RETROSPECTIVE STUDIES
Value of Echocardiography and Electrocardiography as Screening Tools Prior to Doxorubicin Administration William Ratterree, DVM, Tracy Gieger, DVM, DACVIM, DACVR, Romain Pariaut, DVM, DACVIM, Carley Saelinger, VMD, Keith Strickland, DVM, DACVIM
ABSTRACT The dose-limiting toxicity of doxorubicin is cardiotoxicosis. The authors of this report hypothesized that by using their institution’s adopted guidelines (that involve prescreening echocardiography and electrocardiography), they would detect preexisting cardiac abnormalities that preclude doxorubicin administration in ,10% of dogs. Of 101 dogs, only 6 were excluded from doxorubicin administration based on electrocardiogram abnormalities, with a majority of those arrhythmias classified as ventricular premature contractions. One patient was excluded based on echocardiogram alone due to hypertrophic cardiomyopathy. The incidence of cardiotoxicity in treated dogs was 8% (8/101). Additional pretreatment and ongoing studies are indicated to identify risk factors for cardiotoxicity. (J Am Anim Hosp Assoc 2012; 48:---–---. DOI 10.5326/JAAHA-MS-5680)
Introduction
In canine patients, the reported incidence of doxorubicin-
Doxorubicin (Adriamycin) is one of the most clinically effective
induced cardiomyopathy with subsequent congestive heart failure
and widely used chemotherapeutics in veterinary and human
is 2.3–8.6%.8–10 The study of this syndrome in dogs is challenging
1
medicine. In veterinary medicine, doxorubicin is used to treat
because of the lack of standardized prescreening and ongoing
lymphoma, osteosarcoma, hemangiosarcoma, and a variety of car-
monitoring tests. Monitoring methods that have been evaluated
cinomas.2 Doxorubicin has been used in human medicine to treat
include electrocardiography (ECG), echocardiography, and mea-
leukemias, lymphomas, osteosarcomas, soft-tissue sarcomas, and
surement of cardiac troponins.11 Even the administration of sele-
breast and esophageal carcinomas.
3
nium and vitamin E concurrently with doxorubicin was evaluated
Doxorubicin has been shown to be effective in all phases of
in one study, but no difference was observed in either the in-
the cell cycle and has multiple mechanisms of action, including
cidence or severity of cardiac damage.12 Based on these studies,
intercalation of DNA, formation of free radicals, inhibition of
the maximum recommended lifetime dose of doxorubicin in dogs
topoisomerase II enzymes (which unwind DNA for transcription),
is 240 mg/m2 (typically eight doses of doxorubicin/dog), but 150–
and chelation of divalent cations.2,4,5 In dogs, the dose-limiting
180 mg/m2 is rarely exceeded in typical chemotherapy protocols.
toxicity of doxorubicin is cardiotoxicosis. The exact mechanism
Although, this lifetime dose is likely safe for most dogs, cardio-
of injury is unclear, but a majority of evidence supports a com-
myopathy has been observed at lower doses such as 90 mg/m2.2,8
3,6,7
ponent of free radical damage.
Free radical accumulation in
Ideally, prescreening tests could be used to identify dogs at risk
conjunction with a decrease in endogenous antioxidants leads to
for developing cardiomyopathy, and ongoing tests could be
an enhanced oxidative stress situation, which results in loss of
used to monitor dogs for early signs of doxorubicin-induced
myofibrils and vacuolization of the myocardial cells.
3
From the Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA. Correspondence: wratterree@vetmed.lsu.edu (W.R.)
ª 2012 by American Animal Hospital Association
cardiomyopathy.
ECG electrocardiogram; FS fractional shortening; LVEF left ventricular ejection fraction; LVIDd left ventricular internal dimension in diastole; LVIDs left ventricular internal dimension in systole
JAAHA.ORG
1
The screening tests for all dogs prior to receiving doxorubicin
the echocardiograms (K.S. or R.P.). Echocardiograms were not
at the authors’ institution include physical examination, six-lead
routinely repeated during the course of the chemotherapy protocol.
electrocardiogram, and a two-dimensional echocardiogram per-
Recheck echocardiograms were performed at the discretion of the
formed by a board-certified cardiologist to evaluate the patients
attending clinician if suspected complications arose, which included
for any underlying cardiac pathology that would exclude them
development of a heart murmur, arrhythmia, or cardiac changes
from receiving doxorubicin based on the stated criteria adopted
seen on thoracic radiographs. Patients were monitored with six-lead
at this institution. The purpose of our study was to further eval-
ECG prior to the first administration of doxorubicin and prior
uate the usefulness of performing a prescreening echocardiogram
to each subsequent dose. Thoracic auscultation was performed at
and electrocardiogram in patients prior to doxorubicin adminis-
each routine examination prior to chemotherapy administration
tration. The authors hypothesize that routine echocardiography in
to monitor existing heart murmurs and to detect new arrhythmias
addition to an ECG is a low-yield test that will detect pre-existing
or murmurs.
cardiac abnormalities that preclude doxorubicin administration in ,10% of dogs based on the authors’ institution’s exclusion
Exclusion Criteria for Doxorubicin Administration
criteria.
Patients were evaluated for underlying cardiac abnormalities with auscultation, ECG, and echocardiogram prior to receiving doxo-
Materials and Methods
rubicin. Patients were not excluded based on abnormalities (i.e.,
Patient Selection
murmurs, arrhythmias) solely found on auscultation. Patients
Medical records from client-owned dogs treated at the authors’
that had underlying arrhythmias on ECG were recommended to
institution’s oncology department from Jan 2000 to Dec 2009
have a further evaluation with a 24 hr Holter monitorc. Patients
were reviewed. Dogs that had histologically or cytologically con-
that had underlying electrical disturbances, including bigeminal/
firmed tumors, that were anticipated to receive at least one dose
trigeminal ventricular premature contractions, ventricular tachy-
of doxorubicin, had an ECGa with a complete echocardiogramb
cardia, and/or supraventricular tachycardia were deemed ineligi-
performed within the 30 days prior to doxorubicin administra-
ble for doxorubicin. Using traditional measurements of systolic
tion, and had a complete medical record were included in this
function, patients were deemed ineligible for doxorubicin if they
retrospective study. Abstracted information from the medical
had systolic compromise with a FS ,20%. Patients were also ex-
records included breed, age, sex, type and stage of neoplasia,
cluded if they had underlying cardiomyopathy or severe valvular
presence or absence of a heart murmur, presence or absence of an
insufficiency. Due to the lack of established veterinary cardiac ex-
ausculted arrhythmia, and thoracic radiographic abnormalities.
clusion criteria for doxorubicin administration, these recommen-
The following were recorded in regards to doxorubicin adminis-
dations have been adopted for doxorubicin administration at the
tration: date(s) of administration; dose/administration (recorded
authors’ institution.
2
in mg/m or mg/kg); total number of doses/patient; total dose (mg/m2); and any deviation from the original protocol. The in-
Chemotherapy
formation gathered regarding the cardiac evaluation included
Doxorubicind was administered as a single agent or in combina-
fractional shortening (FS), left ventricular internal dimension in
tion with other chemotherapeutics, depending on the tumor type.
systole (LVIDs), left ventricular internal dimension in diastole
It was administered at a dose of 1 mg/kg in patients weighing
(LVIDd), evaluating cardiologist (K.S. or R.P.), date of echocardio-
,15 kg and at a dose of 30 mg/m2 in patients weighing .15 kg.
gram, abnormal findings during examination, reasons for exclusion
Doxorubicin was administered q 3 wk when administered as a
of doxorubicin administration, whether recheck echocardiograms
single agent protocol and q 4–8 wk when administered as a part
were performed, ECG findings, date of ECGs, any arrhythmias
of a multidrug protocol. The initial mean dose intensity of the
observed, time to onset of cardiac abnormalities, nature of any
patients that received a dose of 1 mg/kg was 0.28 mg/kg/wk
diagnosed cardiomyopathy, and medications prescribed for car-
(range, 0.25–0.33 mg/kg/wk) and the initial mean dose inten-
diac disease.
sity of the patients that received a dose of 30 mg/m2 was 8.0 mg/m2/wk (range, 5–10 mg/m2/wk). The administration of
Cardiac Evaluations
doxorubicin was given as a single IV bolus diluted 50:50 with
Two-dimensional echocardiograms were performed on all pa-
5% dextrose in watere (in dogs ,15 kg) or as an IV infusion
tients prior to doxorubicin administration regardless of the pri-
diluted in 500 mL of normal salinef. The dose was delivered at
mary neoplasia. One of two board-certified cardiologists performed
1 mg/min.
2
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48:2 Mar/Apr 2012
Screening Tests Prior to Doxorubicin Administration
Results
dogs received four doses, one received five doses, and one dog
Patient Characteristics
received six doses. For the 79 dogs that received 30 mg/m2/
Of the 120 medical records that were reviewed, 19 were excluded
administration, the median total number of doses was three. Within
due to insufficient data. A total of 101 dogs met the inclusion
this subpopulation of dogs, 13 dogs received one dose, 13 dogs
criteria for this retrospective study, including 6 intact females,
received two doses, 21 dogs received three doses, 16 dogs re-
44 spayed females, 10 intact males, and 41 castrated males. The
ceived four doses, 14 dogs received five doses, and 2 dogs re-
median age was 9 yr (range, 1–15 yr). The population consisted of
ceived six doses. The median total cumulative dose of those
15 mixed-breed dogs, 13 golden retrievers, 13 Labrador retrievers,
patients was 90 mg/m2 (range, 30–180 mg/m2).
7 German shepherd dogs, 5 boxers, 3 Staffordshire bull terriers, 3 Rhodesian ridgebacks, 3 rottweilers, 3 schnauzers, 2 Doberman
Prescreening for Doxorubicin Administration
pinschers, 2 bassett hounds, 2 Maltese, 2 bullmastiffs, 2 Scottish
All 101 dogs included in this study received predoxorubicin screen-
terriers, 2 shih tzu, 2 toy poodles, 2 Yorkshire terriers, and 1 dog
ing with a physical examination, six-lead ECG, and a conven-
each from 20 other breeds.
tional echocardiogram. Six dogs were excluded from doxorubicin
The majority of cases were lymphoma (n¼50), including
administration due to cardiac abnormalities found on these diag-
stage I (n¼1), stage III (n¼4), stage IV (n¼22), and stage V
nostics, and one dog was excluded due to owner intolerance of any
(n¼23). The remaining population consisted of 15 hemangio-
potential cardiac side effects with doxorubicin administration.
sarcomas (8 splenic, 3 subcutaneous, 1 renal, 1 intramuscular, 1
In this subpopulation of excluded dogs, the mean age was 10 yr.
lingual, 1 intestinal), 12 osteosarcomas (10 appendicular, 2 axial),
These six patients had a variety of tumors, including lymphoma
6 transitional cell carcinomas (5 bladder, 1 urethra), 5 thyroid
(n¼3), hemangiosarcoma (n¼1), thyroid carcinoma (n¼1), and
carcinomas, 2 grade 3 soft-tissue sarcomas, 2 mammary carcino-
transitional cell carcinoma (n¼1). Of the six patients that were
mas, 2 bile duct adenocarcinomas, and 1 each of acute lympho-
excluded, 50% were at-risk-breeds such as boxers (n¼2) and
blastic leukemia, mesothelioma, intestinal adenocarcinoma, nasal
Doberman pinschers (n¼1). Cardiac murmurs were ausculted in
planum squamous cell carcinoma, perianal carcinoma, pulmonary
two of these patients, and an arrhythmia was ausculted in one
adenocarcinoma, and splenic histiocytic sarcoma.
patient. Abnormalities were detected in predoxorubicin ECGs
Of the 101 dogs evaluated, 29% were noted to have a heart
in 83% (5/6) of the excluded patients, with a majority of those
murmur at the initial presentation. The murmurs were classified
arrhythmias classified as ventricular premature contractions. A 24
(on a scale of 1–6) as grade 1 (n¼7), grade 2 (n¼14), grade 3
hr continuous Holter examination was performed in four dogs
(n¼5), and grade 4 (n¼1). Two of the murmurs were not graded.
with ECG abnormalities. Holter examinations revealed multifocal
The detection of a heart murmur after varying doses of doxo-
ventricular premature contractions (n¼1), bigeminal/trigeminal
rubicin administration was noted in three dogs (after 60 mg/m2
ventricular premature contractions (n¼2), and numerous cou-
2
plets with ventricular tachycardia (n¼1). Echocardiograms in
in two dogs and after 90 mg/m in one dog). Thoracic radiographs were performed prior to chemotherapy
these patients revealed moderate subaortic stenosis (n¼1), mild
administration in 97% of the patients for staging purposes. Cardiac
concentric ventricular hypertrophy (n¼1), trace mitral regurgi-
or pulmonary vasculature abnormalities were noted in seven cases.
tation (n¼1), and moderate mitral regurgitation (n¼2). One
These abnormalities consisted of right heart enlargement (n¼2),
patient had a normal exam. These five patients with underlying
enlarged main pulmonary artery (n¼2), left atrial enlargement
electrical disturbances and echocardiogram abnormalities were
(n¼1), left-sided cardiomegaly (n¼1), and a globoid cardiac sil-
excluded from doxorubicin treatment. Alternative chemotherapy
houette suggestive of pericardial effusion that was confirmed on
was at the discretion of the attending clinician, but consisted of
an echocardiogram (n¼1).
mitoxantroneg.
Doxorubicin Administration
to the first dose of doxorubicin. Of the six patients that were
Doxorubicin was administered to a total of 94 dogs. Of these, 15 dogs
excluded from doxorubicin administration, only one was excluded
received a dose of 1 mg/kg, and the remaining 79 received a dose
due to echocardiographic results alone. Structural abnormalities
Every patient in this study received an echocardiogram prior
of 30 mg/m . For dogs that received 1 mg/kg, the median total
were observed in 59.4% of the 101 dogs (Table 1), but the majority
cumulative dose of doxorubicin was 3 mg/kg (range, 1–6 mg/kg).
of those dogs were not excluded from doxorubicin administration.
Within this subpopulation of dogs, four dogs received one dose,
There was no diffuse myocardial (neoplastic) infiltration observed in
one dog received two doses, four dogs received three doses, four
the 101 patients. The median FS recorded in the overall population
2
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3
ventricular cavity size. The patient had no laboratory or clinical
TABLE 1
evidence of hypovolemia, no clinical evidence of hyperthyroidism,
Echocardiogram Results of the 101 Patients Prior to Doxorubicin Administration Number of patients
Echocardiogram results
41
No abnormalities
9
and a normal systolic blood pressure (135 mm Hg). The patient was treated with mitoxantrone and was ultimately euthanized 472 days after diagnosis due to an oral fibrosarcoma.
Mild mitral insufficiency Trace mitral and tricuspid insufficiency
Cardiotoxicity
5
Trace tricuspid insufficiency
Of the 94 dogs administered doxorubicin, 7.4% (7/101) developed
4
Trace mitral insufficiency
arrhythmias or conduction disturbances during routine ECG
3
Mild mitral insufficiency and trace aortic insufficiency
monitoring that precluded additional doses of doxorubicin. The
3
Moderate mitral and tricuspid insufficiency
arrhythmias or conduction disturbances noted on the ECG were
2
Mild mitral and aortic insufficiency
ventricular premature contractions (n¼3), atrial premature con-
2
Mild mitral and tricuspid insufficiency
tractions (n¼1), right bundle branch block (n¼1), and supra-
2
Moderate mitral insufficiency
ventricular tachycardia (n¼2). The majority (72%) of these
1
Concentric left ventricular hypertrophy
1
Mild mitral and aortic insufficiency and trace tricuspid and pulmonic insufficiency
arrhythmias did not need medical intervention. Therapy for
1
Mild mitral, aortic, and pulmonic insufficiency
developed supraventricular tachycardia. The mean cumulative
1
Mild mitral insufficiency and trace tricuspid valve insufficiency
dose from onset of cardiac arrhythmias was 90 mg/m2 (range,
1
Moderate mitral and tricuspid insufficiency and pleural effusion
rubicin to identification of the cardiac arrhythmias was 124 days.
1
Moderate mitral insufficiency and mild left ventricular hypertrophy
When doxorubicin therapy was still indicated in these patients
1
Moderate subaortic stenosis
1
Moderate mitral insufficiency and mild tricuspid insufficiency
1
Mild concentric ventricular hypertrophy
patients that developed doxorubicin-induced cardiotoxcity.8,13
1
Heart base mass (chemodectoma)
1*
Hypertrophic cardiomyopathy
Echocardiograms were repeated in six of these patients, which
1
Mild aortic stenosis
1
Mild mitral insufficiency, trace tricuspid insufficiency, and positive for heartworm
1
Mild mitral and tricuspid insufficiency and pericardial effusion
1
Trace mitral and tricuspid insufficiency and a heart base mass (suspected chemodectoma)
12
1
Mild mitral insufficiency, moderate tricuspid insufficiency, and positive for heartworm
1
Trace mitral and aortic insufficiency
1
Mild mitral insufficiency and trace aortic and tricuspid insufficiency
* Sole patient excluded from doxorubicin administration based on echocardiogram findings
congestive heart failure was indicated in the two patients that
30–150 mg/m2). The median time from the initial dose of doxo-
due to tumor burden, mitoxantrone (5–6 mg/m2 IV) was substituted in their protocol. These clinical substitutions were based on previous reports of these arrhythmias being demonstrated in
showed no structural explanation for these arrhythmias in four of the patients. Doxorubicin-induced cardiomyopathy was diagnosed via echocardiography in 2.1% (2/94) of the patients that received doxorubicin. These patients developed clinical signs such as exercise intolerance, coughing, respiratory distress, and labored breathing. Of these two patients, one had a heart murmur detected on initial cardiac auscultation. The total dose of doxorubicin for the two dogs that developed congestive heart failure was 60 mg/m2 and 150 mg/m2. The number of days from the initial dose of doxorubicin administration to the diagnosis of doxorubicininduced cardiomyopathy was 160 days and 163 days. The dose intensity for these two patients was 7.5 mg/m2/wk and 10 mg/m2/wk. Conventional echocardiographic parameters of left ventricular
was 37%. FS measurements in the population were ,20% (n¼1),
size and function were obtained in the initial exam and com-
20–25% (n¼9), 26–30% (n¼15), 31–35% (n¼20), 36–40%
pared with the follow-up exam (Table 2). The decrease in FS for
(n¼20), and .40% (n¼36). The one patient that was excluded
the two cases was 14% and 19%. Of these two patients, only one
due to structural abnormalities was diagnosed with suspected hy-
of these dogs had structural abnormalities on initial echocar-
pertrophic cardiomyopathy. This patient had no abnormalities on
diogram examination (atrioventricular valve regurgitation), al-
either physical exam or the ECG. The echocardiogram revealed
though these abnormalities were not considered severe enough
a concentric left ventricular wall hypertrophy and a decrease in left
to exclude them from doxorubicin administration. These patients
4
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48:2 Mar/Apr 2012
Screening Tests Prior to Doxorubicin Administration
Typically, the presence of ECG or echocardiographic abnormali-
TABLE 2
ties prompts the clinician to discontinue the use of doxorubicin.
Patients with Echocardiographically Confirmed Dilated Doxorubicin-Induced Cardiomyopathy Pre- and Postdoxorubicin Administration
man patients has been extensively studied because most patients
Patient
LVIDd (cm)
LVIDs (cm)
FS (%)
LA (cm)
that have left ventricular dysfunction exhibit no clinical signs or
1 (pre)
4.86
2.91
40
2.7
31
symptoms. The most sensitive and specific test to monitor for
2 (pre)
4.6
3.6
22
3.2
20
toxicity is serial endomyocardial biopsies of the ventricle.15–18 This
1 (post)
5.15
4.05
21
3
30.9
test is not routinely performed due to the morbidity and mortality
2 (post)
5.4
4.9
8
4.9
19.2
associated with the procedure. Particular expertise is needed to
Weight (kg)
FS, fractional shortening; LA, left atrium; LVIDd, left ventricular internal dimension in diastole; VDIDs left ventricular internal dimension in systole.
Monitoring for doxorubicin-induced cardiomyopathy in hu-
perform the biopsy and to histologically evaluate the sample.15 The endomyocardial biopsy may be overly sensitive in detecting doxorubicin toxicity and may either delay or preclude treatment
were treated with traditional cardiac medical management, and
with doxorubicin when sufficient cardiac reserve is available.15
their survival time from diagnosis was 2 days and 51 days. These
Endomyocardial biopsy has not been described for cardiac moni-
patients were treated with a combination of one or multiple cardiac
toring in veterinary medicine.
medications consisting of furosemideh, enalaprili, pimobendanj, k
The measurement of left ventricular ejection fraction (LVEF)
l
digoxin , and diltiazem . The two patients were eventually eu-
either by radionuclide angiocardiography or echocardiography is
thanized with refractory congestive heart failure.
used to monitor human patients receiving doxorubicin. Radionuclide angiography using 99mTc-pertechnetate is preferred due to
Discussion
its superior reproducibility in measuring LVEF and its proven
The hypothesis of this study was that routine echocardiography in
ability to reduce the incidence of congestive heart failure sec-
addition to electrocardiogram is a low-yield test and will detect
ondary to administration of doxorubicin when used as a serial
pre-existing cardiac abnormalities that preclude doxorubicin ad-
monitoring tool.19–25 Neither of those studies have been performed
ministration in ,10% of dogs based on the authors’ institution’s
in veterinary medicine and would likely be technically challenging
exclusion criteria. In this study, only 6/101 (5.9%) dogs were
in small animal patients. As a general rule, younger human
excluded from doxorubicin administration due to either echo-
patients receiving doxorubicin are monitored with echocardiog-
cardiographic or ECG abnormalities. The majority of these (5/6,
raphy rather than radionuclide evaluation to lower their exposure
83%) dogs had ECG abnormalities detected prior to the first
to radiation.
doxorubicin administration. The echocardiogram alone only ex-
There are no current published guidelines in veterinary
cluded one patient due to structural abnormalities, which was con-
medicine that indicate the degree or severity of underlying cardiac
sistent with hypertrophic cardiomyopathy. Based on these findings,
disease that instructs the clinician to exclude doxorubicin from
a single echocardiogram as a predoxorubicin staging test is a low-
their chemotherapeutic protocol. In this study, patients that had
yield procedure, but can detect significant cardiac abnormalities
underlying electrical disturbances, a systolic compromise with a
in a small number of patients.
FS ,20%, an underlying cardiomyopathy, or severe valvular in-
In a study by Hanai et al. (1996), M-mode echocardiography
sufficiency were deemed ineligible for doxorubicin. These cri-
was able to detect alterations in FS in dogs receiving doxorubicin.14
teria highlighted the patients that had cardiac compromise, and
The alterations in FS did not consistently correlate with post-
doxorubicin administration was deemed an unnecessary risk based
mortem histologic changes of the myocardium.14 It has been
on clinical judgment. Additional strict clinical studies would be
suggested that echocardiography to measure FS can be used as
needed to determine the validity of these adopted guidelines used
a screening test for at-risk breeds.4 This suggestion could be fol-
to exclude patients from doxorubicin administration. In a study by
lowed based on the fact that 50% of the excluded patients in this
Gillings et al. (2009) a toxicity grading scheme was adopted by
study are considered at-risk breeds. Due to lack of noninvasive
from the National Cancer Institute’s Common Terminology Cri-
monitoring techniques and financial restraints, ECG and echocar-
teria for Adverse Events to evaluate prolonged infusion times of
diography are the primary methods used to monitor doxorubicin-
doxorubicin.9 Those guidelines attempted to establish a basis for
induced cardiomyopathy. These tests are used for sequential
serial monitoring of veterinary patients with ECG and echo-
monitoring techniques in animals receiving doxorubicin, but do not
cardiograms; however, they did not address the patient’s pre-
indicate if or when an animal will develop dilated cardiomyopathy.
existing underlying cardiac disease. In human medicine, specific
JAAHA.ORG
5
guidelines for ongoing monitoring with radionuclide angiocar-
It is important to note that not all dogs that develop
diography have been adopted. Those guidelines consist of a base-
doxorubicin-induced cardiomyopathy exhibit ECG abnormalities.
line measurement of LVEF either before beginning doxorubicin
In a review of five dogs that died of congestive heart failure due to
or before a cumulative dose of 100 mg/m2. If the baseline mea-
doxorubicin-induced cardiomyopathy, ECG results were incon-
surement of LVEF is #30% then doxorubicin should not be ad-
sistent.6 Three of the five dogs had normal six-lead ECG readings,
ministered.21 Due to the lack of historical studies in veterinary
while the other two exhibited premature ventricular complexes
medicine, more data are needed to specifically outline what pa-
and atrial fibrillation.6 It should be noted that in this study,
tients should or should not receive doxorubicin based on their
ECGs were performed prior to each dose of doxorubicin; how-
underlying cardiac disease.
ever, continuous Holter monitoring was not routine, which could
ECG arrhythmias in this population of dogs receiving doxo-
have detected underlying arrhythmias in these patients. In an
rubicin were noted in 7/94 (7.4%) patients. The reported incidence
experimentally-induced doxorubicin cardiotoxicity model of 10
of ECG abnormalities seen after doxorubicin administration in
dogs, it was suggested that ventricular dysrhythmias could serve
8,9
veterinary patients is 12–17.7%.
Arrhythmias can be observed
as an early warning sign of cardiotoxicity because they were
either during or after completion of the intended chemotherapy
evident at lower cumulative doses.7 The lowest cumulative dose
protocol. ECG changes include supraventricular arrhythmias,
that a ventricular dysrhythmia was observed was 44 mg/m2.
ventricular premature contractions, sinus tachycardia, T wave or
However, the correlation between ECG abnormalities and his-
S-T segment changes, atrioventricular block, and R wave am-
tologically confirmed cardiomyopathy was not evident in all of
plitude changes.2,6–9 In this study, the majority of arrhythmias (5/7)
the dogs.
observed did not need medical intervention. In the study by
In humans, the cardiac abnormalities reported can vary
Mauldin et al. (1992), 17.7% (31/175) of patients developed
from slight ECG abnormalities to fatal congestive heart failure.26
ECG abnormalities following doxorubicin administration.8 In
The reported incidence of ECG abnormalities in humans with
the current study, a smaller percent of patients (7.4%) developed
doxorubicin-induced cardiomyopathy is 11–30%.8,26–28 Non-
arrhythmias postdoxorubicin administration. In the study by
specific ECG changes observed in humans include ST-T wave
Mauldin et al. (1992), all patients received a dose of 30 mg/m2.
abnormalities, premature atrial contractions and ventricular beats,
In the current study, 15.9% (15/94) patients received a dose of
prolonged Q-T intervals, supraventricular arrhythmias, and QRS
1 mg/kg due because they weighed ,15 kg. Thus, s significant
axis shifts.26,28,29 These ECG abnormalities are usually dismissed
percentage of patients in the current study received a lower dose/
as being transient in human patients, and treatment with doxo-
administration and lower total dose/patient, which could have
rubicin is not halted. It has been suggested that some ECG
contributed to the lower incidence of arrhythmias. Other con-
abnormalities such as QRS voltage changes can indicate early
founding factors for the lower incidence of arrhythmias in this
myocardial damage.8,26,27
study would be a smaller sample size in this study (n¼94) com-
In dogs, the incidence of doxorubicin-induced cardiomyop-
pared with the previous study (n¼175). In a recent study investi-
athy with subsequent congestive heart failure has been reported
gating prolonged administration infusions, it was suggested that
in one study as 4% (7/175) with a median cumulative dose for all
extending the infusion duration significantly reduces the incidence
seven dogs of 150 mg/m2 (range, 90–210 mg/m2)8. Another study
of conduction abnormalities in dogs receiving doxorubicin che-
reported the incidence as 8.6% (4/46) with a cumulative median
motherapy.9 In the current study, doxorubicin was administered
dose of the affected dogs of 155 mg/m2 (range, 150–180 mg/m2)17.
as a longer infusion (1 mg/min), which could also account for
More recently, a third study reported the incidence as 2.3% (3/133).9
the lower incidence of arrhythmias. In the study by Gillings et al.
Congestive heart failure in dogs has been reported secondary to
(2009), the reported incidence of ECG abnormalities was 12% (16/
cumulative doses of doxorubicin ranging from 90 mg/m2 to 265
133).9 In that study, the median cumulative dose of doxorubicin
mg/m2.2,6,8,9 The median survival of canine patients that develop
2
2
was 120 mg/m (range, 53.2–180 mg/m ). In comparison, the me2
dian cumulative dose in this study was 90 mg/m (range, 30–180 2
mg/m ). The incidence of doxorubicin-induced cardiotoxicity has 8
congestive heart failure secondary to doxorubicin administration has been reported to be 48 hr and 90 days.6,8 Dilated cardiomyopathy, presumed to be doxorubicin-induced
long been proven to be dose-dependent in people. The lower
cardiomyopathy, developed in 2.1% of this patient population. All
cumulative dose in the current study compared with the study by
of these patients had a preadministration echocardiogram and
Gillins et al. (2009) could be an explanation for the lower incidence
a recheck echocardiogram at the onset of clinical signs consistent
of cardiotoxicity in this population of veterinary patients.
with heart failure. Echocardiographic findings consistent with
6
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Screening Tests Prior to Doxorubicin Administration
doxorubicin-induced cardiomyopathy included increased left
a low-yield test; however, in a small population of animals it can
ventricular end systolic internal dimensions, decreased FS, decreased
detect life-threatening abnormalities. Further studies are needed
left ventricular ejection time, and reduced left ventricular posterior
to determine if serial echocardiography can reduce the incidence
wall thickness.6 In this study, all of the patients that were diagnosed
of doxorubicin-induced cardiomyopathy in dogs. Ideally, pro-
with doxorubicin-induced cardiomyopathy had an increase in
spective, controlled, studies comparing additional parameters
left ventricular systolic dimensions and a mean decrease in FS of
such as echocardiographic measurements of diastolic function,
16.5%. One limitation of this study was that these patients were
tissue Doppler, or circulating levels of cardiac biomarkers would
only presumptively diagnosed with doxorubicin-induced cardio-
be valuable.
myopathy because necropsies were not performed. Due to the fact that these animals had no echocardiographic evidence of cardiomyopathy prior to doxorubicin administration and no other cardiotoxic agents were administered to these patients, they were presumptively diagnosed with doxorubicin-induced cardiomyopathy. Treatment of congestive heart failure was unsuccessful, and median survival was 26.5 days. The survival times in previous studies of dogs with doxorubicin-induced cardiomyopathy were 48 hr and 90 days.6,8 This study had inherent limitations. A majority of the echocardiograms were performed by one cardiologist (K.S., n¼86), but a small number were performed by another cardiologist (R.P., n¼15). Thus, recommendations regarding the eligibility of a patient to receive doxorubicin may have varied. Another limitation was a lack of necropsy data performed on the patients receiving doxorubicin, which would have allowed the authors to detect
FOOTNOTES a ECG equipment; Philips Pagewriter 200, Philips, Bothell WA b Echocardiogram equipment; Philips iE33, Philips, Bothell WA c Holter equipment; Trillium 5000, Forest Medical LLC, East Syracuse NY d Doxorubicin; Doxorubicin HCl, Pfizer, New York NY e 5% dextrose in water; 5% Dextrose Injection, Baxter Healthcare Corporation, Deerfield IL f Normal saline; 0.9% Sodium Chloride, Baxter Healthcare Corporation, Deerfield IL g Mitoxantrone; Mitoxantrone Injection USP, Hospira, Lake Forest, IL h Furosemide; FuroTabs, Baxter Animal Health, Dublin, OH i Enalapril; Enalapril Maleate, Mylan Pharmaceuticals, Morgantown, WV j Pimobendan; Vetmedin, Boehringer Ingelheim, St Joseph, MO k Digoxin; Digoxin HCl, West-ward Pharmaceuticals, Eatontown, NJ l Diltiazem; Diltiazem Hydrochloride, Mylan Pharmaceuticals, Morgantown, WV
cardiac damage not identified on echocardiogram. Another limitation is that one outcome of interest, cardiotoxicity, occurs at a low frequency, so it is difficult to draw specific conclusions from this particular study. Although continuous Holter monitors were not routinely used as a monitoring technique in this study, it is plausible to conceive they could have discovered underlying electrical disturbances that routine ECGs failed to detect in this population of patients. Due to the risk of other toxicities (such as gastrointestinal and hematologic toxicity) in dogs weighing ,15 kg, doxorubicin was administered at lower doses (1 mg/kg instead of 30 mg/m2) in smaller patients. The lower dose in those patients (n¼15) could have influenced the incidence of cardiotoxicity in this study creating an inherent limitation.
Conclusion Based on this institution’s stated guidelines, routine echocardiography in conjunction with ECG prior to doxorubicin administration will detect pre-existing cardiac abnormalities that limit doxorubicin administration in ,10% of dogs. Echocardiograms did allow further characterization of underlying heart disease in patients that had detectable heart murmurs on physical examination declaring them eligible for doxorubicin. The addition of echocardiography to predoxorubicin screening in all patients is
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