Tailored exercise as a protective tool in cardio-oncology rehabilitation: A narrative review

Abstract

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review 125 Arch Med Deporte 2020;37(2):125-135 Revisión Resumen La patología cardiovascular es la primera causa de morbilidad y muerte entre los pacientes supervivientes de cáncer, después de segundas neoplasias. La prevención de cardiotoxicidades inducidas por tratamientos oncológicos constituye una meta en la Oncología. La Asociación Americana de la Oncología Clínica recientemente ha destacado la importancia del ejercicio físico como componente co-adyuvante esencial en el tratamiento contra el cáncer. El ejercicio físico puede dar protección en la cardiotoxicidad desde un punto de vista molecular y fisiológico. Dos tipos de entrenamiento destacan: entrenamiento cardiovascular y de fuerza. Esta revisión pretende recoger evidencia y extraer conclusiones sobre la efectividad del ejercicio físico ante la cardiotoxicidad. Para ello revisamos la literatura científica bajo criterios PRISMA. Estudios basados en el efecto del ejercicio físico y mediciones cardiacas a lo largo de procesos oncológicos (tratamiento oncológicos y supervivientes) fueron seleccionados. Como resultado, 1087 estudios fueron recuperados y 33 estudios fueron seleccionados, comprendiendo 2778 sujetos. La mayoría de los estudios (n=29) examinaron el efecto del entrenamiento cardiovascular en la cardiotoxicidad. No hubo estudios que analizaran exclusivamente el entrenamiento de Fuerza. Observamos una escasez de efecto sistémico a lo largo debido a la alta heterogeneidad. De cualquier modo, los estudios combinando entrenamiento cardiovascular y de fuerza parecen demostrar resultados prometedores. En resumen, las guías clínicas deberían animar a implementar programas de ejercicio físico en el entorno médico y garantizar intervenciones efectivas. Asimismo, deberían implementarse protocolos individualizados en unidades de Rehabilitación Cardio-Oncológica. Finalmente, resulta imperativo promover el mensaje de evitar la inactividad física en el paciente oncológico. Palabras clave: Patología cardiovascular. Cáncer. Cardiotoxicidad. Ejercicio & Rehabilitación Cardio-Oncológica. Summary Cardiovascular disease is the leading cause of long-term morbidity and death among cancer survivors, after second malig-nancies. Preventing cancer treatment-induced cardiotoxicity (CTC) constitutes a crucial endpoint in oncology, from oncology treatment implementation. The American Association of Clinical Oncology has recently highlighted the role of physical exercise as an essential component of co-adjuvant cancer treatment and cancer survivor care programs. Exercise training may protect from cardiotoxicity on a molecular and physiological basis. Two major types of training in this field are: cardiovascular and resistance/strength training. Little is known about the effects of these modalities of exercise on CTC. This narrative review aimed to gather evidence and extract conclusions about the effectiveness of exercise training on CTC. To do so, we reviewed scientific literature under a sophisticated approach in line with the PRISMA project guidelines. Studies on physical training exercise effects and cardiac-related measures throughout the cancer stages (cancer treatment and survivorship) were selected. Data collection comprised extracting information of study features, exercise training characteristics and related effects. As a result, 1087 studies were retrieved from database search and 33 studies were selected, comprising 2778 participants. Most of the studies (n = 29) examined the effects of cardiovascular training on CTC. No studies analysed the effects of resistance-based training. We observed a lack of systematic effect of exercise across studies due to the high heterogeneity (e.g., many studies did not follow the guidelines for training interventions in cancer settings). However, studies combining both cardiovascular and resistance components showed promising results. To sum up, higher adherence to clinical guides should be encouraged to implement physical exercise interventions in medical settings and to ensure intervention effectiveness. Moreover, perso-nalized protocols and routines should be implemented in Cardio-Oncology Rehabilitation Units. Finally, it is mandatory to avoid physical inactivity in patients with cancer.

Full text

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review
125
Arch Med Deporte 2020;37(2):125-135
Revisión
Resumen
La patología cardiovascular es la primera causa de morbilidad y muerte entre los pacientes supervivientes de cáncer, después
de segundas neoplasias. La prevención de cardiotoxicidades inducidas por tratamientos oncológicos constituye una meta
en la Oncología. La Asociación Americana de la Oncología Clínica recientemente ha destacado la importancia del ejercicio
físico como componente co-adyuvante esencial en el tratamiento contra el cáncer. El ejercicio físico puede dar protección
en la cardiotoxicidad desde un punto de vista molecular y siológico. Dos tipos de entrenamiento destacan: entrenamiento
cardiovascular y de fuerza. Esta revisión pretende recoger evidencia y extraer conclusiones sobre la efectividad del ejercicio
físico ante la cardiotoxicidad. Para ello revisamos la literatura cientíca bajo criterios PRISMA. Estudios basados en el efecto del
ejercicio físico y mediciones cardiacas a lo largo de procesos oncológicos (tratamiento oncológicos y supervivientes) fueron
seleccionados. Como resultado, 1087 estudios fueron recuperados y 33 estudios fueron seleccionados, comprendiendo 2778
sujetos. La mayoría de los estudios (n=29) examinaron el efecto del entrenamiento cardiovascular en la cardiotoxicidad. No
hubo estudios que analizaran exclusivamente el entrenamiento de Fuerza. Observamos una escasez de efecto sistémico a
lo largo debido a la alta heterogeneidad. De cualquier modo, los estudios combinando entrenamiento cardiovascular y de
fuerza parecen demostrar resultados prometedores. En resumen, las guías clínicas deberían animar a implementar programas
de ejercicio físico en el entorno médico y garantizar intervenciones efectivas. Asimismo, deberían implementarse protocolos
individualizados en unidades de Rehabilitación Cardio-Oncológica. Finalmente, resulta imperativo promover el mensaje de
evitar la inactividad física en el paciente oncológico.
Palabras clave:
Patología cardiovascular.
Cáncer. Cardiotoxicidad.
Ejercicio & Rehabilitación
Cardio-Oncológica.
Summary
Cardiovascular disease is the leading cause of long-term morbidity and death among cancer survivors, after second malig-
nancies. Preventing cancer treatment-induced cardiotoxicity (CTC) constitutes a crucial endpoint in oncology, from oncology
treatment implementation. The American Association of Clinical Oncology has recently highlighted the role of physical exercise
as an essential component of co-adjuvant cancer treatment and cancer survivor care programs. Exercise training may protect
from cardiotoxicity on a molecular and physiological basis. Two major types of training in this eld are: cardiovascular and
resistance/strength training. Little is known about the eects of these modalities of exercise on CTC. This narrative review
aimed to gather evidence and extract conclusions about the eectiveness of exercise training on CTC. To do so, we reviewed
scientic literature under a sophisticated approach in line with the PRISMA project guidelines. Studies on physical training
exercise eects and cardiac-related measures throughout the cancer stages (cancer treatment and survivorship) were selected.
Data collection comprised extracting information of study features, exercise training characteristics and related eects. As a
result, 1087 studies were retrieved from database search and 33 studies were selected, comprising 2778 participants. Most of
the studies (n = 29) examined the eects of cardiovascular training on CTC. No studies analysed the eects of resistance-based
training. We observed a lack of systematic eect of exercise across studies due to the high heterogeneity (e.g., many studies
did not follow the guidelines for training interventions in cancer settings). However, studies combining both cardiovascular
and resistance components showed promising results. To sum up, higher adherence to clinical guides should be encouraged
to implement physical exercise interventions in medical settings and to ensure intervention eectiveness. Moreover, perso-
nalized protocols and routines should be implemented in Cardio-Oncology Rehabilitation Units. Finally, it is mandatory to
avoid physical inactivity in patients with cancer.
Key words:
Cardiovascular disease.
Cancer. Cardiotoxicity.
Exercise & Cardio-Oncology
Rehabilitation.
Recibido: 30/10/2019
Aceptado: 25/12/2019
Tailored exercise as a protective tool in cardio-oncology
rehabilitation: a narrative review
David García-González1, Txomin Pérez-Bilbao1,2, Alejandro de la Torre-Luque3, Escarlata López Ramírez4,
Jesús García-Foncillas López5,6*, Alejandro F. San Juan1*
1Departamento de Salud y Rendimiento Humano, Facultad de Ciencias de la Actividad Física y del Deporte-INEF, Universidad Politécnica de Madrid (UPM), Madrid, Spain. 2CES
Don Bosco University, Department of Physical Education, Madrid, Spain. 3Centre for Biomedical Research in Mental Health (CIBERSAM), Department of Psychiatry. Autonomous
University of Madrid (UAM), Madrid, Spain. 4Department of Oncology, Radiation oncologist. Chief medical ocer, GenesisCare, Spain. 5School of Medicine. Autonomous University
of Madrid (UAM), Madrid, Spain. 6Department of Oncology, Cancer Institute, University Hospital “Fundación Jiménez Díaz”, Autonomous University of Madrid (UAM), Madrid,
Spain. *Sharing senior authorship.
Ejercicio individualizado como herramienta protectora en la
rehabilitación cardio-oncológica: revisión narrativa
Correspondencia: Txomin Perez-Bilbao
E-mail: tperez@escuelaprofesionaldonbosco.com
SEMED-FEMEDE research Award of the year 2019

David García-González,
et al.
126 Arch Med Deporte 2020;37(2):125-135
Introduction
Nowadays in the United States of America, cancer is the second
cause of death. It is expected that in the years 2025-2030, cancer will
exceed cardiovascular diseases as the principal cause of death1. In turn,
cardiovascular disease (CVD) is the leading cause of long-term morbidity
and death among cancer survivors, after second malignancies2.
Cardiotoxicity is dened by the National Cancer Institute as “toxicity
that aects the heart”. No single, universally denition is accepted at
present. Traditionally and thematically cardiotoxicity has been linked
with a decline in the Left Ventricular Ejection Fraction (LVEF). According
to the European Society of Cardiology, cardiotoxicity leading to heart
failure is dened as a decrease in the LVEF >10% points to a value be-
low the lower limit of normality on an echocardiograph, and a relative
reduction in global longitudinal strain of >15% from baseline3. Heart
structure disfunction, haemodynamic ow alterations, hypertension,
valvular disease, arrhythmias, thrombotic events and peripheral vascular
disease are related with this Cardio-Oncology concept.
By and large, there is a strong connection between cancer
treatment-induced cardiotoxicity (CTC) and CVD over treatment and
cancer survivorship4,5. For instance, congestive heart failure because
of cancer therapy has been linked to a 3.5-fold increased mortality risk
compared with idiopathic cardiomyopathy6.
Preventing CTC constitutes a crucial endpoint in oncology.
Nowadays, an increasing interest in CTC exists in order to encourage
individualized treatment planning and the promotion of quality of life
across cancer treatment and survivorship. Thus, several studies have
provided new insight on the relationship between chemotherapy
agents7,8, adjuvant endocrine therapy8, and monoclonal antibodies and
CTC8. Likewise, some studies have stress the association of radiotherapy
exposure (Figure 1) and CTC7-10.
Based on experience in the area of cardiac rehabilitation and
exercise oncology units, the potential use of physical exercise as a
co-adjuvant treatment has been endorsed11. Mounting evidence has
proved that physical exercise improves cardiovascular function and
facilitates cardiac rehabilitation12,13. The American Association of Clinical
Oncology (ASCO) has recently highlighted the role of physical exercise as
an essential component of cancer survivor care programs14. In this line,
the American Heart Association (AHA) suggests the implementation of
tailored exercise for Cardio-Oncology Rehabilitation15.
Exercise training may protect from cardiotoxicity on a molecular
basis. In this sense, exercise promotes eective regulation of calcium
channel in ryanodine receptors, which are involved in heart contrac-
tile function16. Moreover, physical exercise may contribute antioxidant
agents to be produced and mitochondrial function be improved17-19.
From a patient point of view, physical exercise has signicant benets
to tackle CTC. Several modalities of exercise training are present in
rehabilitation contexts, two major types of training in this eld are: car-
diovascular and resistance/strength training. The bulk of studies have
concentrated on cardiovascular programs and their eectiveness to
prevent CTC20-22. Some studies have reported the benets of resistance
physical training on cardiovascular and musculoskeletal systems and its
potential protective eects, specically in Sprague- Dawley rats which
were induced CTC through doxorubicin23,24. Little is known about the
eects of these interventions in cancer patients and survivors. Moreo-
ver, integrated programs (i.e., programs combining cardiovascular and
resistance components) have been scarcely studied.
This narrative review aimed to examine the scientic literature in
order to explore and gather studies focused on physical training appli-
cations as adjuvant interventions to tackle CTC. Moreover, we intended
to describe the main features of interventions that have been proven
eective to deal with CTC (e.g., treatment duration, training components,
outcomes to consider). Finally, we aimed at providing recommendations
and some guidelines to design physical training interventions in cancer
settings, considering their cardioprotective benets.
Methods
Search strategy and article selection criteria
This narrative review relied on a comprehensive protocol, covering
an ascendant and descendant approach to gather evidence on the
eects of physical training to prevent from CTC. Four renowned elec-
tronic databases were searched: Medline PubMed, PEDro, Scopus and
Web of Science. Also, the list of references of three reference reviews
on physical training and cardiotoxicity was reviewed4,20,21 as well as the
list of references of all the articles included in this study (descendant
approach).
Electronic databases were searched in October 5th 2018. A broad-
scope and inclusive initial search strategy was carried out with no restric-
tions in specie, population or age, in order to identify a wide collection
of studies on training exercise eects. Thus, search queries included
‘cancer’ (or ‘neoplasms’), ‘cardiotoxicity’ and ‘exercise’ as keywords (as
well as their related thesaurus terms: for cardiotoxicity, ‘cardiac toxicity’,
or ‘heart toxicity’; and for exercise, ‘physical training’, ‘physical activity’,
‘physical exercise’, ‘acute exercise’, or ‘exercise training’).
Inclusion criteria for studies were: a) studies analyzing the eects
of a physical training- based intervention on human adults samples;
Figure 1. Left Breast Cancer Radiotherapy with Volume Modulated
Arc (VMAT) and 6-10 MV.
Orange: 42’56 Gy (breast)
Blue: < 5 Gy (coronary vessels).

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review
127
Arch Med Deporte 2020;37(2):125-135
b) studies comprising cancer patients or survivors; c) studies reporting
comparative results (i.e., between-group or pre-post test) regarding
cardiovascular markers or cardiopulmonary exercise test (e.g., heart rate,
cardiopulmonary volume, left ventricular ejection fraction, VO2peak);
d) being an empirical study published in scientic journals; e) article
written in English. The exclusion criteria were: a) non-human samples;
b) studies combining physical-training treatments and other types of
interventions dierent than usual care (e.g., a surgical intervention,
nutritional supplementation, pulmonary/breathing physical therapy
protocols, yoga); c) descriptive studies or qualitative studies; d) studies
comprising patients without a history of cancer.
Data extraction and quality assessment
Articles were screened for a reviewer on an initial review of title,
abstract, and keywords. Pre-selected papers were fully read to ratify the
selection. An independent peer reviewer conrmed the appropriateness
of every paper to be included in this study. Discrepancies on paper
selection were resolved by discussion.
Relevant data was extracted using a coding manual. An indepen-
dent reviewer supervised data entered in the data collection form. Data
collected from every study were: a) sample size and composition (i.e.,
type of cancer participants, cancer stage); b) age range; c) country of
recruitment; d) study design; e) VO2peak and/or cardiac outcome; f)
type of exercise training intervention (i.e., aerobic, resistance training,
and combined); g) treatment duration and number of sessions; h)
intensity of training; i) results of the intervention; j) side eects derived
from the interventions; k) and quality of studies based in four criteria
described below.
1087 studies were identied through database searching. Studies
excluded after screening titles and abstracts (n=944). Titles and abstracts
identied (n=143). Studies included in narrative review (n=33) (Figure 2).
Quality of studies was assessed by four criteria: a) type of study
design (according to, cohort studies or randomized controlled trial show
a higher level of evidence, than case- controlled studies or descriptive
ones); b) random assignation to interventions; c) confounding control
(control of potential confounders); d) repeated measures (whether the
study had pre-post tests assessments and follow-up). Two reviewers
independently assessed all the studies included in this review. Discre-
pancies were resolved by discussion.
Results
Intervention programs by means of physical exercise in
cancer patients
Thirty-three studies were included in this review (n=2778 patients).
Table 1 displays the main features of these studies. Mean age of par-
ticipants was 47.1 years, and the most common diagnosis was breast
cancer. Sample size of the studies was 84.18 patients on average. Most of
studies was based in North America (15 from EEUU and 10 from Canada);
6 from Europe, and 2 from the rest of the world. Regarding study design,
interventions during treatment vs. survivors vs. both; Exercise during
treatment: 16 studies. Exercise design in survivors: 15. Both: 2 studies.
Most studies were randomized controlled trials (72.72% of articles);
45.45% of them controlled for confounding factors (mainly type of on-
cology treatment, age and free- cancer time) in randomization or data
analysis. On the other hand, most of articles assessed outcomes pre-post
tests (60.61% of manuscripts) and 39.39% included follow- up. In terms
of type of exercise programs, the bulk of studies used cardiovascular
training. Four studies delivered programs integrating cardiovascular and
strength modalities (intervention exercise group). Finally, there was a
trend towards 3 days/week exercise sessions (45-50 mints. per session):
20 studies. With these 3 weekly exercise sessions, the 150 mints/week,
cardiovascular exercise recommendations of American and Australian
oncological Societies are fullled25,26.
Cardiovascular training in human
The intervention by means of physical exercise in humans extrapo-
lates the type of cardiovascular physical exercise, times and intensities
used in the research carried out on rodents27-31.
In the study of Kirkham et al32, the intensity of the exercise to try to
diminish the cardiotoxicity associated with the use of doxorubicin was
70% of the cardiac frequency of reserve of each patient, similar in exer-
cise intervention: Acute (1 single bout) & Intensity seen in rat model30.
Haykowsky et al33 shows that initiation of trastuzumab is associated
with left ventricular cavity dilation and reduced ejection fraction despite
aerobic training. Although this important study doesn’t count with a
control non-exercise group.
Resistance training (strength) in human
Nowadays, there are no exclusive strength interventions in humans
trying to reduce CTC in oncological patients (measuring specically
cardiac biomarkers). This could provide new research opportunities.
Figure 2. Flow Diagram.
Scientic articles identied in
electronic databases: Pubmed,
PEDro, Scopus & Web of
Science: (n= 1.087)
Articles excluded after
records analysis:
(n= 944)
• Duplicated papers.
• Animal exercise
interventions.
• No link with Cardiotoxicity in
Cardio-Oncology.
• Exercise interventions in
combination with others
(pharmacological, nutritional
upplementation, mental
stress management…)
Full-text articles excluded,
with reasons:
(n=110)
Full-text articles assessed
for eligibility:
(n= 143)
Studies included in this
Narrative Review:
(n= 33)

David García-González,
et al.
128 Arch Med Deporte 2020;37(2):125-135
Study Sample
size
Mean
age
Cancer
site
Severity Type of
intervention
Intervention particularities Outcome Results
Patient samples
Courneya
et al
242 49.2 Breast I-IIIA CV vs. ST Aerobic Exercise Group: 3 days/w;
intensity: 60-80% from maximal
VO2 per 15-45 min.
Resistance Training: 3days/w +
9 exercises x 2 sets of 8-12 rep.;
intensity: 60-80% (one repetition
maximum).
VO2 Peak. VO2 peak increased
by 0.2% in aerobic
exercise group and
decreased by 5% in
the resistance training
group.
Courneya
et al
122 53.2 Lym-
phoma
All stages CV Three days/w with 12 weekly
sessions, 15-45 min a session.
VO2 Peak VO2 peak increased
by 17% in the exercise
group.
Courneya
et al
301 50 Breast I-IIIC CV vs.
combined
Standard Aerobic Exercise: 3
days/w x 25-30 min; intensity: 55-
75% from VO2 max.
High Aerobic Exercise Group: 3
days/w x 50-60 min; intensity: 55-
75% from VO2 peak.
Combined Exercise: 3 days/w of CV
training with sessions of 25-30 min
(intensity: 55-75% from VO2 peak) +
2 sets x 10-12 rep (intensity: 60-
75% one-repetition maximum).
VO2 Peak VO2 peak decreased by
12% in the standard
aerobic exercise group,
9% in the high aerobic
exercise group, and by
13% in the combined
exercise group.
Dolan et al 242 49.2 Breast II-IIIA CV vs. ST Aerobic Exercise Group: 3 days/w,
with sessions of 15-45 min (intensi-
ty: 60-80% from VO2 peak).
Resistance Training Group: 3
days/w x 2 sets of 8-12 rep and 9
exercises (intensity: 60-70% of one-
repetition maximum).
VO2 Peak. The resistance training
(and the usual care
group) showed
increase in VO2 peak.
Both exercise groups
showed moderate
correlation between
VO2 peak change and
hemoglobin.
Haykowsky
et al
17 53 Breast
with
HER2
All stages CV Three days/w x 16 weeks x 30-60
min (intensity: 60-90% from VO2
peak).
VO2 Peak. LV
volume and
LVEF. HR. BP.
VO2 peak positively co-
rrelated with exercise
adherence. Interven-
tion led to resting
BP volume increase
and ejection function
decrease.
Hornsby et al 20 48.5 Breast IIB-IIIC CV Three days/w and sessions of 15-45
min (intensity: 60-100% from VO2
peak). The program lasted 12 wee-
ks (last two with higher intensity:
100% from VO2 peak).
VO2 Peak. HR.
BP. LVEF.
VO2 peak increased by
13% in the exercise
group. No signicant
between-group die-
rences in terms of HR,
BP and LVEF.
Jones et al 20 48.5 Breast II-IIIC CV Aerobic Exercise Group: 3 days/w
x 12 weeks x 30-45 min (intensity:
60-100 from VO2 peak).
VO2 Peak.
Brachial artery
ow-mediated
dilation. Circula-
ting endothelial
progenitor cell
count (VEGFR-2,
CD-133/VE-
GFR-2, ALDHbr).
VO2 peak increased
by 13% in the exercise
group.
Higher levels of
circulating progenitor
cell in the exercise
group in comparison
to controls, as well
as greater brachial
dilation.
(Continued)
Table 1. Main features of studies selected in this review.

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review
129
Arch Med Deporte 2020;37(2):125-135
Study Sample
size
Mean
age
Cancer
site
Severity Type of
intervention
Intervention particularities Outcome Results
Kim et al 41 49.8 Breast I-III CV Three days/w and sessions of 30
min (intensity: 60-70% from VO2
peak or HR reserve).
VO2 Peak. HR.
B P.
The exercise group
showed signicant
increases in maximum
systolic BP volume and
VO2 peak, as well as
decreses in resting HR
and resting systolic BP.
Kirkham et al 24 50.5 Breast I-III CV A single session of 45-min treadmill
exercise (intensity: 70% from HR
reserve).
Cardiac biomar-
kers (NT-proB-
NP, cTnT). HR.
Systemic vascu-
lar resistance.
LV volume and
LVEF.
VO2 peak increased
by 15% in the exercise
group.
Higher levels of car-
diac biomarkers in the
exercise group.
LVEF increased by 3%
after intervention in
the exercise group.
Kolden et al 40 55.3 Breast I-III Combined +
stretching
Three days/w with 20-min aerobic
exercise (intensity: 40-70 from VO2
peak) + 20-min strength training
(not reported intensity) +
Stretching.
VO2 Peak.
Resting HR and
B P.
VO2 Peak increased at
post-intervention as-
sessment and follow-
up. Resting systolic
BP across assessment
points.
Ligibel et al 41 47 Breast I-III CV An aerobic exercise program with
sessions of 150 min/w.
VO2 Peak. VO2 peak increased
by 4% in the exercise
group.
MacVicar 45 45.1 Breast II CV Usual Care + Stretching + cardio-
vascular training (3sessions/w;
intensity: 60-85% from resting HR).
VO2 Peak IG increased 40%
of functional capa-
city and maximum
workload.
Scott et al 65 54 Breast IV
(metasta-
tic)
CV vs. Others Aerobic Exercise Group: 3 days/w
x 20-45 min (intensity: 55-80 from
VO2 peak).
Stretching Group: 3 days/w x 20-45
min (12-20 positions).
VO2 Peak. BP. No signicant dieren-
ces between groups.
Segal et al 123 50.9 Breast I-II CV Supervised Group: 3 days/w + 2
days/w at home during 26 weeks.
Home Based Group: 5 days/w of
exercise at home (26 weeks).
VO2 Peak. VO2 peak increased
by 3.5% in supervised
exercise group and
2.4% in the home-
based group.
Segal et al 121 66.3 Prostate All stages CV vs. ST Aerobic Exercise Group: 3 days/w
x 15-45 min sessions during 24
weeks (intensity: 50-75% from
VO2 peak).
Resistance Training: 3 days/w with
10 exercises of 8-12 rep.; intensity:
60-70% from VO2 peak (one
repetition maximum).
VO2 Peak VO2 peak increased
by 0.1% in the aerobic
exercise group and
0.5% in the resistance
training group.
Van Waart
et al
230 50.7 Breast &
colon
II-III CV vs.
combined
Onco Move Group (CV program):
5 days/w x 30 min/day; intensity:
BORG Scale of 12-14.
On Track Group (combined pro-
gram): 3 days/w x 30 min (intensity:
50-80% based on Steep Ramp Test)
+ 2 days/w x 20 min x 2 sets x 8 rep.
x 80% of one-repetition maximum.
VO2 Peak VO2 peak decreased by
18% in the Onco Move
group and by 12% in
the On Track group.
Vincent et
al
34 49 Breast I-III CV Home-based walking aerobic
exercise (3 days/w of 30-40 min
sessions, with 50-60% from HR max
intensity).
VO2 Peak.
Resting HR.
Resting BP
VO2 peak increased
by 11% in the exercise
group. No signicant
between-group
dierences in terms of
HR and BP.
(Continued)

David García-González,
et al.
130 Arch Med Deporte 2020;37(2):125-135
Study Sample
size
Mean
age
Cancer
site
Severity Type of
intervention
Intervention particularities Outcome Results
Survivor samples
Adams et al 63 43.7 Testicu-
lar
Not repor-
ted
CV Supervised treadmill program
consisted of 3 days/w x 12 weeks,
35-min sessions and interval training
(Ventilatory Threshold +4x4 min and
intensity 75-95% from VO2 peak).
VO2 Peak. HR.
BP. Cardiovascu-
lar disease risk.
Carotid arteria
morphology.
Brachial arteria
ow-mediated
dilation
VO2 peak increased
by 11% in the exercise
group.
The exercise group
showed higher
carotid distensibility
and brachial arteria
diameter, and lower
carotid intima-media
thickness.
Brdareski
et al
18 50.5 Breast I-IIIA CV Group 1: Two days/w x 3 weeks and
15-min sessions (intensity: 45-65%
VO2 max).
Group 2: Two days/w x 3 weeks and
15-min sessions (intensity: Borg
Scale scores between 4-6).
VO2 Peak. VO2 peak increased
by 11% in the Group
1 and 18% in the
Group 2.
Courneya
et al
53 59 Breast All stages CV Three days/w x 15-35 min (intensi-
ty: 70-75% from VO2 peak).
VO2 Peak. VO2 peak increased
by 15% in the exercise
group.
Herrero et al 16 50.5 Breast I-II Combined Aerobic training: 3 days/w (intensi-
ty: 70-80% from HR max).
Resistance Training: 3 days/w x
1-3 sets of 11 exercises and 8-15
rep. (intensity: 8-15 one-repetition
maximum).
VO2 Peak. VO2 peak increased
by 8% in the exercise
group.
Herrero et al 11 47 Breast I-II Combined Training period: 3 days/w during
eight w, 90-min sessions. After the
intervention, participants were
instructed to return following their
sedentary lifestyle.
VO2 Peak. VO2 peak decreased
signicantly after
returning to sedentary
lifestyle routines.
Hsieh et al 96 57.9 Breast All Combined A program consisted of 2-3 weekly
sessions of 60 min (intensity: 45-
75% from HR reserve; not specied
for resistance training).
VO2 Peak. HR.
B P.
The exercise group
showed increases in
VO2 volume (over 16%)
and resting HR.
Hutnick et al 49 50.4 Breast All Combined Three days/w of 40-90 min.
sessions.
Aerobic Exercise: 10-20 min with
intensity 60-70% from functioning
capacity.
Resistance training: Four upper &
lower exercise x 1-3 sets of 8-12
rep.
HR peak. HR peak increased in
the exercise group
from the 3-month
follow-up after the
intervention.
Jones et al 90 66 All
(Cancer
patients
with
heart
failure)
II-IV CV A 3-Month program comprising
supervised Exercise + home
Sessions until 12 months. 3 days/w
x 20-45 min (intensity: 60-70% from
HR reserve).
VO2 Peak.
Cardiovascular
risk prole.
VO2 peak increased
by 9% in the exercise
group.
No between-group
dierences in cardio-
vascular risk prole.
Jones et al 50 Not
repor-
ted
Prostate I-II CV Aerobic walking Exercise of 5
days/w x 30-45 min, a session
(intensity: 55-100 from VO2 peak).
VO2 Peak.
Brachial artery
ow mediated
dilation.
VO2 peak increased
by 9% in the exercise
group.
Higher brachial arterial
diameter after the
intervention only in
the exercise group.
(Continued)

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review
131
Arch Med Deporte 2020;37(2):125-135
Study Sample
size
Mean
age
Cancer
site
Severity Type of
intervention
Intervention particularities Outcome Results
Musanti et al 42 50.5 Breast I-IIIB CV vs. ST vs.
Combined vs.
Others
Aerobic exercise Group: 3 days/w
(intensity: 40-85% from HR reserve).
Resistance Training Group: 3 days/w
x 1 set of 10-12 rep (intensity: 3-8
from one-repetition maximum).
Combined Exercise Group: 4-5
days/w aerobic training + 2 days/w
resistance training.
VO2 Peak. No signicant
between-group
dierences reported.
Pinto et al 46 57.3 Colorec-
tal
I-III CV 12-week home-based physical
activity counselling (2-5 days/w x
10-30 min, with intensity 64-76%
from maximal HR).
VO2 peak. VO2 peak: Conrol
Group =Increased
15%. Exercise Group
=Increased 32%
Rahnama
et al
29 Ran-
ge:
50-65
years
old
Breast I-IIIB Combined Aerobic Exercise: 2 days/w x 25-45
min sessions (intensity: 45-65%
from HR maximum) + Resistance
training: 2 days/w consisting of 3
sets x 10-14 rep. x 9 exercises.
VO2 Peak. Res-
ting HR. BP.
VO2 peak increased
by 15% in the exercise
group.
The exercise group
showed signicant
decrease in resting HR
and resting BP after
intervention.
Rogers et al 41 53 Breast I-IIIA CV Combined individual and collective
group aerobic exercise group.
VO2 Peak. No signicant
between-group die-
rences reported.
Rogers et al 222 54.4 Ductal
Carci-
noma &
breast
I-IIIA CV Twelve sessions of supervised
Exercise + 6 group discussion and
individual Sessions. 3-5 days/w x
15-50 min.
VO2 Peak. VO2 peak increased
by 12% in the exercise
group.
Schneider
et al
113 55.9 Breast Not
reported
Combined Combined individual aerobic +
resistance exercise: 2-3 days/w of
60-min sessions. Aerobic exercise
lasted 40 min (intensity: 40-75%
from HR reserve). Resistance trai-
ning lasted 10 min (intensity not
specied).
VO2 Peak. BP.
Resting HR.
BP decreased while
exercise intervention
was delivered.
Resting HR and BP
decreased at post-
intervention. Also, V02
peak increased by 13%
in this condition.
Thorsen et al 111 39.1 Lympho-
ma, tes-
ticular,
breast
and
other
gyne-
cologic
Cancers
All stages CV Home-based program: 2 days/w
x 30 min (13-15 based on BORG
Scale).
VO2 Peak VO2 peak: Control
Group =Increased
3,1 ml/kg/min. Home
Exercise Group =In-
creased 6,4 ml/kg/min
Note: The 33 bibliographic references included in Table 1 can be found online in Annex 1.
CV: cardiovascular training; ST: Strength; HR: heart rate; w: weeks; rep.: repetitions; VO2 : Volume of oxygen consumed; BP: Blood pressure; LV: Left ventricle; LVEF: left ventricular ejection
function; NT-proBNP: B-type natriuretic peptide; cTnT: Cardiac Troponin T.
Discussion
Our narrative review aimed to ll the research gap on how physi-
cal exercise may contribute to reduce cardiotoxicities associated with
oncological treatments (chemotherapy, radiotherapy, hormonotherapy
and / or immunotherapy).
Current diagnostic techniques are important to keep in mind
when talking about cardiotoxicity: Diagnostic imaging and Biomarkers
in cardio-oncology. Traditionally, left ventricular ejection fraction (LVEF)
has been used (i.e., a 2D echocardiogram) to quantify cardiotoxicity
(Figure 3). However, a cardiac injury may exist underlying an apparently
‘normal’ heart’s ejection (i.e., without a decrease in the LVEF), as some
authors have demonstrated signicant false-positive rates of LVEF-
based tools34. Cardiac Magnetic Resonance Imaging is considered as
the gold standard for the assessment of systolic and diastolic cardiac
function and allows for direct imaging of the myocardium7 (Figure
4). Lately, cardiac biomarkers (e.g., troponin I, natriuretic peptide B-
type) have emerged as a promising alternative to study cardiotoxicity.

David García-González,
et al.
132 Arch Med Deporte 2020;37(2):125-135
However, inconsistent evidence and limited predictive value have
found so far7. More recently, Galán-Arriola et al.,35 have identied by
serial multiparametric cardiac Magnetic Resonance, intracardiom-
yocyte edema in T2 mapping as the earliest marker of anthracycline
cardiotoxicity, in the absence of T1 mapping, extracellular volume or
left ventrical motion defects.
It seems to be that key elements behind any carcinogenic process is
the dysregulation of signs controlling the proliferation of cellular division
and inammation36. By means of the regulation of certain proteins and
hormonal levels in the bloodstream, physical exercise might prevent
some chemical signs associated with cancer.
Figure 3. 2D Echocardiography showing aberrant movement and hypokinesia of inferior wall and septum in a patient diagnosed of
dilated myocardiopathy as a consequence of doxorubicin, trastuzumab and radiotherapy treatment for breast cancer.
Figure 4. Cardiac Magnetic Resonance Imaging to evaluate function, morphology and viability.
Left ventricle lightly dilated and global hypokinesis with LVEF 31%, in a patient diagnosed with Hodgkin lymphoma 30 years before treated with radiotherapy.
Reviewing the available evidence, it becomes evident that the
etiology of cardiotoxicity is multifactorial. Nevertheless, it is clear that in
the scientic literature, the following mechanisms related to molecular
and cellular biology are repeated:
− Disorder and dysfunction of the Ryanodine receptors (RyR)16,37.
− Disorder and dysfunction, both at a structural and contractile
level, of the Myosin heavy chain (MHC)24,38,39.
− Disorder and Dysfunction in the Tyrosine Kinase protein40,41.
− Excess of production of Reactive Oxygen Species (ROS) and
Reactive Nitrogen Species (RNS)18,19.
− Deciency and mitochondrial dysfunction17,42,43.

Tailored exercise as a protective tool in cardio-oncology rehabilitation: a narrative review
133
Arch Med Deporte 2020;37(2):125-135
The improvement of the vascularization tissue seems to improve
not only the tissue oxygenation but also the action of the antitumor
treatments. In the case of treatment with anthracyclines, physical exer-
cise lightens these products in order to not be stored in the organism
and generate toxic eects in the cardiovascular system44,45.
It is important to emphasize the role accumulation of doxorubicin
in muscular tissues of rats. This accumulation would explain the dys-
functions associated not only with the cardiovascular system, but also
with the skeletal muscle system. Research literature found a reduction
in the tumor size linked to exercise. Through physical exercise, the
bioavailability of anthracyclines may improve, as well as the eciency
of the drug in its antitumor aspect.
Moreover, Pedersen et al.46, demonstrated the immunological
protective eect of exercise in mice. The interaction between epine-
phrine, muscular interleukin 6 and Natural Killer cells generated marked
reductions in tumor incidence, growth and metastasis.
Exercise improves the vessel reactivity before the treatment of
anthracyclines. In the group where physical exercise was carried out,
vasoreactivity obtained values signicantly better than the sedentary
group.
Exercise interventions have been obtained results of improvement
in cardiac function and cardiac damage markers during treatments with
anthracyclines30,32. Perhaps with the knowledge that is currently availa-
ble, said cardiac dysfunction may have been reduced or prevented by
physical exercise before or during anthracycline treatments.
There are no exclusive strength interventions in humans trying to
reduce CTC in oncological patients.
The fact to do a special mention of the strength training in this arti-
cle, is related with the tumoral disease and with the consequences with
respect to the organ we have focused: the heart. In cardiotoxicity with
oncological origin 2 types of patients could be found from a medical
point of view: one will be seen from the oncology focus, and the other
from the pathology and functionality of cardiology.
The studies by Bredahl et al.23 and Pfannenstiel et al.24 focused on
interventions using resistance exercise on Sprague-Dawley rats which
cardiotoxicity were induced by doxorubicin. The intervention through
physical exercise is done prior to the administration of doxorubicin. The
resistance exercise allows to maintain levels of strength and prevent
muscle mass loss induced by doxorubicin; one of the most common
side eects in chemotherapy. Pfannenstiel et al.24, shows that this
muscle- protective eect could not only be quantied with respect to
a greater muscle mass, but also in a lower mortality rate: 13% mortality
in the strength group vs 27% sedentary group. The strength group also
had a cardioprotective eect with respect to heart mass and function.
Although Cardiac Rehabilitation Units (CRU) are doing an excellent
work, we based our proposal of strength training in Cardio-Oncology
on 2 aspects:
− The levels of strength developed by the patients outside the CRU
are higher to those developed inside the hospital units47. Thus, the
goal of minimize the risk of accident by performing the higher
intensity strength work into the CRU is questioned and encourages
us to promote individualized exercise units that include strength
exercise in cancer patients.
− Dening Repetition Maximum (RM) as the maximal weight that can
be lifted once with correct lifting technique48. It is also considered
the gold standard for assessing muscle strength in non-laboratory
situations48. There are some examples in the literature in patients
with heart disease in which the strength training was performed
at intensities of 80-90% of 1 Repetition Maximum (1RM), in coro-
nary patients49-51, intensities up to 60% 1RM in bilateral work (both
members), and up to 80% 1RM in unilateral work, in patients with
heart failure with an ejection fractions of 20% according to NYHA
Classication (New York Heart Association)52. This could be extrapo-
lated to oncological patients with risk of CTC due to the treatments.
The World Health Organization53 included specic strength work in
its guides on Global Recommendations on Physical Activity for Health.
Traditionally, cardiovascular training has been considered as the
most protective physical exercise applied in medicine. In the 80s of
the twentieth century, exercise- based interventions in oncological
patients have already been used54. Later on, the rst guide that linked
physical exercise and oncology was developed54. More recently, the
experts in the delivery of exercise-based interventions in cancer patients
recommend combined interventions, comprising cardiovascular and
strength training55.
Strength training components may yield very benecial eects in
cancer patients56-58 improvements in cardiovascular function, increases
in VO2peak, a decrease in fatigue levels, increases in muscular strength
and density of osseous mass, improvement in the quality of life, preven-
tion of sarcopenia and dynapenia, and a decrease in the percentages
of fat mass.
From early studies in exercise oncology until today, many advances
linked to the clinical exercise physiology have been made. It has even
been discovered that the skeletal muscle is an endocrine, exocrine and
paracrine organ59, and produced proteins (including dierent cytokines
and peptides) are known as myokines.
At present, it is starting to be considered that physical exercise
might generate, in each training session, peaks of chemical compo-
nents, which could be used not only as co-adjuvant anticarcinogenic
treatment60, but also for 26 dierent chronic diseases61. We propose
combined exercise interventions to reduce the risks of Cardiotoxicity
in cancer patients as co-adjuvant treatment: Cardiovascular Training in
combination with Strength Training. Recently, the AHA has conrmed
this combined tailored exercise in his Cardio-Oncology Rehabilitation
Statement15.
Conclusions
Cancer treatments cause dysfunction in muscular tissue (cardiac,
skeletal and smooth muscle) and loss of muscular strength. Physical
exercise can oset the side eects of cancer treatments. There are bio-
logical reasons (cellular, molecular and biochemical release) that explain
the cardiovascular and muscular protective eect of exercise in Exercise
Oncology. It is advisable to introduce intervention programs with per-
sonalized physical exercise in cancer patients for the protective eects
that it generates. Training interventions should comprise cardiovascular
and muscular strength exercise with personalized frequencies, intensities

David García-González,
et al.
134 Arch Med Deporte 2020;37(2):125-135
and specic durations for every patient. It is necessary to avoid physical
inactivity in patients with cancer.
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