Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer
Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer
Pedro Veronese 0 1
Denise Tessariol Hachul 0 1
Mauricio Ibrahim Scanavacca 0 1
Ludhmila Abrahão Hajjar 0 1
Tan Chen Wu 0 1
Luciana Sacilotto 0 1
Carolina Veronese 1
Francisco Carlos da Costa Darrieux 0 1
0 Clinical Unit of Arrhythmia and Pacing, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo - São Paulo , São Paulo , Brazil , 2 Oncology Department, Cancer Institute (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo ±São Paulo , São Paulo , Brazil , 3 Clinical Department, The University of North Carolina at Chapel Hill ± Chapel Hill , North Carolina , United States of America
1 Editor: Claudio M. Costa-Neto, University of São Paulo , BRAZIL
Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Twenty-three consecutive patients with breast cancer were followed prospectively during
ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc
and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to
chemotherapy (baseline), immediately after the first phase of anthracycline and
cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type
natriuretic peptide (BNP) levels were also measured.
Compared to baseline values, the QTc interval was significantly prolonged after the AC
phase (439.7 ± 33.2 ms vs. 472.5 ± 36.3 ms, p = 0.001) and after T treatment (439.7 ± 33.2
ms vs. 467.9 ± 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0
pg/mL [min-max: 6.0±85.0] vs. 6.0 pg/mL [min-max: 6.0±22.0], p < 0.001) and after T
treatment (25.0 pg/mL [min-max: 6.0±80.0] vs. 6.0 pg/mL [min-max: 6.0±22.0], p < 0.001)
compared to baseline values.
In this prospective study of patients with non-metastatic breast cancer who underwent ACT
chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were
In addition to skin cancer, breast cancer is the most common type of cancer in women.
Advancements in chemotherapy strategies for breast cancer patients have contributed to high
remission rates. However, chemotherapy-related cardiotoxicity has been a subject of intensive
research all over the world. Among other findings, the research characterized acute and
subacute cardiotoxicity by acute coronary artery syndrome, pericarditis, myocarditis, cardiac
arrhythmias, or QT interval prolongation [
]. Such cardiac changes may occur during
chemotherapy treatment or even up to two weeks after the conclusion of chemotherapy .
Chronic cardiotoxicity may result in a reduced left ventricle ejection fraction (LVEF), heart
failure, or death [
Anthracyclines, which are routinely used to treat breast cancer, may induce acute, subacute,
and chronic cardiotoxicity, and the latter is usually caused by cumulative doses of 400 mg/m2
or greater [
Corrected QT interval (QTc) prolongation and other measures derived from the QTc
interval, such as the dispersion of the QTc (QTdc) and the transmural dispersion of repolarization
(DTpTe), are markers of potentially lethal arrhythmias, e.g., torsades de pointes [
Previous studies in patients with non-Hodgkin lymphoma who received anthracyclines
have demonstrated QTc interval prolongation and increased QTdc [
]. However, the
chemotherapeutic doses used in this population were much higher than those used to treat breast
cancer patients. Similar findings were observed in breast cancer patients with HER2 protein
expression who were consequently exposed to both anthracycline and trastuzumab .
Although anthracyclines prolong the QTc interval, [
] it remains unclear whether breast
cancer patients who were exposed specifically to the chemotherapy regimen with anthracycline
(A; doxorubicin), cyclophosphamide (C) and taxane (T; paclitaxel), known as the ACT
regimen, may present with QTc, QTdc and DTpTe prolongation.
The primary objective of this study was to evaluate the effect of the ACT chemotherapy
regimen on the QTc interval in the early phase of treatment. The secondary objectives were 1) to
evaluate the effect of ACT chemotherapy on the QTdc and DTpTe values; 2) to assess any
changes in cardio-specific biomarkers, such as troponin and B-type natriuretic peptide (BNP);
and 3) to assess the clinical manifestations of cardiotoxicity, including the presence of cardiac
arrhythmias, congestive heart failure (CHF), angina and cardiovascular death in patients with
breast neoplasms who were undergoing ACT chemotherapy.
Twenty-seven consecutive patients diagnosed with non-metastatic breast cancer were selected
from August 2015 to February 2017 and were all under treatment at the Cancer Institute of the
State of São Paulo (ICESP). The patients were undergoing adjuvant or neoadjuvant
chemotherapy based on the Institute's standardized protocol for ACT chemotherapy, including
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anthracycline (doxorubicin), cyclophosphamide and taxane (paclitaxel) infusion. None of the
patients had any known structural heart diseases or previous cardiovascular events. None of
the patients had received previous chemotherapy or radiotherapy. All the patients were
prospectively followed up and had a 12-lead electrocardiogram (EKG) recorded prior to
chemotherapy initiation (baseline), immediately after the end of the first phase of chemotherapy
(anthracycline and cyclophosphamide [AC] phase), and immediately after the end of the
second phase (final) with paclitaxel (T). Serum troponin, BNP, and electrolytes (potassium,
magnesium, and calcium) were measured at baseline, immediately after the AC phase of
chemotherapy, and immediately after the T phase of chemotherapy.
The Scientific Committee of Instituto do CoracËão (InCor-HCFMUSP) and the Institutional
Review Board (CAPPesq) of the Hospital das Clínicas da Faculdade de Medicina da
Universidade de São Paulo (HCFMUSP) approved the study protocol. Written informed consent was
obtained from each patient, and the study was conducted in accordance with the Declaration
Electrocardiography and toxicity assessments
All patients underwent an EKG soon after treatment. EKGs were recorded with a portable
digital electrocardiograph (TEB C 30+, TEB Ltda, São Paulo, Brazil) with 10-sec recordings at a 25
mm/sec speed and a standard voltage of 1.0 mV (10 mm). The QT interval was manually
measured using the tangent method from the beginning of the QRS complex to the end of the T
wave from all 12 leads [
]. Whenever the end of the T wave could not be determined in
any given lead, this lead was excluded from the analysis. The QTc interval was calculated in
lead V5 using Bazett's formula (QTc = QT interval / RR interval). QTc values greater than
460 ms for women were considered abnormal [
]. QTdc was manually calculated by the
difference between the longest and the shortest QTc intervals measured across the 12 leads.
Whenever the end of the T wave could not be determined in a lead, this lead was excluded
from the analysis. QTdc values greater than or equal to 50 ms were considered abnormal.
DTpTe was manually calculated by the difference between the greatest and the smallest Tpeak
to Tend (TpTe) interval measured across the 12 leads [
]. All measurements were made by
the same cardiologist who was blinded to the patients' data, and the measurements were later
confirmed by a second cardiologist. Occasional disagreements were resolved by consensus.
Clinical evaluations of the patients were performed during clinical visits; determination of
cardiac arrhythmias relied on symptoms and the data from the resting EKGs.
Troponin I levels were determined by a sandwich immunoassay in three stages using direct
chemiluminescence technology and consistent quantities of two monoclonal antibodies. An
adjuvant reactant was included to reduce nonspecific binding. For this purpose, the ADVIA
Centaur1 Tnl-Ultra1 commercial kit (Siemens Healthcare Diagnostics, Tarrytown, NY,
USA) was used with an automated detection system from the same manufacturer. The results
are presented in pg/mL with a 99% detection threshold of 6 pg/mL.
Serum concentrations of BNP were obtained using a sandwich immunoassay in two stages
using direct chemiluminescence technology and consistent quantities of two monoclonal
antibodies. For this purpose, the ADVIA Centaur1 Tnl-Ultra1 commercial kit (Siemens
Healthcare Diagnostics, Tarrytown, NY, USA) was used with an automated detection system from
the same manufacturer. The results are presented in pg/mL, and the reference value for normal
BNP serum concentration is below 100 pg/mL.
The ACT chemotherapy regimen consisted of doxorubicin, cyclophosphamide, and
paclitaxel. This regimen was divided in two phases. The first phase comprised four cycles of AC
(doxorubicin + cyclophosphamide) infused at intervals of 21 days. The total duration of the
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first (AC) phase was 63 days as follows: every 21 days, patients received an IV bolus infusion of
60 mg/m2 doxorubicin, 600 mg/m2 cyclophosphamide, and 20 mg dexamethasone. The
second (T) phase lasted 8 weeks with weekly IV infusions of 100 mg/m2 paclitaxel and 8 mg
dexamethasone. All patients received ondansetron before infusion of chemotherapeutic agents.
Qualitative characteristics of the women undergoing chemotherapy are described using
absolute and relative frequencies, and quantitative characteristics are described using summarized
measures (mean and standard deviation are used for parametric variables; median, minimum,
and maximum values are used for non-parametric variables).
The values of the EKG parameters are reported using summarized measures at each
evaluation timepoint. The values at different timepoints were compared using ANOVAs with repeat
measures followed by multiple Bonferroni comparisons, except for the comparisons of
troponin and BNP levels where the Friedman test was used followed by non-parametric multiple
comparisons for longitudinal data, when necessary.
The significance level applied for all statistical tests was 5%.
Twenty-seven consecutive female patients with breast neoplasms were evaluated. Two patients
discontinued the research protocol, and another two were excluded from the study due to
metastatic disease progression during the follow-up period. Thus, 23 patients completed the study.
The mean follow-up duration was 8 months.
Demographics, clinical characteristics, and laboratory results of the 23 patients are shown
in Table 1. None of the patients showed any evidence of structural heart disease at baseline,
and nine patients exhibited stage I hypertension. All electrolyte levels were normal before and
after the treatment.
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The three patients who were previously on beta blockers (BBs) were maintained on the
same dose of medication throughout the EKG measurements. The same occurred with three
patients who were on selective serotonin reuptake inhibitors (SSRIs).
QTc interval measurements were significantly increased after the first (AC) phase of
chemotherapy compared to the baseline values (472.5 ± 36.3 ms vs. 439.7 ± 33.2 ms; p = 0.001).
There was also a significant increase in the QTc interval after the final (T) phase compared to
baseline (467.9 ± 42.6 ms vs. 439.7 ± 33.2 ms; p < 0.001), as shown in Table 2. In our series,
nine patients (39, 14%) presented with a QTc interval > 500 ms, but none of them suffered
life-threatening arrhythmias (See S1 Table).
The QTdc was not significantly different (p = 0.20) compared to baseline neither after the
AC phase (46.8 ± 28.0 ms vs. 57.0 ± 19.3 ms) nor at the end of chemotherapy (46.8 ± 28.0 ms
vs. 54.0 ± 16.8 ms). The DTpTe was also not significantly different (p = 0.89) compared to
baseline neither after the AC phase (33.5 ± 15.0 ms vs. 32.6 ± 12.1 ms) nor at the end of
chemotherapy (33.5 ± 15.0 ms vs. 34.4 ± 10.4 ms). The results are shown in Table 3.
Serum BNP levels were not significantly different (p = 0.43) compared to baseline neither
after the AC phase (13.0 pg/mL [min-max: 3.0±81.0] vs. 12.0 pg/mL [min-max: 5.0±103.0])
nor at the end of chemotherapy (13.0 pg/mL [min-max: 3.0±81.0] vs. 12.0 pg/mL [min-max:
Regarding troponin, there was a statistically significant increase in the serum values
compared to the baseline values both after the AC phase (6.0 pg/mL [min-max: 6.0±22.0] vs. 23.0
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pg/mL [min-max: 6.0±85.0], p < 0.001) and at the end of chemotherapy (6.0 pg/mL
[minmax: 6.0±22] vs. 25.0 pg/mL [min-max: 6.0±80.0], p < 0.001), as shown in Table 4.
During the clinical follow-up period, no cases of death, angina, CHF, or cardiac arrhythmia
were detected. The main symptoms observed were nausea, vomiting, weakness, and transient
muscular pain associated with the chemotherapy.
The present prospective study contributes data on patients with breast neoplasms who
underwent an ACT chemotherapy regimen (doxorubicin, cyclophosphamide, and paclitaxel),
demonstrating prolongation of the QTc interval and an elevation in serum troponin levels among
Prolongation of the QT interval is one of the manifestations of acute and subacute
chemotherapy-induced cardiotoxicity. Chemotherapy-induced cardiotoxicity, which can also
manifest as the emergence of cardiac arrhythmias and alterations in ventricular repolarization,
has not been fully elucidated. Such cardiac changes occur during chemotherapy treatment or
even up to two weeks after the conclusion of chemotherapy [
]. Kitagawa et al. showed that
patients with breast neoplasms who underwent a chemotherapy regimen with epirubicin,
cyclophosphamide and 5-fluorouracil presented with QTc interval prolongation [
Tanriverdi et al. demonstrated that patients with breast neoplasms with HER2 expression who
underwent a chemotherapy regimen with trastuzumab and anthracycline (epirubicin) also
presented with QTc interval prolongation [
]. However, prolongation of the QTc interval in
women with HER2-negative breast cancer undergoing the specific chemotherapy treatment
regimen of doxorubicin, cyclophosphamide, and paclitaxel has never been studied until now.
Our study included only female patients with a mean age of 50 years old, where 13% used
BBs and another 13% used SSRIs. Although BBs may shorten the QT interval and SSRIs may
prolong it, our patients on both therapies were maintained on the same doses of their
medications during all three EKG measurements and were exposed to the same ACT regimen as
other patients throughout the study.
Prolongation of the QTc interval, which was the main endpoint of our study, was observed
after the ACT chemotherapy regimen compared to baseline values. Chemotherapy agents
act on the ion channels, particularly on sodium, potassium, and calcium channels, leading
to the prolongation of cardiac cell action potentials (APs). AP prolongation, from the
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electrocardiographic viewpoint, translates into an increase in the QT interval. Individuals with
this electrocardiographic alteration exhibit increased electrical heterogeneity of the
myocardium, which results in the appearance of an early post-potential-triggered activity, which is an
electrophysiological mechanism of electrical impulse generation that acts as a substrate for
severe ventricular arrhythmias, such as torsades de pointes [
]. As demonstrated by
Zamorano et al. , the patients most at risk of developing torsades de pointes are those with a QTc
interval > 500 ms or a ΔQTc > 60 ms (i.e. change from baseline). In our series, nine patients
(39, 14%) presented with a QTc interval > 500 ms, but none of them suffered life-threatening
arrhythmias, which may be partially explained by the acute and subacute transient toxicity of
Contrary to the findings of previous studies, our study did not observe any statistically
significant differences in the secondary endpoints of QTdc or DTpTe [
et al. studied patients with non-Hodgkin lymphoma who underwent doxorubicin infusion and
demonstrated an increased QTdc [
]. A similar QTdc result was also shown by Kuittinen
et al. in patients with non-Hodgkin lymphoma who underwent chemotherapy with high doses
of anthracycline and cyclophosphamide [
]. It is important to note that these two studies
evaluated patients with non-Hodgkin lymphoma who received different chemotherapy
regimens at higher doses than those used in breast cancer. Tanriverdi et al. showed an increase in
QTdc in breast cancer patients with a chemotherapy regimen that was different than that used
in our work and consisted of trastuzumab, epirubicin and cyclophosphamide [
]. QTdc and
DTpTe more reliably reflect the heterogeneity of ventricular repolarization, but their
electrocardiographic measurements can be technically difficult to perform when the QTc interval
prolongation is mild due to lower doses of chemotherapy agents. The number of patients
included in our study may have also contributed to our inability to demonstrate such
differences. Another possible explanation is that changes in the QTc interval may occur earlier than
changes in QTdc and DTpTe.
Troponin is a sensitive and specific biomarker of acute and subacute cardiotoxicity in
patients undergoing chemotherapy with anthracyclines, as shown by Horacek et al [
Nevertheless, in patients with breast neoplasms undergoing the ACT regimen (doxorubicin,
cyclophosphamide, and paclitaxel), this biomarker had not yet been studied. We demonstrated a
significant increase in troponin, which is a marker of cell damage, at the end of the first (AC)
phase and at the end of chemotherapy (after T) compared to baseline values. Cardinale et al.
demonstrated that patients receiving high doses of doxorubicin had elevated serum troponin
levels within the first 12±72 hours after starting treatment, with a decrease in the left
ventricular ejection fraction after 7 months [
]. Markman et al. demonstrated that QTc
prolongation was also associated with ventricular dysfunction in adulthood ; therefore, the acute
changes in the ECG observed in our series as well as the elevation of troponin may reflect
acute and subacute cardiotoxicity. We did not find a linear correlation between serum
troponin dosage and QTc interval magnitude; however, changes in QTc interval magnitude can
have other possible causes, such as a direct effect of chemotherapy on ventricular
repolarization. The clinical significance of this finding requires further study.
Another important biomarker, BNP, shows conflicting data in the literature, and its
elevation was demonstrated by Mavinkurve et al. to be a marker of cardiotoxicity [
], mainly in
the context of hematological neoplasms. Among breast cancer patients treated with the
doxorubicin, cyclophosphamide and paclitaxel chemotherapy regimen, levels of BNP have not yet
been studied. In our study, we did not observe an elevation in BNP levels, likely because our
patient population had structurally normal hearts and because the chemotherapy doses were
lower than those used on patients with hematological neoplasms [
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During the prospective follow-up period, we did not detect any of the secondary clinical
endpoints, namely, CHF, cardiac arrhythmias, or death.
Several authors have demonstrated that the cardiotoxic effects of anthracyclines occur with
cumulative doses of these chemotherapeutic agents [
]. Systolic dysfunction, the main
complication associated with anthracyclines, can be observed at anthracycline doses of 400 mg/m2
or higher. In our study, we demonstrated that lower doses of doxorubicin (only 240 mg/m2)
may cause acute and subacute cardiotoxicity, as shown by QTc prolongation and the rise in
troponin levels. Early detection of QTc interval prolongation, which indicates the potential
risk of malignant arrhythmias and sudden cardiac death, can provide an optimal monitoring
of breast cancer patients undergoing an ACT regimen, both regarding the concentrations of
electrolytes affecting the QT interval (potassium, calcium, and magnesium) and the
introduction of medications that are known to prolong it. Further studies are needed to determine
whether the administration of drugs such as BBs and angiotensin-converting enzyme (ACE)
inhibitors can offer some protection during ACT treatment.
An open question in our study is whether these QT interval changes may disappear during
long-term follow-up. Kuittinen et al. have demonstrated that the QTc interval prolongation
and increase in QTdc observed in patients with non-Hodgkin lymphoma who received high
doses of anthracycline and cyclophosphamide were reversible and recovered to normal values
within 3 months after the end of chemotherapy [
Markman et al. showed that adult patients who survived pediatric neoplasms, were
treated with anthracyclines and exhibited QTc interval prolongation in the acute phase also
demonstrated ventricular dysfunction in adult life [
]. Given that this was a pediatric
population, most of the tumors were probably of hematological origin, which are known to be
treated with higher cumulative doses of anthracyclines. Whether our patients with breast
neoplasms who displayed greater QT interval prolongation in the acute phase are at a
higher risk of progressing to left ventricular dysfunction in the future merits further
Our study has some limitations. Although the number of patients is small, we also
demonstrated that QT interval prolongation and elevated troponin levels occurred during the acute
and subacute phases of ACT chemotherapy treatment. The criteria for arrhythmia
documentation were based on clinical complaints and resting EKGs. A longer clinical follow-up duration
and the use of Holter monitoring tools might increase detection of the clinical endpoints. The
time for normalization of the QTc interval in the EKG of these patients with breast cancer is a
limitation of our study and merits further investigation.
In patients with breast neoplasms undergoing an ACT chemotherapy regimen, we observed
prolongation of the QTc interval and elevated troponin levels during the treatment period;
meanwhile, BNP serum levels were unchanged, and no alterations in QTdc or DTpTe were
noted. There were no reports of clinical events, including arrhythmias, heart failure, angina, or
death, during the study. The clinical significance of these findings requires additional
observational and longitudinal studies with a longer follow-up period.
S1 Table. Values measured from the QTc interval.
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The authors thank Mr. Rogerio Ruscitto for the statistical support, and Dr. MoÃnica Samuel
AÂ vila Grinberg for her cooperation.
Conceptualization: Pedro Veronese, Ludhmila Abrahão Hajjar, Francisco Carlos da Costa
Data curation: Pedro Veronese.
Investigation: Pedro Veronese.
Formal analysis: Pedro Veronese, Francisco Carlos da Costa Darrieux.
Methodology: Pedro Veronese, Ludhmila Abrahão Hajjar, Francisco Carlos da Costa
Project administration: Mauricio Ibrahim Scanavacca, Francisco Carlos da Costa Darrieux.
Resources: Pedro Veronese.
Software: Pedro Veronese, Tan Chen Wu.
Supervision: Denise Tessariol Hachul, Mauricio Ibrahim Scanavacca, Francisco Carlos da
Validation: Pedro Veronese, Francisco Carlos da Costa Darrieux.
Visualization: Pedro Veronese, Luciana Sacilotto, Francisco Carlos da Costa Darrieux.
Writing ± original draft: Pedro Veronese, Carolina Veronese.
Writing ± review & editing: Pedro Veronese, Carolina Veronese.
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