Aerobic Exercise-Induced Changes in Cardiorespiratory Fitness in Breast Cancer Patients Receiving Chemotherapy: A Systematic Review and Meta-Analysis

Abstract

While performing aerobic exercise during chemotherapy has been proven feasible and safe, the efficacy of aerobic training on cardiorespiratory fitness (CRF) in women with breast cancer undergoing chemotherapy has not yet been systematically assessed. Therefore, the objective of this work was to determine (a) the efficacy of aerobic training to improve CRF; (b) the role of aerobic training intensity (moderate or vigorous) on CRF response; (c) the effect of the aerobic training mode (continuous or interval) on changes in CRF in women with breast cancer (BC) receiving chemotherapy. A systematic review and meta-analysis were conducted as per PRISMA guidelines, and randomized controlled trials comparing usual care (UC) and aerobic training in women with BC undergoing chemotherapy were eligible. The results suggest that increases in CRF are favored by (a) aerobic training when compared to usual care; (b) vigorous-intensity aerobic exercise (64–90% of maximal oxygen uptake, VO2max) when compared to moderate-intensity aerobic exercise (46–63% of VO2max); and (c) both continuous and interval aerobic training are effective at increasing the VO2max. Aerobic training improves CRF in women with BC undergoing chemotherapy. Notably, training intensity significantly impacts the VO2max response. Where appropriate, vigorous intensity aerobic training should be considered for women with BC receiving chemotherapy.

Full text

cancers
Review
Aerobic Exercise-Induced Changes in
Cardiorespiratory Fitness in Breast Cancer Patients
Receiving Chemotherapy: A Systematic Review
and Meta-Analysis
Guilherme Maginador 1, Manoel E. Lixandrão2, Henrique I. Bortolozo 1, Felipe C. Vechin 2,
Luís O. Sarian 1, Sophie Derchain 1, Guilherme D. Telles 2, Eva Zopf 3, Carlos Ugrinowitsch 2
and Miguel S. Conceição1,2,4,*
1
Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Campinas, Campinas,
São Paulo 13083-881, Brazil; guilherme.maginador@gmail.com (G.M.); hbortolozo@gmail.com (H.I.B.);
sarian@unicamp.br (L.O.S.); sophie.derchain@gmail.com (S.D.)
2School of Physical Education and Sport, University of São Paulo, São Paulo 05508-030, Brazil;
manelix.ef@gmail.com (M.E.L.); felipe.cassaro@yahoo.com.br (F.C.V.); guitelles11@hotmail.com (G.D.T.);
ugrinowitsch@gmail.com (C.U.)
3Department of Exercise Oncology, Mary MacKillop Institute for Health Research, Australian Catholic
University, Melbourne 3000, Australia; Eva.Zopf@acu.edu.au
4Faculty of Physical Education, University of Campinas, Campinas 13083-851, Brazil
*Correspondence: conceicao.miguel0106@gmail.com; Tel.: +55-11-3091-8733
Received: 21 June 2020; Accepted: 30 July 2020; Published: 11 August 2020


Abstract:
While performing aerobic exercise during chemotherapy has been proven feasible and
safe, the efficacy of aerobic training on cardiorespiratory fitness (CRF) in women with breast cancer
undergoing chemotherapy has not yet been systematically assessed. Therefore, the objective of this
work was to determine (a) the efficacy of aerobic training to improve CRF; (b) the role of aerobic
training intensity (moderate or vigorous) on CRF response; (c) the effect of the aerobic training
mode (continuous or interval) on changes in CRF in women with breast cancer (BC) receiving
chemotherapy. A systematic review and meta-analysis were conducted as per PRISMA guidelines,
and randomized controlled trials comparing usual care (UC) and aerobic training in women with BC
undergoing chemotherapy were eligible. The results suggest that increases in CRF are favored by
(a) aerobic training when compared to usual care; (b) vigorous-intensity aerobic exercise (64–90% of
maximal oxygen uptake, VO
2max
) when compared to moderate-intensity aerobic exercise (46–63%
of VO
2max
); and (c) both continuous and interval aerobic training are effective at increasing the
VO
2max
. Aerobic training improves CRF in women with BC undergoing chemotherapy. Notably,
training intensity significantly impacts the VO
2max
response. Where appropriate, vigorous intensity
aerobic training should be considered for women with BC receiving chemotherapy.
Keywords: aerobic fitness; breast cancer; exercise rehabilitation; VO2max
1. Introduction
According to the World Health Organization (WHO), cancer was the leading cause of death
worldwide in 2018. Two million new cases and over 600,000 deaths were attributed to breast cancer
(BC) alone [
1
]. In BC patients, anticancer therapy most commonly involves chemotherapy and
is considered crucial in improving survival [
2
]. Despite its positive clinical effect, chemotherapy
has been associated with debilitating side effects [
3
], such as muscle atrophy [
4
,
5
], cancer-related
fatigue [
6
–
8
], and cardiotoxicity [
9
–
11
]. Further, a 31% impairment in cardiorespiratory fitness (CRF),
Cancers 2020,12, 2240; doi:10.3390/cancers12082240 www.mdpi.com/journal/cancers

Cancers 2020,12, 2240 2 of 14
as measured by the peak/maximal oxygen consumption (VO
2max
), has been observed in women with
BC undergoing adjuvant chemotherapy [
12
]. This is a concern, given that emerging evidence suggests
that CRF is a significant prognostic marker, with data indicating that a poor VO
2max
is associated
with a poorer quality of life, treatment-induced cardiotoxicity, and an increased risk of cancer-related
mortality [13–16].
Aerobic training has been shown to improve CRF and other cancer-related health outcomes in
cancer patients [
17
,
18
], which has led major health organizations to include aerobic exercise in their
physical activity guidelines for cancer patients [
19
,
20
]. However, the efficacy of aerobic training on CRF
specifically in women with BC undergoing chemotherapy has not yet been systematically assessed,
and it remains unclear what the most effective training protocols are with regard to training intensity
and mode. For instance, Segal et al. (2001) [
21
] compared a continuous aerobic exercise guideline-based
training group (chemotherapy +150 min of moderate (50–60% of VO
2max
) continuously walking)
versus an usual care (UC) non-exercising group. The authors showed that, after 26 weeks of training,
the VO
2max
decreased by 0.3 mL
·
kg
−1
min
−1
in the training group and increased by 0.2 mL
·
kg
−1
min
−1
in the UC group. Conversely, Jones et al. [
22
] showed that 12 weeks of moderate/vigorous-intensity
aerobic training (55–100%-VO
2max,
20–45 min-, 3 times/week) increased the VO
2max
(from 19.5
±
7.6 to
22.1
±
7.0 mL
·
kg
−1
min
−1
) in women with BC undergoing chemotherapy. Taken together, these results
suggest that aerobic training intensity may play a role when aiming to improve VO
2max
in women
with BC undergoing chemotherapy. Considering aerobic training mode, both continuous and interval
aerobic training have shown to successfully impact cardiac function and hence CRF in BC patients
undergoing chemotherapy [
22
–
24
]. Thus, identifying the most effective aerobic training protocols to
increase VO
2max
, a strong predictor of symptom burden; cardiac function; [
12
] and mortality, may help
to mitigate short- and long-term health issues in BC survivors.
In order to account for differences in aerobic training protocols between studies and factors
such as low statistical power (small sample sizes) in randomized controlled trials, we conducted a
meta-analysis. A meta-analysis summarizes data from different studies and allows testing for the
effects of moderator variables (e.g., exercise intensity, mode of aerobic training), thereby improving
the estimated precision of the factors affecting the changes in VO
2max
. The purpose of this systematic
review and meta-analysis was to determine: (a) the efficacy of aerobic training to increase CRF
(measured by VO
2max
); (b) the role of aerobic training intensity (moderate or vigorous) on the VO
2max
response; (c) the effect of the aerobic training mode (continuous or interval) on the changes in VO
2max
in women with BC receiving chemotherapy.
2. Methods
2.1. Protocol and Registration
The systematic review was registered with PROSPERO (CRD42019134584), and the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic review reporting
were followed [25].
2.2. Search Strategy and Information Sources
A systematic literature review was performed using three major databases (PubMed, Scopus,
and Web of Science). The last search was performed on November 1st, 2019. This search
was applied with no limits to publication year, type, and status. The MeSH terms were
combined as follows: ((((“breast carcinoma” [Title/Abstract] OR “breast neoplasm” [Title/Abstract]
OR “breast tumor” [Title/Abstract] OR “breast cancer” [Title/Abstract] OR “mammary cancer”
[Title/Abstract] OR “mammary carcinoma” [Title/Abstract]))) AND ((chemotherapy [Title/Abstract]
OR “adjuvant chemotherapy” [Title/Abstract] OR “neoadjuvant chemotherapy” [Title/Abstract] OR
chemoradiotherapy [Title/Abstract] OR radiochemotherapy [Title/Abstract] OR “neoadjuvant therapy”
[Title/Abstract] OR “adjuvant therapy” [Title/Abstract]))) AND ((“exercise training” [Title/Abstract] OR

Cancers 2020,12, 2240 3 of 14
“aerobic exercise” [Title/Abstract] OR “training exercise” [Title/Abstract] OR exercise [Title/Abstract]
OR “physical exercise” [Title/Abstract] OR “endurance exercise” [Title/Abstract] OR endurance
[Title/Abstract] OR “high-intensity interval training*” [Title/Abstract] OR HIIT [Title/Abstract] OR
“sprint interval training*” [Title/Abstract] OR “physical activity” [Title/Abstract])). Two researchers
conducted the review independently (GM and HB). Discrepancies between researchers were discussed
and, if necessary, a third researcher was consulted (MSC). Reference lists of identified articles were also
searched for additional relevant articles on the topic.
2.3. Eligibility Criteria
Only English-language studies, Pilot Studies (PS), and Randomized Controlled Trials (RCT)
comparing the effects of aerobic training (continuous or interval; home-based or under professional
supervision) and usual care on the VO
2max
of women with BC undergoing chemotherapy (adjuvant
or neoadjuvant) were included. Studies that included participants of any age with histologically
confirmed BC undergoing chemotherapy in combination with other treatments were considered (e.g.,
radiotherapy or hormonal therapy). Studies that evaluated different types of cancer (e.g., breast, ovarian,
rectal, etc.) were only included if data from a breast cancer-only group were provided. The primary
outcome for this systematic review and meta-analysis was CRF, measured by the maximum oxygen
uptake (VO2max or VO2peak). Training intensity and mode were used as moderator variables.
The exclusion criteria were as follows: (i) duplicated articles; (ii) duplicated data; (iii) articles
without original data (e.g., comments, reviews, case reports, and technical reports); (iv) studies with
dietary counseling or intervention; (v) studies involving metastatic breast cancer patients; and (vi)
studies with no usual care-only group.
2.4. Study Selection and Data Extraction
To reduce the selection bias potential, the titles and abstracts of all studies were independently
evaluated by two investigators (GM and HIB). Duplicated studies were excluded, and the remaining
ones were screened, assessed for eligibility criteria, and then forwarded to data extraction.
Data extraction was performed by three independent reviewers (GM, HIB, and MSC) for the following
variables: authors, year of publication, sample size, treatment protocol, exercise protocol, and pre
and post-intervention mean
±
standard deviation (SD) values of the VO
2max
/VO
2peak
. The data
extraction procedures were standardized using a pre-piloted Excel spreadsheet. To test for possible
coding drift, we randomly selected 30% of the studies for recoding following procedures outlined by
Cooper et al. [26]. The mean agreement between coders was 95%.
2.5. Assessment of Risk of Bias within and across Studies and Quality
The risk of bias of the included studies was independently assessed by two authors (CU and
MSC) using the Revised Cochrane risk-of-bias tool for Randomized Trials (RoB2) [27]. The following
five domains were assessed: {1} bias arising in the randomization process; {2} bias due to deviations
from intended interventions; {3} bias due to missing outcome data; {4} bias in the measurement of the
outcome and {5} bias in the selection of the reported result. Each domain was classified as having
{1} LOW risk of bias; {2} SOME CONCERN of risk of bias and {3} HIGH risk of bias. The Revised
Cochrane risk-of-bias data is presented in Figure 1.

Cancers 2020,12, 2240 4 of 14
Cancers 2020, 12, x 4 of 14
Figure 1. Risk of bias assessment for the studies included in the meta-analysis. Footnotes: AE =
Aerobic Training; UC = Usual Care.
2.6. Training Protocol Classification
Each study was reviewed regarding the prescribed aerobic training protocol. Some studies
implemented a periodized aerobic training protocol (i.e., progressive increase in training load), while
others used a constant relative training intensity throughout the experimental period. To determine
the predominant training intensity, we identified the intensity in which patients performed most of
the training sessions. Training intensities were classified as moderate or vigorous. We used the
American College of Sports Medicine (ACSM) equivalence table to determine the relative training
intensity [28] of all the studies (Table 1). Further, the training protocols were classified as either
interval or continuous training, and the total minutes of training were determined. Warm-up and
cool down minutes were not included when computing the total training minutes.
It is important to highlight that seven out of nine studies measured the VO2max directly. Mijwel
et al. 2018 [29] estimated the VO2max using a submaximal cycle ergometer test. Ma 2018 [23] indirectly
measured VO2max using a treadmill exhaustion protocol. Seven studies measured VO2 directly using
an exhaustion protocol on a cycle ergometer (Jones et al. 2013 [22]; Lee et al. 2019 [24]; Moller et al.
2015 [30]; Mowafy et al. 2016 [31]) or treadmill (Al-Majid et al. 2015 [32]; Courneya et al. 2007 [33];
Kim et al. 2006 [34]). It is also necessary to report that five studies conducted the VO2max measurement
and the training on the same device [22–24,31,32], while four other studies measured the VO2max and
conducted the training on different devices [29,30,33,34].
Figure 1.
Risk of bias assessment for the studies included in the meta-analysis. Footnotes: AE =
Aerobic Training; UC =Usual Care.
2.6. Training Protocol Classification
Each study was reviewed regarding the prescribed aerobic training protocol. Some studies
implemented a periodized aerobic training protocol (i.e., progressive increase in training load),
while others used a constant relative training intensity throughout the experimental period.
To determine the predominant training intensity, we identified the intensity in which patients
performed most of the training sessions. Training intensities were classified as moderate or vigorous.
We used the American College of Sports Medicine (ACSM) equivalence table to determine the relative
training intensity [
28
] of all the studies (Table 1). Further, the training protocols were classified as either
interval or continuous training, and the total minutes of training were determined. Warm-up and cool
down minutes were not included when computing the total training minutes.
It is important to highlight that seven out of nine studies measured the VO
2max
directly.
Mijwel et al. 2018 [29]
estimated the VO
2max
using a submaximal cycle ergometer test. Ma 2018 [
23
]
indirectly measured VO
2max
using a treadmill exhaustion protocol. Seven studies measured VO
2
directly using an exhaustion protocol on a cycle ergometer (Jones et al. 2013 [
22
]; Lee et al. 2019 [
24
];
Moller et al. 2015 [
30
]; Mowafy et al. 2016 [
31
]) or treadmill (Al-Majid et al. 2015 [
32
]; Courneya et al.
2007 [
33
]; Kim et al. 2006 [
34
]). It is also necessary to report that five studies conducted the VO
2max
measurement and the training on the same device [
22
–
24
,
31
,
32
], while four other studies measured the
VO2max and conducted the training on different devices [29,30,33,34].

Cancers 2020,12, 2240 5 of 14
Table 1. Descriptive data of the studies included in the meta-analysis.
Al-Majid et al. [32] Courneya et al. [33] Jones et al. [22] Kim et al. [34] Lee et al. [24] Ma [23] Mijwel et al. [29] Moller et al. [30] Mowafy et al. [31]
PUBLICATION
YEAR 2015 2007 2013 2006 2019 2018 2018 2015 2016
AGE
USUAL CARE 52.7 ±10.7 49 46 ±11 48.3 ±8.8 44.7 ±11.2 43.5 ±6.3 52.6 ±10.2 46.95 ±9.19 45
TRAINING 47.9 ±10.4 49 51 ±6 51.3 ±6.7 49.1 ±7.9 44.2 ±5.7 54.4 ±10.3 48.49 ±8.41 45
(N)
USUAL CARE 7 73 10 19 15 33 51 10 20
TRAINING 6 71 10 22 15 31 70 10 20
CHEMOTHERAPY
NEO Y Y
ADJ Y Y Y Y Y Y Y Y
TYPE
NON TAX
AC Y Y Y Y Y Y Y
CYC Y Y
FE100C, CE120F Y
TRAST
TAXANE Y Y Y Y
TRAINING PROTOCOL
DURATION
(weeks) 12 18 12 8 8 16 16 12 16
MODE CON CON CON CON INT INT CON CON CON
VOLUME MEAN
(min/week) 90 97.5 102 90 63 150 60 150 45
INTENSITY VIG VIG MOD VIG VIG VIG VIG MOD VIG
TIME (min) ×INTENSITY
LIGHT 336 -
MODERATE 130 315 795 574 1800 -
VIGOROUS 1050 1170 400 720 960 802 -
MAXIMAL 30 168
VO2 OUTCOMES
USUAL CARE
PRE 23.8 ±2.9 * 24.8 ±6.2 * 17.5 ±4.8 * 1597 ±357 †18.7 ±7.1 * 1210 ±258 †2.19 ±0.53 ‡30.5 ±5.0 * 21.1 ±2.5 *
POST 17.5 ±2.8 23.5 ±5.4 16.0 ±4.0 1630 ±351 16.1 ±6.0 984 ±157 1.94 ±0.52 27.7 ±6.8 21.0 ±2.4
TRAINING
PRE 26.1 ±2.6 25.2 ±7.2 19.5 ±7.6 1671 ±349 19.7 ±8.7 1134 ±268 2.10 ±0.47 27.1 ±6.4 21 ±2.5
POST 26.0 ±2.5 25.7 ±7.4 22.1 ±7.0 1810 ±369 19.4 ±6.6 1594 ±190 2.06 ±0.45 22.4 ±6.5 30.8 ±3.5
NEO =neoadjuvant; ADJ =adjuvant; TAX =taxane; AC =anthracycline; CYC =cyclophosphamide; TRAST =trastuzumab; CON =continuous; INT =interval; VIG =vigorous;
MOD =moderate
. LIGHT =37–45% of VO
2max
; MODERATE =46–63% of VO
2max
; VIGOROUS =64–90% of VO
2max
; MAXIMAL =
≥
91% of VO
2max
. * Unit: mL
·
kg
−1·
min
−1
;
†
mL
·
min
−1
;
‡L·min−1. It was not possible to identify the time that was performed at each training intensity; however, as the training was performed until exhaustion, it was classified as vigorous.

Cancers 2020,12, 2240 6 of 14
3. Statistical Analysis
Initially, pre- to post-training effect sizes (ES) were calculated according to Equation (1). Then,
the between-group difference effect sizes (d) for the dependent variable (i.e., maximum oxygen uptake
(VO
2max
)) were calculated according to Equations (2–5) for each study. We estimated the pre- to
post-correlation for VO
2max
and its respective confidence interval using a bootstrapping approach
based on previously published [
35
] and unpublished data from our group. In order to be conservative,
we used the lower limit of the confidence interval obtained from the bootstrapping estimate of the
pre- to post-training correlation for all studies (r=0.611). The heterogeneity for between-study
variability was verified with the I
2
statistics, with thresholds set as I
2
=25% (low), I
2
=50% (moderate),
and I2=75%
(high) [
36
]. Due to the high between-study heterogeneity, the data were analyzed using a
random-effect model.
To investigate the potential effect of exercise intensity on the VO
2max
, we converted the exercise
intensity into a categorical variable with two levels—I) low to moderate intensity; and II) vigorous
intensity—which was included as a moderator variable. Similarly, the training mode was included as
a categorical variable with two levels: I) continuous and II) interval training. The total volume (i.e.,
minutes per week) and training intervention period (i.e., the total number of training weeks) were
included as continuous moderator variables in the meta-regression models. A sensitivity analysis,
removing one study at a time and re-analyzing the summary effect, was performed to identify possible
highly influential studies. Studies were considered influential if the removal significantly changed
the summary effect (i.e., change going from significant to non-significant) [
37
]. Publication bias was
verified using the funnel plot, Kendall’s tau with continuity, and Egger ’s regression approaches.
In cases of significant publication bias, the fill and trim procedure was implemented. All the data were
analyzed using the rma and forest functions available in the metafor package for Rstudio (Version
3.6.3). The significance level was set at p<0.05. Data are presented as the mean
±
standard error or
standard deviation and confidence interval.
ES =Meanpost −Meanpre
SDpre , (1)
d=CMeanposttreatment −Meanpretreatment−Meanpostcontrol −Meanprecontrol 
SDchangepooled 
, (2)
SDchangepooled =v
u
tntreatment−1SD2
changetreatment +ncontrol−1SD2
changecontrol
ntreatment +ncontrol−2
, (3)
C=1−3
4ntreatment +ncontrol−2, (4)
SDchange =qSD2
pre +SD2
post −2·rpre−postcorrelation ·SDpre ·SDpost. (5)
4. Results
The initial search returned 1967 studies, and 998 duplicated studies were removed. For the
remaining studies (969), the titles and abstracts were screened and 919 were excluded. The remaining
50 studies were assessed for eligibility, considering our inclusion criteria. Forty-one studies were
excluded, and nine studies were included in the systematic review and meta-analysis. The search and
study selection process is depicted in Figure 2.

Cancers 2020,12, 2240 7 of 14
Cancers 2020, 12, x 7 of 14
Figure 2. Flow chart of the search process.
The present meta-analysis included nine studies that compared structured aerobic training vs.
usual care (i.e., no exercise), which resulted in nine treatment outcome measures. The overall number
of participants in the nine studies were 493. The average pre- to post-intervention change in the
VO2max was 9.97% (ES: 0.62 95%CI: −0.29 to 1.53) and −10.18% (ES: −0.54 95%CI: −0.99 to −0.10) for the
training and usual care groups, respectively. The overall between-group effect size difference for the
VO2max favored the aerobic training group (d: 1.19 ± 0.38 95%CI: 0.45 to 1.94) (Figure 3).
Figure 3. Forest plot for maximum oxygen consumption (VO2max) between the structured aerobic
training groups and usual care (no exercise) groups. Footnotes: data are shown as between-group
effect size difference (d) and 95% confidence interval.
Figure 2. Flow chart of the search process.
The present meta-analysis included nine studies that compared structured aerobic training vs.
usual care (i.e., no exercise), which resulted in nine treatment outcome measures. The overall number
of participants in the nine studies were 493. The average pre- to post-intervention change in the VO
2max
was 9.97% (ES: 0.62
95%
CI:
−
0.29 to 1.53) and
−
10.18% (ES:
−
0.54
95%
CI:
−
0.99 to
−
0.10) for the training
and usual care groups, respectively. The overall between-group effect size difference for the VO
2max
favored the aerobic training group (d: 1.19 ±0.38 95%CI: 0.45 to 1.94) (Figure 3).
Cancers 2020, 12, x 7 of 14
Figure 2. Flow chart of the search process.
The present meta-analysis included nine studies that compared structured aerobic training vs.
usual care (i.e., no exercise), which resulted in nine treatment outcome measures. The overall number
of participants in the nine studies were 493. The average pre- to post-intervention change in the
VO2max was 9.97% (ES: 0.62 95%CI: −0.29 to 1.53) and −10.18% (ES: −0.54 95%CI: −0.99 to −0.10) for the
training and usual care groups, respectively. The overall between-group effect size difference for the
VO2max favored the aerobic training group (d: 1.19 ± 0.38 95%CI: 0.45 to 1.94) (Figure 3).
Figure 3. Forest plot for maximum oxygen consumption (VO2max) between the structured aerobic
training groups and usual care (no exercise) groups. Footnotes: data are shown as between-group
effect size difference (d) and 95% confidence interval.
Figure 3.
Forest plot for maximum oxygen consumption (VO2max) between the structured aerobic
training groups and usual care (no exercise) groups. Footnotes: data are shown as between-group effect
size difference (d) and 95% confidence interval.

Cancers 2020,12, 2240 8 of 14
The subgroup analyses revealed a significant effect favoring vigorous-intensity aerobic training
protocols in increasing VO
2max
(Table 2). Regarding the training mode/type, both continuous and
interval aerobic training significantly increased the VO2max.
Table 2.
Effects of training intensity and training mode on the maximum oxygen consumption (VO
2max
)
compared to usual care (no exercise) subgroup analyses.
Subgroup N◦participants d(95%CI) pValue
Training intensity
Low- to moderate [22,30] 20 0.20 (−1.44 to 1.85) 0.81
Vigorous [23,24,29,31–34] 235 1.47 (0.60 to 2.34) 0.0009
Training mode
Continuous [22,29–34] 209 1.01 (0.19 to 1.83) 0.0157
Interval [23,24] 46 1.79 (0.28 to 3.29) 0.02
lower to moderate: 40–59% of heart rate reserve; vigorous: 60–89% of heart rate reserve; d: between-group effect
size difference; I2: heterogeneity for between-studies variability.
The meta-regression analyses did not produce significant betas for both continuous variables:
total session exercise volume and total intervention period (p>0.05). The sensitivity analysis
demonstrated that CRF was not highly affected by any of the individual studies. Visual inspection of
the funnel plot showed seven studies outside the funnel limits (five in the left and two in the right);
both Kendall’s tau with continuity correction (tau =0.55; p=0.04) and the Egger’s regression intercept
did not show significant bias (z=2.0019; p=0.04) (Figure 4). As the fill and trim procedure did not
change the effect size estimate, we maintained the initial analysis.
Cancers 2020, 12, x 8 of 14
The subgroup analyses revealed a significant effect favoring vigorous-intensity aerobic training
protocols in increasing VO2max (Table 2). Regarding the training mode/type, both continuous and
interval aerobic training significantly increased the VO2max.
Table 2. Effects of training intensity and training mode on the maximum oxygen consumption
(VO2max) compared to usual care (no exercise) subgroup analyses.
Subgroup N° participants d (95%CI) p Value
Training intensity
Low- to moderate [22,30] 20 0.20 (−1.44 to 1.85) 0.81
Vigorous [23,24,29,31–34] 235 1.47 (0.60 to 2.34) 0.0009
Training mode
Continuous [22,29–34] 209 1.01 (0.19 to 1.83) 0.0157
Interval [23,24] 46 1.79 (0.28 to 3.29) 0.02
lower to moderate: 40–59% of heart rate reserve; vigorous: 60–89% of heart rate reserve; d: between-
group effect size difference; I2: heterogeneity for between-studies variability.
The meta-regression analyses did not produce significant betas for both continuous variables:
total session exercise volume and total intervention period (p > 0.05). The sensitivity analysis
demonstrated that CRF was not highly affected by any of the individual studies. Visual inspection of
the funnel plot showed seven studies outside the funnel limits (five in the left and two in the right);
both Kendall’s tau with continuity correction (tau = 0.55; p = 0.04) and the Egger’s regression intercept
did not show significant bias (z = 2.0019; p = 0.04) (Figure 4). As the fill and trim procedure did not
change the effect size estimate, we maintained the initial analysis.
Figure 4. Funnel plot of studies comparing the maximum oxygen consumption (VO2max) between
the structure aerobic training and usual care (no exercise) groups.
Figure 4.
Funnel plot of studies comparing the maximum oxygen consumption (VO2max) between the
structure aerobic training and usual care (no exercise) groups.

Cancers 2020,12, 2240 9 of 14
5. Discussion
Emerging evidence on the prognostic significance of CRF, measured by VO
2max
, underpins the
clinical importance of developing effective strategies to prevent and/or recover low VO
2max
in women
with BC. Given that aerobic training is the upmost recommended exercise intervention to improve
CRF, we conducted the first meta-analysis to assess: (a) the efficacy of aerobic training to increase
VO
2max
; (b) the effect of moderate and vigorous intensity aerobic training on the VO
2max
response;
(c) the effect of the aerobic training mode (continuous or interval) on the changes in VO
2max
in women
with BC receiving chemotherapy. Our main results show that: (a) aerobic exercise training significantly
increases the VO
2max
compared with UC; (b) only vigorous-intensity aerobic exercise (64–90% of
VO
2max
) significantly increases VO
2max
, with no effect for moderate-intensity aerobic protocols (46–63%
of VO
2max
); and (c) both continuous and interval aerobic training are effective at increasing VO
2max
.
Taken together, our results suggest that, where appropriate in clinical practice, vigorous aerobic training
performed with continuous or interval training mode should be considered to improve the CRF in
women with BC undergoing chemotherapy.
Previous studies [
17
,
18
] have demonstrated the feasibility, safety, and overall effectiveness of
aerobic training for patients with BC undergoing chemotherapy; however, there is no consensus
regarding the most appropriate training intensity and mode to optimize training-induced adaptations.
Most studies involving BC patients have prescribed aerobic training based on guidelines from the
Clinical Society of Oncology of Australia (COSA) [
38
], the American College of Sport Medicine
(ACSM) [
39
], and the American Cancer Society (ACS) [
40
]. These guidelines recommend that patients
with BC should perform 150 min of moderate or 75 min of vigorous intensity aerobic exercise per
week. Our data support this recommendation, and three out of seven studies [
23
,
31
,
32
] (Figure 3)
demonstrated that vigorous intensity aerobic training was effective in significantly improving the
VO
2max
compared to usual care. These findings are supported by a study that directly compared
different exercise intensities in patients undergoing chemotherapy and found that moderate to vigorous
intensity exercise led to more significant improvements in cardiorespiratory fitness and physical
function and decreased the severity of adverse effects such as nausea, vomiting, pain, and physical
fatigue to a greater degree than low-intensity exercise [
41
]. Altogether, these results suggest that,
where appropriate, the prescription of vigorous intensity aerobic training should be considered for
women with BC; however, additional randomized clinical trials are still necessary to substantiate both
the safety and efficacy of these training protocols in larger cohorts.
Eight out of nine studies included in our review treated women with BC using anthracycline
(AC)-based chemotherapy, which commonly induces cardiotoxicity, one of the most debilitating
chemotherapy-related side effects [
42
–
44
]. To date, AC-induced cardiotoxicity most commonly presents
as a decrease in the left ventricular ejection fraction (LVEF) [
45
] and, ultimately, heart failure
[9,43]
.
Cardiotoxicity can occur at any time during AC infusion and up to years or decades later, known as
late onset chronic cardiotoxicity [
46
,
47
]. A meta-analysis by Haykowsky et al. [
48
] showed that
vigorous-to-maximal aerobic exercise was more effective than moderate-intensity exercise at improving
the LVEF and VO
2max
in patients with heart failure. A corollary from Haykowsky’s study is
that women with BC should be encouraged to perform vigorous aerobic training to prevent/treat
chemotherapy-associated decreases in LVEF. Accordingly, it has been shown that vigorous exercise can
prevent toxicity-related reductions in chemotherapy dose, which is critical in order to restrain tumor
growth [
17
,
41
]. Importantly, exercise protocols with vigorous intensities have shown to produce robust
increases in VO
2max
when compared to moderate intensity protocols, regardless of the equalization in
training volume [
49
]. Additionally, the exercise intensity seems not to affect training adherence [
50
].
Accordingly, higher levels of physical fitness are associated with greater adherence [
51
,
52
] and inversely
associated with fatigue levels in women with BC [53].
Vigorous or high-intensity aerobic training is normally performed as interval training [
54
]. It is
well known that the longer an individual can exercise at intensities close to the minimum velocity
of VO
2max
, the greater the gains in VO
2max
appear to be [
54
–
56
]. Due to the nature of interval

Cancers 2020,12, 2240 10 of 14
training, which includes short sets of vigorous to maximal exercise (
≥
90% of VO
2max
) interspaced
by low-intensity recovery periods, the maintenance of training intensity during aerobic exercise is
possible. Our moderator analysis suggests that both continuous and interval aerobic training are
effective at increasing VO
2max
. There is some compelling evidence that vigorous intensity continuous
aerobic training performed during chemotherapy counteracts cancer-related fatigue, which can last up
to 12 months after treatment completion, and reduces the time to return to work as compared with the
UC group [
57
]. However, we acknowledge that performing continuous aerobic training at vigorous
intensities is very demanding and may not be feasible for women with BC undergoing chemotherapy,
thus interval training should be considered as a viable alternative. Additionally, some studies have
demonstrated that interval training is more effective than continuous training to at increasing VO
2max
in heart failure patients with reduced ejection fraction [
58
] or coronary artery disease [
59
], which may
be an important consideration for patients with chemotherapy-associated cardiotoxicity.
The present meta-analysis has some limitations. According to our classification, only two studies
assessed moderate-intensity aerobic training, and only two studies investigated an interval training
mode, which makes it hard to draw definitive conclusions. Moreover, the high risk of bias of the
included trials needs to be considered (Figure 1), which seems to be mainly related to the difficulty of
blinding the interventions in eight out of nine included trials. It is therefore important to point out that
the bias assessment for those items does not reflect a low quality of study design, but expresses the
inevitable bias introduced by the lack of blinding. Another source of bias in the analysis is the CRF
assessment method. Two studies assessed VO
2max
indirectly, thus there is a small chance of bias with
regard to the prescribed training intensity and training-induced increase in VO
2max
. However, as the
magnitude of the effect size in Ma 2018 [
23
] was large and small in Mijwel et al. 2018 [
29
], one may
suggest that the likely bias is negligible or small. It is reasonable to suggest that the differences in effect
sizes were due to the higher training volume and more intensive training regimen. Thus, larger and
better blinding-controlled trials should be conducted to properly resolve this issue.
The data of the present manuscript indicate that high-intensity aerobic training can be performed
by women with BC under chemotherapy regardless of the training method (continuous or interval
training), however there are several considerations that need to be taken into account in clinical
practice. High-intensity continuous training (walking/run, 5x week at 70% of VO
2peak
for 30 min) may
be very demanding for this cohort. Thus, performing high-intensity interval training (e.g., cycling 3x
of 3 min at 90% of VO
2peak
, with intervals cycling at 30% of VO
2peak
, 3x week) seems to be a more
feasible alternative, as it is less time-consuming and more enjoyable. Further, while several studies
prescribe exercise intensity based on heart rate, chemotherapy may influence a patient’s heart rate.
Although heart rate can be easily monitored on a daily basis, and heart hate reserve can be calculated,
the training intensity can be influenced. Hence, a watt-based training prescription represents a less
error-prone method. On the other hand, there is mounting evidence that breast cancer chemotherapy
protocols elicit high levels of fatigue, which can greatly decrease a patient’s ability to maintain a
target Wattage. Finally, when the training sessions are not performed with the same equipment
(e.g., stationary bike, treadmill) that is used for the CRF assessment, the training intensity may have
been a little under due to non-specific training-induced peripheral adaptations (i.e., at the skeletal
muscle level).
6. Conclusions
In summary, our findings indicated that aerobic exercise increases the VO
2max
in women with BC
undergoing chemotherapy. We also showed that vigorous intensities (64–90% of VO
2max
) performed
with continuous or interval aerobic training are effective at increasing the VO
2max
in women with BC
undergoing chemotherapy. Performing continuous aerobic training at vigorous intensities is very
demanding and, thus, interval aerobic training should be considered as a viable option for women
with BC. While this work supports the benefits of aerobic exercise, additional clinical investigations are
warranted to determine the effects of different exercise modalities, timings, and durations and to identify

Cancers 2020,12, 2240 11 of 14
optimal aerobic training regimens to not only improve CRF but also counteract treatment-related
side-effects, such as cardiotoxicity, in women with BC.
Author Contributions:
Conceptualization: G.M., E.Z., M.S.C.; Performed searches: G.M., H.I.B., and M.S.C.;
Data extraction: G.M., H.I.B., G.D.T., M.S.C.; Performed risk of bias assessment: C.U., F.C.V., M.S.C.; Methodology:
F.C.V., M.E.L., C.U.; Software: M.E.L., C.U., L.O.S.; Supervision: S.D., M.S.C.; Writing—original draft: G.M.,
M.E.L., C.U., S.D., M.S.C. All the authors have read and agreed to the published version of the manuscript.
Please turn to the CRediT taxonomy for the term explanation. Authorship must be limited to those who have
contributed substantially to the work reported. All authors have read and agreed to the published version of
the manuscript.
Funding: No external sources of funding were used in the preparation of this manuscript.
Acknowledgments:
The authors would like to express gratitude to the S
ã
o Paulo Research Foundation (FAPESP;
Grant No. 2015/19756-3), the National Council for Scientific and Technological Development (CNPq grant
No. 303742/2018-6 and No. 303085/2015-0), and the Coordination of Improvement of Higher Education
Personnel-Brazil (CAPES grant #001).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
World Health Organization International Agency for Research on Cancer. Globocan. 2018. Available online:
http://gco.iarc.fr/today (accessed on 12 November 2019).
2.
Jemal, A.; Ward, E.M.; Johnson, C.J.; Cronin, K.A.; Ma, J.; Ryerson, A.B.; Mariotto, A.; Lake, A.J.; Wilson, R.;
Sherman, R.L.; et al. Annual Report to the Nation on the Status of Cancer, 1975–2014, Featuring Survival.
JNCI J. Natl. Cancer Inst. 2017,109, 1–22. [CrossRef]
3.
Partridge, A.H.; Burstein, H.J.; Winer, E.P. Side Effects of Chemotherapy and Combined Chemohormonal
Therapy in Women with Early-Stage Breast Cancer. JNCI Monogr.
2001
,2001, 135–142. [CrossRef] [PubMed]
4.
Mazzuca, F.; Onesti, C.E.; Roberto, M.; Di Girolamo, M.; Botticelli, A.; Begini, P.; Strigari, L.; Marchetti, P.;
Muscaritoli, M. Lean body mass wasting and toxicity in early breast cancer patients receiving anthracyclines.
Oncotarget 2018,9, 25714–25722. [CrossRef] [PubMed]
5.
Freedman, R.J.; Aziz, N.; Albanes, D.; Hartman, T.; Danforth, D.; Hill, S.; Sebring, N.; Reynolds, J.C.;
Yanovski, J.A. Weight and Body Composition Changes during and after Adjuvant Chemotherapy in Women
with Breast Cancer. J. Clin. Endocrinol. Metab. 2004,89, 2248–2253. [CrossRef] [PubMed]
6.
Tavio, M.; Milan, I.; Tirelli, U. Cancer-related fatigue (review). Int. J. Oncol.
2002
,21, 1093–1099. [CrossRef]
7.
Campos, M.P.O.; Hassan, B.J.; Riechelmann, R.; Del Giglio, A. Cancer-related fatigue: A practical review.
Ann. Oncol. 2011,22, 1273–1279. [CrossRef]
8.
Hofman, M.; Ryan, J.L.; Figueroa-Moseley, C.D.; Jean-Pierre, P.; Morrow, G.R. Cancer-related fatigue:
The scale of the problem. Oncologist 2007,12, 4–10. [CrossRef]
9.
Von Hoff, D.D.; Layard, M.W.; Basa, P.; Davis, H.L., Jr.; Von Hoff, A.L.; Rozencweig, M.; Muggia, F.M.
Risk Factors for Doxorubicin-lnduced Congestive Heart Failure. Ann. Intern. Med.
1979
,91, 710. [CrossRef]
10.
Khouri, M.G.; Douglas, P.S.; Mackey, J.R.; Martin, M.; Scott, J.M.; Scherrer-Crosbie, M.; Jones, L.W.
Cancer therapy-induced cardiac toxicity in early breast cancer: Addressing the unresolved issues. Circulation
2012,126, 2749–2763. [CrossRef]
11.
Yeh, E.T.H.; Bickford, C.L. Cardiovascular complications of cancer therapy: Incidence, pathogenesis,
diagnosis, and management. J. Am. Coll. Cardiol. 2009,53, 2231–2247. [CrossRef]
12.
Jones, L.W.; Courneya, K.S.; Mackey, J.R.; Muss, H.B.; Pituskin, E.N.; Scott, J.M.; Hornsby, W.E.; Coan, A.D.;
Herndon, J.E.; Douglas, P.S.; et al. Cardiopulmonary Function and Age-Related Decline Across the Breast
Cancer Survivorship Continuum. J. Clin. Oncol. 2012,30, 2530–2537. [CrossRef] [PubMed]
13.
Sloan, R.A.; Sawada, S.S.; Martin, C.K.; Church, T.; Blair, S.N. Associations between cardiorespiratory fitness
and health-related quality of life. Health Qual. Life Outcomes 2009,7, 3–7. [CrossRef] [PubMed]
14.
Schmid, D.; Leitzmann, M.F. Cardiorespiratory fitness as predictor of cancer mortality: A systematic review
and meta-analysis. Ann. Oncol. 2015,26, 272–278. [CrossRef]
15.
Herrero, F.; Balmer, J.; San Juan, A.F.; Foster, C.; Fleck, S.J.; Perez, M.; Canete, S.; Earnest, C.P.; Lucia, A.
Is cardiorespiratory fitness related to quality of life in survivors of breast cancer? J. Strength Cond. Res.
2006
,
20, 535–540. [CrossRef]

Cancers 2020,12, 2240 12 of 14
16.
Yu, A.F.; Flynn, J.R.; Moskowitz, C.S.; Scott, J.M.; Oeffinger, K.C.; Dang, C.T.; Liu, J.E.; Jones, L.W.;
Steingart, R.M. Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors
of ERBB2 -Positive Breast Cancer. JAMA Cardiol. 2020,5, 309. [CrossRef] [PubMed]
17.
Furmaniak, A.C.; Menig, M.; Markes, M.H. Exercise for women receiving adjuvant therapy for breast cancer.
Cochrane Database Syst. Rev. 2016,9, CD005001. [CrossRef]
18.
Singh, B.; Spence, R.R.; Steele, M.L.; Sandler, C.X.; Peake, J.M.; Hayes, S.C. A Systematic Review and
Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women with Stage II+Breast Cancer.
Arch. Phys. Med. Rehabil. 2018,99, 2621–2636. [CrossRef]
19.
Hayes, S.C.; Newton, R.U.; Spence, R.R.; Galvao, D.A. The Exercise and Sports Science Australia position
statement: Exercise medicine in cancer management. J. Sci. Med. Sport 2019,22, 1175–1199. [CrossRef]
20.
Campbell, K.L.; Winters-Stone, K.M.; Wiskemann, J.; May, A.M.; Schwartz, A.L.; Courneya, K.S.;
Zucker, D.S.; Matthews, C.E.; Ligibel, J.A.; Gerber, L.H.; et al. Exercise Guidelines for Cancer Survivors:
Consensus Statement from International Multidisciplinary Roundtable. Med. Sci. Sports Exerc.
2019
,51,
2375–2390. [CrossRef]
21.
Segal, R.; Evans, W.; Johnson, D.; Smith, J.; Colletta, S.; Gayton, J.; Woodard, S.; Wells, G.; Reid, R.
Structured Exercise Improves Physical Functioning in Women with Stages I and II Breast Cancer: Results of
a Randomized Controlled Trial. J. Clin. Oncol. 2001,19, 657–665. [CrossRef]
22.
Jones, L.W.; Fels, D.R.; West, M.; Allen, J.D.; Broadwater, G.; Barry, W.T.; Wilke, L.G.; Masko, E.; Douglas, P.S.;
Dash, R.C.; et al. Modulation of Circulating Angiogenic Factors and Tumor Biology by Aerobic Training in Breast
Cancer Patients Receiving Neoadjuvant Chemotherapy. Cancer Prev. Res.
2013
,6, 925–937. [CrossRef] [PubMed]
23.
Ma, Z. Effect of anthracycline combined with aerobic exercise on the treatment of breast cancer. Pak. J. Pharm.
Sci. 2018,31, 1125–1129. [PubMed]
24.
Lee, K.; Kang, I.; Mack, W.J.; Mortimer, J.; Sattler, F.; Salem, G.; Dieli-Conwright, C.M. Feasibility of
high intensity interval training in patients with breast Cancer undergoing anthracycline chemotherapy:
A randomized pilot trial. BMC Cancer 2019,19, 653. [CrossRef] [PubMed]
25.
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Grp, P. Preferred Reporting Items for Systematic Reviews
and Meta-Analyses: The PRISMA Statement (Reprinted from Annals of Internal Medicine). Phys. Ther.
2009
,
89, 873–880. [CrossRef]
26.
Cooper, H.; Hedges, L.V.; Valentine, J.C. (Eds.) Handbook of Research Synthesis and Meta-Analysis, 3rd ed.;
Russell Sage Foundation: New York, NY, USA, 2009; ISBN 9780871541635.
27.
Sterne, J.A.C.; Savovic, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.-Y.;
Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ
2019,366, l4898. [CrossRef]
28.
Garber, C.E.; Blissmer, B.; Deschenes, M.R.; Franklin, B.A.; Lamonte, M.J.; Lee, I.-M.; Nieman, D.C.; Swain, D.P.
Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory, Musculoskeletal, and
Neuromotor Fitness in Apparently Healthy Adults. Med. Sci. Sport. Exerc. 2011,43, 1334–1359. [CrossRef]
29.
Mijwel, S.; Backman, M.; Bolam, K.A.; Olofsson, E.; Norrbom, J.; Bergh, J.; Sundberg, C.J.; Wengström, Y.;
Rundqvist, H. Highly favorable physiological responses to concurrent resistance and high-intensity interval
training during chemotherapy: The OptiTrain breast cancer trial. Breast Cancer Res. Treat.
2018
,169,
93–103. [CrossRef]
30.
Møller, T.; Lillelund, C.; Andersen, C.; Bloomquist, K.; Christensen, K.B.; Ejlertsen, B.; Nørgaard, L.;
Wiedenbein, L.; Oturai, P.; Breitenstein, U.; et al. The challenge of preserving cardiorespiratory fitness in
physically inactive patients with colon or breast cancer during adjuvant chemotherapy: A randomised
feasibility study. BMJ Open Sport Exerc. Med. 2015,1, e000021. [CrossRef]
31.
Mowafy, Z.M.E.; Zoheiry, I.M.I.; Elmonem, M.G.A.; Katter, D. Efficacy of aerobic training on maximal oxygen
consumption and total leukocytes count after chemotherapy in breast cancer patients. Int. J. PharmTech Res.
2016,9, 34–40.

Cancers 2020,12, 2240 13 of 14
32.
Al-Majid, S.; Wilson, L.D.; Rakovski, C.; Coburn, J.W. Effects of Exercise on Biobehavioral Outcomes of
Fatigue During Cancer Treatment. Biol. Res. Nurs. 2015,17, 40–48. [CrossRef]
33.
Courneya, K.S.; Segal, R.J.; Mackey, J.R.; Gelmon, K.; Reid, R.D.; Friedenreich, C.M.; Ladha, A.B.; Proulx, C.;
Vallance, J.K.H.; Lane, K.; et al. Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving
Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial. J. Clin. Oncol.
2007
,25, 4396–4404.
[CrossRef] [PubMed]
34.
Kim, C.-J.; Kang, D.; Smith, B.A.; Landers, K.A. Cardiopulmonary responses and adherence to exercise in
women newly diagnosed with breast cancer undergoing adjuvant therapy. Cancer Nurs.
2006
,29, 156–165.
[CrossRef] [PubMed]
35.
Conceicao, M.S.; Junior, E.M.M.; Telles, G.D.; Libardi, C.A.; Castro, A.; Andrade, A.L.L.; Brum, P.C.; Urias, U.;
Kurauti, M.A.; Junior, J.M.C.; et al. Augmented Anabolic Responses after 8-wk Cycling with Blood Flow
Restriction. Med. Sci. Sports Exerc. 2019,51, 84–93. [CrossRef] [PubMed]
36. Higgins, J.P.T. Measuring inconsistency in meta-analyses. BMJ 2003,327, 557–560. [CrossRef]
37.
Lixandr
ã
o, M.E.; Ugrinowitsch, C.; Berton, R.; Vechin, F.C.; Conceiç
ã
o, M.S.; Damas, F.; Libardi, C.A.;
Roschel, H. Magnitude of Muscle Strength and Mass Adaptations Between High-Load Resistance Training
Versus Low-Load Resistance Training Associated with Blood-Flow Restriction: A Systematic Review and
Meta-Analysis. Sport. Med. 2018,48, 361–378. [CrossRef]
38.
Cormie, P.; Atkinson, M.; Bucci, L.; Cust, A.; Eakin, E.; Hayes, S.; McCarthy, S.; Murnane, A.; Patchell, S.;
Adams, D. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med. J. Aust.
2018,209, 184–187. [CrossRef]
39.
Schmitz, K.H.; Courneya, K.S.; Matthews, C.; Demark-Wahnefried, W.; Galv
ã
o, D.A.; Pinto, B.M.; Irwin, M.L.;
Wolin, K.Y.; Segal, R.J.; Lucia, A.; et al. American College of Sports Medicine Roundtable on Exercise
Guidelines for Cancer Survivors. Med. Sci. Sport. Exerc. 2010,42, 1409–1426. [CrossRef]
40.
Park, S.-H.; Knobf, M.T.; Kerstetter, J.; Jeon, S. Adherence to American Cancer Society Guidelines on Nutrition
and Physical Activity in Female Cancer Survivors. Cancer Nurs. 2018,42, 1. [CrossRef]
41.
van Waart, H.; Stuiver, M.M.; van Harten, W.H.; Geleijn, E.; Kieffer, J.M.; Buffart, L.M.; de Maaker-Berkhof, M.;
Boven, E.; Schrama, J.; Geenen, M.M.; et al. Effect of Low-Intensity Physical Activity and Moderate-
to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue,
and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial. J. Clin. Oncol.
2015
,
33, 1918–1927. [CrossRef]
42.
Volkova, M.; Russell, R. Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr. Cardiol.
Rev. 2011,7, 214–220. [CrossRef]
43.
Swain, S.M.; Whaley, F.S.; Ewer, M.S. Congestive heart failure in patients treated with doxorubicin:
A retrospective analysis of three trials. Cancer 2003,97, 2869–2879. [CrossRef] [PubMed]
44.
Buzdar, A.U.; Marcus, C.; Smith, T.L.; Blumenschein, G.R. Early and delayed clinical cardiotoxicity of
doxorubicin. Cancer 1985,55, 2761–2765. [CrossRef]
45.
Scott, J.M.; Khakoo, A.; Mackey, J.R.; Haykowsky, M.J.; Douglas, P.S.; Jones, L.W. Modulation of
Anthracycline-Induced Cardiotoxicity by Aerobic Exercise in Breast Cancer. Circulation
2011
,124, 642–650.
[CrossRef] [PubMed]
46.
Mulrooney, D.A.; Yeazel, M.W.; Kawashima, T.; Mertens, A.C.; Mitby, P.; Stovall, M.; Donaldson, S.S.;
Green, D.M.; Sklar, C.A.; Robison, L.L.; et al. Cardiac outcomes in a cohort of adult survivors of childhood
and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ
2009
,339,
b4606. [CrossRef] [PubMed]
47.
Kremer, L.C.; van Dalen, E.C.; Offringa, M.; Ottenkamp, J.; Voute, P.A. Anthracycline-induced clinical heart
failure in a cohort of 607 children: Long-term follow-up study. J. Clin. Oncol. 2001,19, 191–196. [CrossRef]
48.
Haykowsky, M.J.; Timmons, M.P.; Kruger, C.; McNeely, M.; Taylor, D.A.; Clark, A.M. Meta-analysis of aerobic
interval training on exercise capacity and systolic function in patients with heart failure and reduced ejection
fractions. Am. J. Cardiol. 2013,111, 1466–1469. [CrossRef]
49.
Milanovi´c, Z.; Sporiš, G.; Weston, M. Effectiveness of High-Intensity Interval Training (HIT) and Continuous
Endurance Training for VO2max Improvements: A Systematic Review and Meta-Analysis of Controlled
Trials. Sport. Med. 2015,45, 1469–1481. [CrossRef]

Cancers 2020,12, 2240 14 of 14
50.
Courneya, K.S.; Segal, R.J.; Gelmon, K.; Mackey, J.R.; Friedenreich, C.M.; Yasui, Y.; Reid, R.D.; Proulx, C.;
Trinh, L.; Dolan, L.B.; et al. Predictors of adherence to different types and doses of supervised exercise during
breast cancer chemotherapy. Int. J. Behav. Nutr. Phys. Act. 2014,11, 85. [CrossRef]
51.
Kampshoff, C.S.; Jansen, F.; van Mechelen, W.; May, A.M.; Brug, J.; Chinapaw, M.J.M.; Buffart, L.M.
Determinants of exercise adherence and maintenance among cancer survivors: A systematic review. Int. J.
Behav. Nutr. Phys. Act. 2014,11, 80. [CrossRef]
52.
van Waart, H.; Buffart, L.M.; Stuiver, M.M.; van Harten, W.H.; Sonke, G.S.; Aaronson, N.K. Adherence to and
satisfaction with low-intensity physical activity and supervised moderate-high intensity exercise during
chemotherapy for breast cancer. Support. Care Cancer 2020,28, 2115–2126. [CrossRef]
53.
Huang, H.-P.; Wen, F.-H.; Tsai, J.-C.; Lin, Y.-C.; Shun, S.-C.; Chang, H.-K.; Wang, J.-S.; Jane, S.-W.; Chen, M.-C.;
Chen, M.-L. Adherence to prescribed exercise time and intensity declines as the exercise program proceeds:
Findings from women under treatment for breast cancer. Support. Care Cancer
2015
,23, 2061–2071.
[CrossRef] [PubMed]
54.
Buchheit, M.; Laursen, P.B. High-intensity interval training, solutions to the programming puzzle: Part I:
Cardiopulmonary emphasis. Sport. Med. 2013,43, 313–338. [CrossRef] [PubMed]
55.
Buchheit, M.; Laursen, P.B. High-intensity interval training, solutions to the programming puzzle: Part II:
Anaerobic energy, neuromuscular load and practical applications. Sport. Med.
2013
,43, 927–954.
[CrossRef] [PubMed]
56.
Midgley, A.W.; Mc Naughton, L.R. Time at or near VO2max during continuous and intermittent running.
A review with special reference to considerations for the optimisation of training protocols to elicit the
longest time at or near VO2max. J. Sports Med. Phys. Fit. 2006,46, 1–14.
57.
Mijwel, S.; Jervaeus, A.; Bolam, K.A.; Norrbom, J.; Bergh, J.; Rundqvist, H.; Wengström, Y. High-intensity
exercise during chemotherapy induces beneficial effects 12 months into breast cancer survivorship. J. Cancer
Surviv. 2019,13, 244–256. [CrossRef]
58.
Gomes Neto, M.; Dur
ã
es, A.R.; Conceiç
ã
o, L.S.R.; Saquetto, M.B.; Ellingsen, Ø.; Carvalho, V.O. High intensity
interval training versus moderate intensity continuous training on exercise capacity and quality of life in
patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis. Int. J.
Cardiol. 2018,261, 134–141. [CrossRef]
59.
Liou, K.; Ho, S.; Fildes, J.; Ooi, S.-Y. High Intensity Interval versus Moderate Intensity Continuous Training in
Patients with Coronary Artery Disease: A Meta-analysis of Physiological and Clinical Parameters. Heart Lung
Circ. 2016,25, 166–174. [CrossRef]
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