y, and
QoL indica o s, measu ed a baseline (T0) and e e y h ee mon hs, up o 12 mon hs (T5).
Resul s: CARDIOCARE is a p ojec unded by Ho izon 2020 and en ollmen (WP4) s a ed in
May 2023. Rec ui men and i s da a analysis a e cu en ly unde way.
Conclusions: The CARDIOCARE p ospec i e s udy will con ibu e o de eloping new bes
p ac ice guidelines o managing elde ly mul imo bid b eas cance pa ien s while p ese ing
hei in insic capaci y and imp o ing hei QoL. Fu he mo e, he CARDIOCARE Mobile App
and he wea able de ices will allow clinicians o iden i y ajec o ies ac oss he ca dio oxici y
disease con inuum and hus in e ene in a p e en a i e way on highe - isk pa ien s. Such a
heal hca e app oach will also bene i he heal hca e sys em, which cu en ly spends almos
40% o i s esou ces on pa ien s o e 60, wi h long- e m ca e and hospi al admissions being
he p ima y cos d i e s.
T ial Regis a ion: NCT06334445
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
KEYWORDS: b eas cance ; elde ly; ca dio oxici y; p ospec i e s udy; eHeal h; mobile
applica ion; isk p edic ion model
INTRODUCTION
O e 50% o newly diagnosed b eas cance pa ien s a e olde han 65 and a e pa icula ly
ulne able o he ca dio oxic e ec s o cance ea men and he onse o mul iple
como bidi ies due o age- ela ed isk ac o s (Reddy e al., 2017; Singh e al., 2018). The
cumula i e e ec o isk ac o s in he elde ly b eas cance pa ien esembles a “snowball
e ec ”, whe e baseline age- ela ed isk ac o s and cance - ela ed changes a e u he
exace ba ed by di ec he apy-induced ca dio oxici y (Ca ioli e al., 2020; Mon aze i e al.,
2014), esul ing in se e e mul imo bid condi ions and mo ali y. Unde es ima ing he
ca dio oxici y isk in his ulne able popula ion may lead o inapp op ia e in e en ions and
unde ea men , esul ing in poo e heal h ou comes, Quali y o Li e (QoL) de e io a ion, and
inc eased heal hca e cos s. Conside ing ha elde ly cance pa ien s a e sys ema ically
unde ep esen ed in clinical ials (Reddy e al., 2017), he e a e cu en ly limi ed means o
e ec i ely add ess he complex needs o hese pa ien s and hei ca egi e s, o en esul ing in
unde ea men and subop imal heal h ou comes, wi h nega i e consequences on pa ien s’ QoL
(Reddy e al., 2017). The e o e, in line wi h he Wo ld Heal h O ganisa ion’s iew ha heal h is
a s a e o comple e physical, men al, and social well-being (Wo ld Heal h O ganiza ion, 2006),
b oade , in e disciplina y, and pa ien -o ien ed clinical ials able o p o ide new e idence-
based bes p ac ices o managing elde ly b eas cance pa ien s a e u gen ly needed. To da e,
he mos e ec i e app oach o minimize ca dio oxici y is ea ly de ec ion and ea ly onse o
p ophylac ic ea men . Howe e , al hough ad ances ha e been made in he de ec ion and
managemen o ca diac oxici y based on imaging echniques (i.e., 2D and 3D Echoca diog aphy
and ca diac MRI - Magne ic Resonance Imaging), such ins umen s lack he sensi i i y o de ec
subclinical changes, and indeed de ec ca diac oxici y only once a unc ional impai men
eme ges, p ecluding any chance o e ec i e p e en ion.
Mo eo e , psychological condi ions such as dep ession, dis ess, and anxie y - o en obse ed in
cance pa ien s a e diagnosis (Mohamed e al., 2017) - can inc ease he isk o ca dio ascula
complica ions (Busso i and Sommalunga, 2018). Fu he mo e, people p esen ing nega i e
a ec i i y and social inhibi ion a e exposed o a highe isk o ca dio ascula disease han
hose no p esen ing such pe sonali y asse s and ha his kind o nega i e a ec i i y is
signi ican ly associa ed wi h highe sys olic and dias olic blood p essu e (Denolle e al. 2003;
Lin e al. 2020). Simila ly, p olonged exposu e o s ess ul li e ci cums ances may p edic
subsequen hype ension and ca dio ascula disease (Roseng en e al., 2004). The e o e, he
In eg a ed Ca e o Olde People (ICOPE) guidelines ecommend ha ECGs and bioma ke s
(e.g., oponin I, BNP) assessmen s, as well as a de ailed e alua ion o pa ien s’ in insic
capaci y - de ined as hei o e all physical and psycho-social cha ac e is ics - a e included in a
gold-s anda d ollow-up p o ocol o es ablish new, holis ic, and pa ien -o ien ed bes p ac ices
o he managemen o elde ly cance pa ien s a isk o ca dio oxic e ec s associa ed wi h
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
oncological ea men s (Chianca e al., 2022).
NOVELTY AND STUDY AIM
So a , no ex ensi e s udies ha e allowed he collec ion o all necessa y da a o c ea e a
meaning ul assessmen o elde ly b eas cance pa ien s’ in insic capaci y and QoL. Thus, he
CARDIOCARE p ospec i e s udy will adop echnologically ad anced ools o collec a la ge
amoun o da a on elde ly b eas cance pa ien s’ physical, psycho-social, and beha iou al
pa ame e s o be e iden i y pa ien s a isk o de eloping ca dio oxici y due o oncological
ea men s and imp o e hei psychological and physical well-being du ing and a e hei
oncological ca e pa hway.
Since Augus 2021, a CARDIOCARE e ospec i e s udy has been unning wi h b eas cance
pa ien s aged ≥ 65 wi h and wi hou ca dio ascula diseases a baseline (T0) and pa ien s ≥ 55
wi h a b eas cance diagnosis and ca diac damage and oxici y be o e s a ing any ac i e
ea men o b eas cance . Mul imodal e ospec i e da a ha e been e ie ed om exis ing
da abases in i e o he six clinical cen es belonging o he CARDIOCARE conso ium (BOCOC,
IEO, KSBC, NKUA, and UOI), o de elop a isk p edic ion model o ca dio oxici y in he elde ly
b eas cance popula ion o be e ined and alida ed h ough he CARDIOCARE p ospec i e
s udy. In he p ospec i e s udy, he ca dio oxici y isk p edic ion model will be en iched wi h
no el biochemical, -omics (me agenomics, mic oRNA (miRNAs), Single Nucleo ide
Polymo phisms (SNPs)), and psychological ma ke s o be e assess how pa ien s’ in insic
capaci y (physical and men al) and QoL a e a ec ed by cance and an icance ea men s and
how hey in luence he isk o de eloping ca diac oxici y. Fu he mo e, he CARDIOCARE
p ospec i e s udy will be he i s one o obse e, in a clinical s udy se ing, how he gu
mic obiome o elde ly b eas cance pa ien s is a ec ed by di e en oncological ea men s,
and i any associa ion exis s be ween he gu mic obiome, ca diac oxici y e iopa hogenesis and
in insic capaci y, pa ing he way o u u e po en ial bio ic ea men s.
OBJECTIVE(S) AND RATIONALE
- S a i y pa ien s aged ≥ 60 wi h b eas cance based on hei isk o de eloping
ca dio oxici y.
Ra ionale: So a , mul iple s udies ha e explo ed he e ec s o speci ic isk ac o s;
howe e , hese ha e ye o deal comp ehensi ely wi h he impac o clinical, biological,
psychological, and beha iou al isk ac o s and hei in e ac ions.
- E alua e he e ec s o eHeal h psychological and beha iou al in e en ions on elde ly
b eas cance pa ien s’ in insic capaci y and QoL and on hei isk o de eloping ca diac
oxici y.
Ra ionale: Al hough ecen s udies associa e psychosocial and beha iou al
cha ac e is ics wi h he isk o de eloping ca dio ascula diseases, hese s udies on
elde ly pa ien s wi h b eas cance a e s ill limi ed (Pede sen e al. 2017). Howe e ,
gaining such knowledge is necessa y o gene a e hypo heses on using eHeal h
in e en ions o suppo his clinical popula ion.
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
P ocedu e May be one single o
wo isi s
Day 0 Mon
h 3
Mon
h 6
Mon
h 9
Mon
h 12
14-25 days
a e he
end o
ea men *
**
Day -15
T0
(sc eenin
g)
T1
(baselin
e)
T ea me
n
s a
T2 T3 T4 T5 Tn
hema ology and
biochemis y) *
ECHO
assessmen ** X X X X§ X
ECG assessmen X X X X§ X
Plasma oponin I
le el assessmen X& X& X X X X
Mammog aphy (i
pa ien did no
unde go
mas ec omy)
X X
Plasma BNP
assessmen X X X X X
Plasma
myelope oxidase
and high-
sensi i i y CRP (i
a ailable)
X X X X X
I/E checklis X
Collec blood
sample o gene ic
analysis
X
Collec plasma
sample o miRNA
analysis
X X
Collec s ool
sample X X
Oncological
ea men
(plan/changes),
cycle
X X X X X X
In o ma ion on
ea men s a us
(ongoing/comple e
d)
X X X X
Concomi an
medica ions X X X X X X§ X X
Gas oin es inal X X
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
P ocedu e May be one single o
wo isi s
Day 0 Mon
h 3
Mon
h 6
Mon
h 9
Mon
h 12
14-25 days
a e he
end o
ea men *
**
Day -15
T0
(sc eenin
g)
T1
(baselin
e)
T ea me
n
s a
T2 T3 T4 T5 Tn
Symp om Ra ing
Sco e (GSRS)
Pa ien Li es yle
ques ionnai e X X
Ve i y comple ion
o sel -
adminis e ed
scales/ques ionnai
es (ePsycHea
App) #
X X X X X X
Cogni i e e ec
assessmen (i he
cen e has
specialized
pe sonnel)
X X X
Ve i y collec ion o
da a om wea able
de ices
X X
Collec in o ma ion
on pa ien ’s ou -o -
pocke expenses
X X
Hand G ip Tes X X X
AE assessmen X X X X X X X
Legend:
ICF: In o med Consen Fo m
BP: Blood P essu e
HR: Hea Ra e
ECHO assessmen : Echoca diog aphic assessmen
ECG: Elec oca diog am
I/E checklis : Inclusion/Exclusion c i e ia checklis
AE: Ad e se E en s
§ Only i possible.
¥ These isi s can be conduc ed in p esence o emo ely, i he cen e can in ol e he equi ed
expe s.
The psychological isi consis s o mee ing he pa ien in pe son (i al eady in he clinical
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
cen e) o emo ely o ouch base abou he s udy: how hey eel abou i and whe he hey
would like some hing o be di e en / modi ied. Wi hin he isi , a mo i a ional in e en ion
will also be ca ied ou o minimise d op-ou s as much as possible.
* Including choles e ols, glucose le els and enal and li e unc ion es s, i a ailable: IL-6, TNF-
, HRV, CRP, Fib inogen, and Fe i in.α
**Including igh and le en icles dimensions and unc ions and dias olic unc ion.
***a he i s isi a e he end o each ea men which should be wi hin 14-25 days. The ime
o hese sample collec ions will a y in ela ion o he he apeu ic schedule o he pa ien .
# Please e e o Table 2 o he p ecise lis o he ques ionnai es and scales eques ed a each
ime poin .
& T oponin can be analyzed ei he a Sc eening OR a Baseline
RECRUITMENT AND FOLLOW-UP
Pa ien ec ui men s a ed in May 2023.
In Oc obe 2023 a new amended e sion o he p o ocol ( e sion 1.2) had been app o ed. The
decision o amend he old p o ocol and c ea e a new e sion o he P ospec i e Clinical S udy
P o ocol in he ace o eme ging new e idence (Boo h e al., 2022; Lyon e al. 2022), an
amendmen was p oposed on he de ini ion o ca dio oxici y and on inclusion c i e ia ela ed
o age and ea men . Mo e speci ically:
- he iden i ica ion o ca dio oxici y includes also he so-called MACEs - Majo
Ca dio ascula Ad e se E ec s, and mo e speci ically he in a-pa ien assessmen o
MACEs, axanes and endoc ine he apies +/- CDK 4/6 inhibi o s we e included among
he inclusion c i e ia,
- he inclusion c i e ia o age dec ease om =>65 o =>60 yea s o age.
STATISTICAL PROCEDURE
STATISTICAL CONSIDERATIONS ON THE DESIGN
The p ima y s a is ical analysis will use an in en ion- o- ea (ITT) app oach. The e o e, all
pa ien s in ol ed in he s udy will be included in he inal analysis. Howe e , based on he
li e a u e, pa ien s who do no achie e a leas h ee mon hs o ollow-up om he s a o
ea men will no be included in he analysis (Ke amida e al., 2019; Sawaya e al., 2011).
Resul s will be p esen ed using desc ip i e s a is ics (mean, s anda d de ia ion, median and
ange o con inuous a iables, and p opo ions o nominal a iables). Pa ien baseline
cha ac e is ics will be compa ed using a wo-sample - es o a nonpa ame ic es o
con inuous a iables, and Pea son’s Chi-squa e es will be used o quali a i e a iables. All
s a is ical analyses will be pe o med using wo- ailed es s and adop ing a 5% signi icance
le el. The e ec o he in e en ions on he p ima y endpoin will be analysed using he Cox
p opo ional haza ds model. Poin es ima es and 95% con idence in e als will be calcula ed
o he haza d a io o he con ol g oup e sus he expe imen al g oup. Any s a is ically
signi ican di e ence be ween he wo g oups a baseline will be balanced by he mul i a iable
adjus men . A logis ic eg ession o Cox p opo ional haza ds model will also be used o
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
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e alua e he e ec o he in e en ions on he seconda y endpoin s in he wo g oups.
Con inuous a iables, such as hose ob ained om imaging and biochemical and molecula
bioma ke s, will be summa ised desc ip i ely a baseline and ollow-up isi s. The di e ences
be ween he wo g oups du ing he di e en ollow-up isi s will be e alua ed by he analysis
o co a iance, conside ing he espec i e baseline measu emen as a co a ian .
Finally, o he cos -e ec i eness analysis, he heal h and QoL ou comes ha will eme ge du ing
he s udy will be used o calcula e he Quali y-Adjus ed Li e-Yea s (QALYs). The cos s will be
combined wi h he QALYs o he cos -u ili y analysis o es ima e he cos -pe -QALYs associa ed
wi h implemen ing he CARDIOCARE model and he in e en ions o eseen by i . The
Inc emen al Cos -E ec i eness Ra io (ICER) will also be calcula ed o e alua e he
CARDIOCARE model’s e ec i eness compa ed o cu en ca e p ac ices. The ICER, which will
be calcula ed using a h eshold app oach, will he e o e allow us o be e unde s and how o
dis ibu e and alloca e he di e en heal hca e esou ces.
SAMPLE SIZE CONSIDERATIONS
To iden i y he adequa e sample size o he CARDIOCARE p ospec i e s udy, a powe analysis
was pe o med wi h 2- ailed alpha = 0.05 and 1 - be a = 0.80. Based on ha , and conside ing
he 21% incidence o ca dio oxici y in ou a ge popula ion and he expec ed 10% d op-ou
a e, i was es ima ed ha a o al o 736 pa ien s ( ha is, 368 pa ien s in he in e en ion a m
and 368 pa ien s in he con ol a m) would be la ge enough o de ec a 40% ela i e isk
educ ion in he incidence o inc eased le els o oponin I ( aken as a ca dio oxici y p oxy) in
his popula ion. Such a sample size would also allow he e alua ion o he e ec i eness o he
beha iou al and psychological in e en ions in eg a ed in o he s udy in mi iga ing, p e en ing,
o delaying he onse o ca dio oxici y associa ed wi h oncological he apies o elde ly b eas
cance pa ien s.
The sample size calcula ion was ollowed by Fishe 's exac es , pe o med using G*Powe
so wa e e sion 3.1.9.4. Conside ing ou powe analysis esul s and he numbe o pa ien s
a ec ed by b eas cance each yea , all clinical cen es in he CARDIOCARE conso ium ag eed
on he inal ec ui men goal o 750 pa ien s (375 o he in e en ion a m and 375 o he
con ol one).
DATA COLLECTION STORAGE AND SECURITY
A well-de ined Da a Managemen Plan has been submi ed, p o iding de ailed in o ma ion on
he p ocedu es ha will be implemen ed o da a collec ion, s o age, p o ec ion, e en ion, e-
use and/o des uc ion, complying wi h he Gene al Da a P o ec ion Regula ion (GDPR).
By design, a obus da a p o ec ion and secu i y s a egy will be implemen ed in all da a
collec ion and s o age p ocedu es in he CARDIOCARE pla o m. As pa o he CARDIOCARE
Da a Managemen and High-Pe o mance Compu ing (HPC), an elec onic Case Repo Fo m
(eCRF) - accessible by all clinical pa ne s - has been de eloped o se e as he da a en y ool
o all pa ien da a. eCRF da a will be uploaded and s o ed enc yp ed o he pla o m and
sys ema ically backed up in ex e nal RAID d i es. An audi Log ope a ion will be implemen ed
o iew he use s’ access his o y o he sys em, enabling he de ec ion o any po en ial da a
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
secu i y b eaches. A e inal quali y checks a he end o he p ospec i e s udy, he eCRF will be
ozen and expo ed o he echnical pa ne s o s a is ical analysis pe o mance.
All membe s o he CARDIOCARE conso ium will ake app op ia e o ganisa ional and
echnical measu es o p e en any e en o abuse, acciden al loss, des uc ion, o damage o
collec ed da a, enabling eins a e he sys em p omp ly i necessa y.
Da a quali y, comple eness and in eg i y will be ensu ed wi h isi s by he Independen Da a
Moni o ing Commi ee (IDMC) membe s, who will ce i y, in each clinical cen e, he iles’
consis ency, adhe ence o he s udy p o ocol and Good Clinical P ac ice guidelines, he accu acy
o he eCRF o ms, and he compliance wi h sa e y epo ing. In es iga o s o each clinical
cen e will acili a e he IDMC membe s’ jobs by coope a ing and enabling di ec access o all
da a sou ces o be e i ied.
S ic con iden iali y o all pe sonal and s udy- ela ed da a is ensu ed. All ec ui ing cen es
will sign an ag eemen documen de ailing hei commi men owa ds complying wi h he
ele an laws, egula ions, codes o p ac ice and obliga ions o publica ion.
ETHICS COMPLIANCE
All in ol ed clinical cen es submi ed he new e sion (1.2) o he CARDIOCARE p ospec i e
s udy p o ocol o hei E hics Commi ees and go o icial app o al.
This mul icen ic p ospec i e s udy has been designed o comply wi h na ional (i.e., Good
Clinical P ac ices) and in e na ional decla a ions (i.e., he Decla a ion o Helsinki) egula ing
p ope e hical esea ch in ol ing human subjec s, wi h W i en In o med Consen which will
be ob ained om all pa icipa ing pa ien s. In pa icula , he s udy conduc is in line wi h he
ollowing egula ions and no ms:
- The Decla a ion o Helsinki, e hical p inciples o medical esea ch in ol ing human
subjec s, e ised Oc obe 2013.
- The Con en ion o he P o ec ion o Human Righ s and Digni y o he Human Being
conce ning he Applica ion o Biology and Medicine: Con en ion on Human Righ s and
Biomedicine, O iedo 1997.
- The Council o In e na ional O ganiza ions o Medical Sciences, in collabo a ion wi h
he Wo ld Heal h O ganiza ion, In e na ional E hical Guidelines o Biomedical Resea ch
In ol ing Human Subjec s, e ised in 2016.
- The Belmon Repo : E hical P inciples and Guidelines o he P o ec ion o Human
Subjec s o Biomedical and Beha io al Resea ch. Depa men o Heal h, Educa ion, and
Wel a e (DHEW) publica ion (DHEW-05-78-0012), Washing on, DC, 1978.
RESULTS
The ac i e phase o he ec ui men p ocess began in May 2023 and p elimina y esul s will be
published in a scien i ic jou nal and made a ailable o consul a ion on he CARDIOCARE
p ojec websi e. Da a analysis and dissemina ion o he s udy esul s will be pe o med in 2024
and 2025.
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
DISCUSSION
The CARDIOCARE isk p edic ion model o ca diac oxici y will allow heal hca e p o ide s o
iden i y and moni o ajec o ies ac oss he ield o ca dio oxici y and hus ad ise and
in e ene p omp ly on high- isk pa ien s while sa ing esou ces on hose p esen ing a low isk
o de eloping ca dio oxici y. The model will be pa icula ly ailo ed o de ec he isk o
ca dio oxici y in elde ly b eas cance pa ien s, ha a e a almos he same isk o
ca dio ascula disease as b eas cance elapse (Ba dia e al. 2012; Pa k e al. 2017).
Fu he mo e, e en when no a al, elde ly b eas cance women a e especially p one o de elop
ca diac mo bidi y as a colla e al e ec o oncological ea men s (Zaga e al., 2016). Indeed, in
his clinical popula ion, cance ea men ca dio oxic e ec s a e o en added o baseline age-
ela ed ac o s and p e-exis ing mo bidi y, leading o d ug in e ac ion complica ions esul ing
om polypha macy (Chang e al., 2019; Mandelbla e al., 2018), poo e heal h ou comes, and
in insic capaci y and QoL de e io a ion (Depboylu, 2020).
Conside ing he abo e, he CARDIOCARE mobile App, wi h i s con en s and heal h moni o ing
sys em, will p o ide elde ly b eas cance women wi h he oppo uni y o lea n how o bes
manage hei mul imo bidi y while p ese ing and enhancing hei physical and psychological
in insic capaci y as well as hei o e all QoL, including hei ela ionship wi h o he s. They will
also bene i om he con inuous and home-based ca e ha he mobile App allows by no i ying
hem p omp ly when one o mo e heal h pa ame e s a e sub-op imal, clinician-de eloped
sugges ions on how o in e ene o imp o e such pa ame e s will ollow igh a e .
In addi ion, he p esen s udy gi es an oppo uni y o es he easibili y o digi al ools (de ices
and mobile applica ion) among his speci ic popula ion o elde ly pa ien s (>=60) and iden i y
he possible a eas ha need imp o emen so ha , in he u u e, hese ypes o digi al ools and
in e en ions can be success ully applied o he speci ic segmen o pa ien s conside ed he e.
Heal hca e p o ide s will also as ly bene i om he heal h moni o ing and echnologically
ad anced ools employed o he cu en p ospec i e s udy. Such de ices, including he Mobile
App, will p o ide clinicians wi h in o ma ion on hei pa ien s’ heal h, mo e in eg a ed han he
in o ma ion hey can ob ain h ough s anda d Elec onic Heal h Reco ds (EHR) ools. The
CARDIOCARE Mobile App and he wea able de ices used o he s udy will, indeed, in o m
heal hca e p o ide s abou se e al cha ac e is ics o hei pa ien s (psychological, beha iou al,
cogni i e, and unc ional) which, based on he mos upda ed scien i ic li e a u e, a e
pa icula ly ele an o de e mine he isk o elde ly b eas cance pa ien s o de eloping
ca diac oxici y when exposed o oncological he apy (Busso i and Sommalunga, 2018; Wang
e al., 2023; Chan e al., 2023; Hill e al., 2023). Fu he mo e, by being in o med on hei
pa ien s’ in insic capaci y (physical and psychological) and o he QoL- ela ed aspec s,
heal hca e p o ide s can mo e easily and quickly iden i y each pa ien ’s ca e gaps and speci ic
needs, and de elop new and mo e in eg a ed bes p ac ices, acili a ing he implemen a ion o
pe sonalised, pa ien -cen ed ca e.
The inno a i e CARDIOCARE model o ca e and i s isk p edic ion model o ca diac oxici y
hold p omise om a socio-economic pe spec i e as well. I is o be unde lined ha almos 40%
o public spending in he heal hca e sec o conce ns people o e 60, wi h long- e m ca e and
hospi al admissions being he p ima y cos d i e s (Joling e al., 2018). Since heal hca e
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
sys ems ha success ully p o ide e ec i e communi y-based ca e and se ices a e likely o
signi ican ly op imise hei public spending (Joling e al., 2018), heal hca e ins i u ions and
insu ance companies a e seeking new ways o dec ease ea men cos s o ch onic diseases
such as cance .
Mo eo e , p e ious esea ch has highligh ed conside ably highe mo ali y a es among b eas
cance pa ien s wi h low socio-economic s a us (i.e., educa ion, employmen , income)
compa ed o hose whose socio-economic s a us is highe (Yu, 2009; Lundq is e al., 2016).
This is a c i ical da um, since socio-economic disad an age may esul in la e -s age diagnosis
and poo e access o and quali y o ca e ecei ed. Using echnologically ad anced ools -
p o ided o pa ien s by he clinical cen es - able o consis en ly moni o se e al heal h
pa ame e s beyond he ime he pa ien s ays a he clinical cen e, he CARDIOCARE
heal hca e model a emp s, on he one hand, o add ess he economic and socie al challenges
ha a lic bo h ou heal hca e sys em inances and he pa ien s in he lowe socio-economic
g oups. Addi ionally, once he p ospec i e s udy is concluded and he da a analysed, a cos -
e ec i eness analysis will be pe o med, compa ing he CARDIOCARE heal hca e model o
cu en p ac ices.
ACKNOWLEDGEMENTS
This wo k has been unded he Eu opean Union’s Ho izon 2020 Resea ch and Inno a ion
P og am unde G an Ag eemen No 945175.
CONFLICTS OF INTEREST
The au ho s ha e no con lic s o in e es o decla e. All co-au ho s ha e seen and ag ee wi h he
con en s o he manusc ip and he e is no inancial in e es o epo .
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h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
JMIR P ep in s Sacco e al
ABBREVIATIONS
CV: Ca dio ascula
ICF: In o med Consen Fo m
BP: Blood P essu e
HR: Hea Ra e
ECHO assessmen : Echoca diog aphic assessmen
ECG: Elec oca diog am
I/E checklis : Inclusion/Exclusion c i e ia checklis
AE: Ad e se E en
BPN: B ain Na iu e ic Pep ide
CRP: C-Reac i e P o ein
CRS: Ca dio Reco ding Session
HGS: Hand G ip Session
QoL: Quali y o Li e
Ca diac MRI: Ca diac Magne ic Resonance Imaging
miRNA: mic oRNA
SNP: Single Nucleo ide Polymo phism
eCRF: elec onic Case Repo Fo m
HER2: Human Epide mal G ow h Fac o Recep o 2
EW = Exp essi e W i ing
BPS = Bes Possible Sel
ABCDE: A = Ac i a ing e en o si ua ion; B = Belie s; C = Consequences; D = Dispu a ion o
belie s; E = E ec i e new app oach
GSRS: Gas oin es inal Symp om Ra ing Sco e
ITT app oach: In en ion- o- ea app oach
QALYs: Quali y-Adjus ed Li e-Yea s
ICER: Inc emen al Cos -E ec i eness Ra io
GDPR: Gene al Da a P o ec ion Regula ion
HPC Pla o m: High-Pe o mance Compu ing pla o m
IDMC: Independen Da a Moni o ing Commi ee
EHR: Elec onic Heal h Reco ds
APPENDIX
Table 2. Sel -adminis e ed scales o each s udy ime poin s
Psychological and beha io al
assessmen
May be one
single o wo
isi s
Day 0 Mon
h 3
Mon
h 6
Mon
h 9
Mon
h 12
Day
-15
T0
T1
(baseline
)
T ea men
s a
T2 T3 T4 T5
h ps://p ep in s.jmi .o g/p ep in /63455 [unpublished, non-pee - e iewed p ep in ]
