Value of Echocardiography and Electrocardiography as Screening Tools Prior to Doxorubicin Administration
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 pre-existing 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.
Introduction
Doxorubicin (Adriamycin) is one of the most clinically effective and widely used chemotherapeutics in veterinary and human medicine.1 In veterinary medicine, doxorubicin is used to treat lymphoma, osteosarcoma, hemangiosarcoma, and a variety of carcinomas.2 Doxorubicin has been used in human medicine to treat leukemias, lymphomas, osteosarcomas, soft-tissue sarcomas, and breast and esophageal carcinomas.3
Doxorubicin has been shown to be effective in all phases of the cell cycle and has multiple mechanisms of action, including intercalation of DNA, formation of free radicals, inhibition of topoisomerase II enzymes (which unwind DNA for transcription), and chelation of divalent cations.2,4,5 In dogs, the dose-limiting toxicity of doxorubicin is cardiotoxicosis. The exact mechanism of injury is unclear, but a majority of evidence supports a component of free radical damage.3,6,7 Free radical accumulation in conjunction with a decrease in endogenous antioxidants leads to an enhanced oxidative stress situation, which results in loss of myofibrils and vacuolization of the myocardial cells.3
In canine patients, the reported incidence of doxorubicin-induced cardiomyopathy with subsequent congestive heart failure is 2.3–8.6%.8–10 The study of this syndrome in dogs is challenging because of the lack of standardized prescreening and ongoing monitoring tests. Monitoring methods that have been evaluated include electrocardiography (ECG), echocardiography, and measurement of cardiac troponins.11 Even the administration of selenium and vitamin E concurrently with doxorubicin was evaluated in one study, but no difference was observed in either the incidence or severity of cardiac damage.12 Based on these studies, the maximum recommended lifetime dose of doxorubicin in dogs is 240 mg/m2 (typically eight doses of doxorubicin/dog), but 150–180 mg/m2 is rarely exceeded in typical chemotherapy protocols. Although, this lifetime dose is likely safe for most dogs, cardiomyopathy has been observed at lower doses such as 90 mg/m2.2,8 Ideally, prescreening tests could be used to identify dogs at risk for developing cardiomyopathy, and ongoing tests could be used to monitor dogs for early signs of doxorubicin-induced cardiomyopathy.
The screening tests for all dogs prior to receiving doxorubicin at the authors’ institution include physical examination, six-lead electrocardiogram, and a two-dimensional echocardiogram performed by a board-certified cardiologist to evaluate the patients for any underlying cardiac pathology that would exclude them from receiving doxorubicin based on the stated criteria adopted at this institution. The purpose of our study was to further evaluate the usefulness of performing a prescreening echocardiogram and electrocardiogram in patients prior to doxorubicin administration. The authors hypothesize that routine echocardiography in addition to an ECG is a low-yield test that will detect pre-existing cardiac abnormalities that preclude doxorubicin administration in <10% of dogs based on the authors’ institution's exclusion criteria.
Materials and Methods
Patient Selection
Medical records from client-owned dogs treated at the authors’ institution's oncology department from Jan 2000 to Dec 2009 were reviewed. Dogs that had histologically or cytologically confirmed tumors, that were anticipated to receive at least one dose of doxorubicin, had an ECGa with a complete echocardiogramb performed within the 30 days prior to doxorubicin administration, and had a complete medical record were included in this retrospective study. Abstracted information from the medical records included breed, age, sex, type and stage of neoplasia, presence or absence of a heart murmur, presence or absence of an ausculted arrhythmia, and thoracic radiographic abnormalities. The following were recorded in regards to doxorubicin administration: date(s) of administration; dose/administration (recorded in mg/m2 or mg/kg); total number of doses/patient; total dose (mg/m2); and any deviation from the original protocol. The information gathered regarding the cardiac evaluation included fractional shortening (FS), left ventricular internal dimension in systole (LVIDs), left ventricular internal dimension in diastole (LVIDd), evaluating cardiologist (K.S. or R.P.), date of echocardiogram, abnormal findings during examination, reasons for exclusion of doxorubicin administration, whether recheck echocardiograms were performed, ECG findings, date of ECGs, any arrhythmias observed, time to onset of cardiac abnormalities, nature of any diagnosed cardiomyopathy, and medications prescribed for cardiac disease.
Cardiac Evaluations
Two-dimensional echocardiograms were performed on all patients prior to doxorubicin administration regardless of the primary neoplasia. One of two board-certified cardiologists performed the echocardiograms (K.S. or R.P.). Echocardiograms were not routinely repeated during the course of the chemotherapy protocol. Recheck echocardiograms were performed at the discretion of the attending clinician if suspected complications arose, which included development of a heart murmur, arrhythmia, or cardiac changes seen on thoracic radiographs. Patients were monitored with six-lead ECG prior to the first administration of doxorubicin and prior to each subsequent dose. Thoracic auscultation was performed at each routine examination prior to chemotherapy administration to monitor existing heart murmurs and to detect new arrhythmias or murmurs.
Exclusion Criteria for Doxorubicin Administration
Patients were evaluated for underlying cardiac abnormalities with auscultation, ECG, and echocardiogram prior to receiving doxorubicin. Patients were not excluded based on abnormalities (i.e., murmurs, arrhythmias) solely found on auscultation. Patients that had underlying arrhythmias on ECG were recommended to have a further evaluation with a 24 hr Holter monitorc. Patients that had underlying electrical disturbances, including bigeminal/trigeminal ventricular premature contractions, ventricular tachycardia, and/or supraventricular tachycardia were deemed ineligible for doxorubicin. Using traditional measurements of systolic function, patients were deemed ineligible for doxorubicin if they had systolic compromise with a FS <20%. Patients were also excluded if they had underlying cardiomyopathy or severe valvular insufficiency. Due to the lack of established veterinary cardiac exclusion criteria for doxorubicin administration, these recommendations have been adopted for doxorubicin administration at the authors’ institution.
Chemotherapy
Doxorubicind was administered as a single agent or in combination with other chemotherapeutics, depending on the tumor type. It was administered at a dose of 1 mg/kg in patients weighing <15 kg and at a dose of 30 mg/m2 in patients weighing >15 kg. Doxorubicin was administered q 3 wk when administered as a single agent protocol and q 4–8 wk when administered as a part of a multidrug protocol. The initial mean dose intensity of the patients that received a dose of 1 mg/kg was 0.28 mg/kg/wk (range, 0.25–0.33 mg/kg/wk) and the initial mean dose intensity 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 doxorubicin was given as a single IV bolus diluted 50:50 with 5% dextrose in watere (in dogs <15 kg) or as an IV infusion diluted in 500 mL of normal salinef. The dose was delivered at 1 mg/min.
Results
Patient Characteristics
Of the 120 medical records that were reviewed, 19 were excluded due to insufficient data. A total of 101 dogs met the inclusion criteria for this retrospective study, including 6 intact females, 44 spayed females, 10 intact males, and 41 castrated males. The median age was 9 yr (range, 1–15 yr). The population consisted of 15 mixed-breed dogs, 13 golden retrievers, 13 Labrador retrievers, 7 German shepherd dogs, 5 boxers, 3 Staffordshire bull terriers, 3 Rhodesian ridgebacks, 3 rottweilers, 3 schnauzers, 2 Doberman pinschers, 2 bassett hounds, 2 Maltese, 2 bullmastiffs, 2 Scottish terriers, 2 shih tzu, 2 toy poodles, 2 Yorkshire terriers, and 1 dog each from 20 other breeds.
The majority of cases were lymphoma (n=50), including stage I (n=1), stage III (n=4), stage IV (n=22), and stage V (n=23). The remaining population consisted of 15 hemangiosarcomas (8 splenic, 3 subcutaneous, 1 renal, 1 intramuscular, 1 lingual, 1 intestinal), 12 osteosarcomas (10 appendicular, 2 axial), 6 transitional cell carcinomas (5 bladder, 1 urethra), 5 thyroid carcinomas, 2 grade 3 soft-tissue sarcomas, 2 mammary carcinomas, 2 bile duct adenocarcinomas, and 1 each of acute lymphoblastic leukemia, mesothelioma, intestinal adenocarcinoma, nasal planum squamous cell carcinoma, perianal carcinoma, pulmonary adenocarcinoma, and splenic histiocytic sarcoma.
Of the 101 dogs evaluated, 29% were noted to have a heart murmur at the initial presentation. The murmurs were classified (on a scale of 1–6) as grade 1 (n=7), grade 2 (n=14), grade 3 (n=5), and grade 4 (n=1). Two of the murmurs were not graded. The detection of a heart murmur after varying doses of doxorubicin administration was noted in three dogs (after 60 mg/m2 in two dogs and after 90 mg/m2 in one dog).
Thoracic radiographs were performed prior to chemotherapy administration in 97% of the patients for staging purposes. Cardiac or pulmonary vasculature abnormalities were noted in seven cases. These abnormalities consisted of right heart enlargement (n=2), enlarged main pulmonary artery (n=2), left atrial enlargement (n=1), left-sided cardiomegaly (n=1), and a globoid cardiac silhouette suggestive of pericardial effusion that was confirmed on an echocardiogram (n=1).
Doxorubicin Administration
Doxorubicin was administered to a total of 94 dogs. Of these, 15 dogs received a dose of 1 mg/kg, and the remaining 79 received a dose of 30 mg/m2. For dogs that received 1 mg/kg, the median total cumulative dose of doxorubicin was 3 mg/kg (range, 1–6 mg/kg). Within this subpopulation of dogs, four dogs received one dose, one dog received two doses, four dogs received three doses, four dogs received four doses, one received five doses, and one dog received six doses. For the 79 dogs that received 30 mg/m2/administration, the median total number of doses was three. Within this subpopulation of dogs, 13 dogs received one dose, 13 dogs received two doses, 21 dogs received three doses, 16 dogs received four doses, 14 dogs received five doses, and 2 dogs received six doses. The median total cumulative dose of those patients was 90 mg/m2 (range, 30–180 mg/m2).
Prescreening for Doxorubicin Administration
All 101 dogs included in this study received predoxorubicin screening with a physical examination, six-lead ECG, and a conventional echocardiogram. Six dogs were excluded from doxorubicin administration due to cardiac abnormalities found on these diagnostics, and one dog was excluded due to owner intolerance of any potential cardiac side effects with doxorubicin administration. In this subpopulation of excluded dogs, the mean age was 10 yr. These six patients had a variety of tumors, including lymphoma (n=3), hemangiosarcoma (n=1), thyroid carcinoma (n=1), and transitional cell carcinoma (n=1). Of the six patients that were excluded, 50% were at-risk-breeds such as boxers (n=2) and Doberman pinschers (n=1). Cardiac murmurs were ausculted in two of these patients, and an arrhythmia was ausculted in one patient. Abnormalities were detected in predoxorubicin ECGs in 83% (5/6) of the excluded patients, with a majority of those arrhythmias classified as ventricular premature contractions. A 24 hr continuous Holter examination was performed in four dogs with ECG abnormalities. Holter examinations revealed multifocal ventricular premature contractions (n=1), bigeminal/trigeminal ventricular premature contractions (n=2), and numerous couplets with ventricular tachycardia (n=1). Echocardiograms in these patients revealed moderate subaortic stenosis (n=1), mild concentric ventricular hypertrophy (n=1), trace mitral regurgitation (n=1), and moderate mitral regurgitation (n=2). One patient had a normal exam. These five patients with underlying electrical disturbances and echocardiogram abnormalities were excluded from doxorubicin treatment. Alternative chemotherapy was at the discretion of the attending clinician, but consisted of mitoxantroneg.
Every patient in this study received an echocardiogram prior to the first dose of doxorubicin. Of the six patients that were excluded from doxorubicin administration, only one was excluded due to echocardiographic results alone. Structural abnormalities were observed in 59.4% of the 101 dogs (Table 1), but the majority of those dogs were not excluded from doxorubicin administration. There was no diffuse myocardial (neoplastic) infiltration observed in the 101 patients. The median FS recorded in the overall population was 37%. FS measurements in the population were <20% (n=1), 20–25% (n=9), 26–30% (n=15), 31–35% (n=20), 36–40% (n=20), and >40% (n=36). The one patient that was excluded due to structural abnormalities was diagnosed with suspected hypertrophic cardiomyopathy. This patient had no abnormalities on either physical exam or the ECG. The echocardiogram revealed a concentric left ventricular wall hypertrophy and a decrease in left ventricular cavity size. The patient had no laboratory or clinical evidence of hypovolemia, no clinical evidence of hyperthyroidism, 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.
Sole patient excluded from doxorubicin administration based on echocardiogram findings
Cardiotoxicity
Of the 94 dogs administered doxorubicin, 7.4% (7/101) developed arrhythmias or conduction disturbances during routine ECG monitoring that precluded additional doses of doxorubicin. The arrhythmias or conduction disturbances noted on the ECG were ventricular premature contractions (n=3), atrial premature contractions (n=1), right bundle branch block (n=1), and supraventricular tachycardia (n=2). The majority (72%) of these arrhythmias did not need medical intervention. Therapy for congestive heart failure was indicated in the two patients that developed supraventricular tachycardia. The mean cumulative dose from onset of cardiac arrhythmias was 90 mg/m2 (range, 30–150 mg/m2). The median time from the initial dose of doxorubicin to identification of the cardiac arrhythmias was 124 days. When doxorubicin therapy was still indicated in these patients 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 patients that developed doxorubicin-induced cardiotoxcity.8,13 Echocardiograms were repeated in six of these patients, which 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 doxorubicin-induced 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 size and function were obtained in the initial exam and compared with the follow-up exam (Table 2). The decrease in FS for the two cases was 14% and 19%. Of these two patients, only one of these dogs had structural abnormalities on initial echocardiogram examination (atrioventricular valve regurgitation), although these abnormalities were not considered severe enough to exclude them from doxorubicin administration. These patients were treated with traditional cardiac medical management, and their survival time from diagnosis was 2 days and 51 days. These patients were treated with a combination of one or multiple cardiac medications consisting of furosemideh, enalaprili, pimobendanj, digoxink, and diltiazeml. The two patients were eventually euthanized with refractory congestive heart failure.
FS, fractional shortening; LA, left atrium; LVIDd, left ventricular internal dimension in diastole; VDIDs left ventricular internal dimension in systole.
Discussion
The hypothesis of this study was that routine echocardiography in addition to electrocardiogram is a low-yield test and will detect pre-existing cardiac abnormalities that preclude doxorubicin administration in <10% of dogs based on the authors’ institution's exclusion criteria. In this study, only 6/101 (5.9%) dogs were excluded from doxorubicin administration due to either echocardiographic or ECG abnormalities. The majority of these (5/6, 83%) dogs had ECG abnormalities detected prior to the first doxorubicin administration. The echocardiogram alone only excluded one patient due to structural abnormalities, which was consistent with hypertrophic cardiomyopathy. Based on these findings, a single echocardiogram as a predoxorubicin staging test is a low-yield procedure, but can detect significant cardiac abnormalities in a small number of patients.
In a study by Hanai et al. (1996), M-mode echocardiography was able to detect alterations in FS in dogs receiving doxorubicin.14 The alterations in FS did not consistently correlate with postmortem histologic changes of the myocardium.14 It has been suggested that echocardiography to measure FS can be used as a screening test for at-risk breeds.4 This suggestion could be followed based on the fact that 50% of the excluded patients in this study are considered at-risk breeds. Due to lack of noninvasive monitoring techniques and financial restraints, ECG and echocardiography are the primary methods used to monitor doxorubicin-induced cardiomyopathy. These tests are used for sequential monitoring techniques in animals receiving doxorubicin, but do not indicate if or when an animal will develop dilated cardiomyopathy. Typically, the presence of ECG or echocardiographic abnormalities prompts the clinician to discontinue the use of doxorubicin.
Monitoring for doxorubicin-induced cardiomyopathy in human patients has been extensively studied because most patients that have left ventricular dysfunction exhibit no clinical signs or symptoms. The most sensitive and specific test to monitor for toxicity is serial endomyocardial biopsies of the ventricle.15–18 This test is not routinely performed due to the morbidity and mortality associated with the procedure. Particular expertise is needed to 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 with doxorubicin when sufficient cardiac reserve is available.15 Endomyocardial biopsy has not been described for cardiac monitoring in veterinary medicine.
The measurement of left ventricular ejection fraction (LVEF) either by radionuclide angiocardiography or echocardiography is used to monitor human patients receiving doxorubicin. Radionuclide angiography using 99mTc-pertechnetate is preferred due to its superior reproducibility in measuring LVEF and its proven ability to reduce the incidence of congestive heart failure secondary to administration of doxorubicin when used as a serial monitoring tool.19–25 Neither of those studies have been performed in veterinary medicine and would likely be technically challenging in small animal patients. As a general rule, younger human patients receiving doxorubicin are monitored with echocardiography rather than radionuclide evaluation to lower their exposure to radiation.
There are no current published guidelines in veterinary medicine that indicate the degree or severity of underlying cardiac disease that instructs the clinician to exclude doxorubicin from their chemotherapeutic protocol. In this study, patients that had underlying electrical disturbances, a systolic compromise with a FS <20%, an underlying cardiomyopathy, or severe valvular insufficiency were deemed ineligible for doxorubicin. These criteria highlighted the patients that had cardiac compromise, and doxorubicin administration was deemed an unnecessary risk based on clinical judgment. Additional strict clinical studies would be needed to determine the validity of these adopted guidelines used to exclude patients from doxorubicin administration. In a study by Gillings et al. (2009) a toxicity grading scheme was adopted by from the National Cancer Institute's Common Terminology Criteria for Adverse Events to evaluate prolonged infusion times of doxorubicin.9 Those guidelines attempted to establish a basis for serial monitoring of veterinary patients with ECG and echocardiograms; however, they did not address the patient's pre-existing underlying cardiac disease. In human medicine, specific guidelines for ongoing monitoring with radionuclide angiocardiography have been adopted. Those guidelines consist of a baseline measurement of LVEF either before beginning doxorubicin or before a cumulative dose of 100 mg/m2. If the baseline measurement of LVEF is ≤30% then doxorubicin should not be administered.21 Due to the lack of historical studies in veterinary medicine, more data are needed to specifically outline what patients should or should not receive doxorubicin based on their underlying cardiac disease.
ECG arrhythmias in this population of dogs receiving doxorubicin were noted in 7/94 (7.4%) patients. The reported incidence of ECG abnormalities seen after doxorubicin administration in veterinary patients is 12–17.7%.8,9 Arrhythmias can be observed either during or after completion of the intended chemotherapy protocol. ECG changes include supraventricular arrhythmias, ventricular premature contractions, sinus tachycardia, T wave or S-T segment changes, atrioventricular block, and R wave amplitude changes.2,6–9 In this study, the majority of arrhythmias (5/7) observed did not need medical intervention. In the study by Mauldin et al. (1992), 17.7% (31/175) of patients developed ECG abnormalities following doxorubicin administration.8 In the current study, a smaller percent of patients (7.4%) developed arrhythmias postdoxorubicin administration. In the study by Mauldin et al. (1992), all patients received a dose of 30 mg/m2. In the current study, 15.9% (15/94) patients received a dose of 1 mg/kg due because they weighed <15 kg. Thus, s significant percentage of patients in the current study received a lower dose/administration and lower total dose/patient, which could have contributed to the lower incidence of arrhythmias. Other confounding factors for the lower incidence of arrhythmias in this study would be a smaller sample size in this study (n=94) compared with the previous study (n=175). In a recent study investigating prolonged administration infusions, it was suggested that extending the infusion duration significantly reduces the incidence of conduction abnormalities in dogs receiving doxorubicin chemotherapy.9 In the current study, doxorubicin was administered as a longer infusion (1 mg/min), which could also account for the lower incidence of arrhythmias. In the study by Gillings et al. (2009), the reported incidence of ECG abnormalities was 12% (16/133).9 In that study, the median cumulative dose of doxorubicin was 120 mg/m2 (range, 53.2–180 mg/m2). In comparison, the median cumulative dose in this study was 90 mg/m2 (range, 30–180 mg/m2). The incidence of doxorubicin-induced cardiotoxicity has long been proven to be dose-dependent in people.8 The lower cumulative dose in the current study compared with the study by Gillins et al. (2009) could be an explanation for the lower incidence of cardiotoxicity in this population of veterinary patients.
It is important to note that not all dogs that develop doxorubicin-induced cardiomyopathy exhibit ECG abnormalities. In a review of five dogs that died of congestive heart failure due to doxorubicin-induced cardiomyopathy, ECG results were inconsistent.6 Three of the five dogs had normal six-lead ECG readings, while the other two exhibited premature ventricular complexes and atrial fibrillation.6 It should be noted that in this study, ECGs were performed prior to each dose of doxorubicin; however, continuous Holter monitoring was not routine, which could have detected underlying arrhythmias in these patients. In an experimentally-induced doxorubicin cardiotoxicity model of 10 dogs, it was suggested that ventricular dysrhythmias could serve as an early warning sign of cardiotoxicity because they were evident at lower cumulative doses.7 The lowest cumulative dose that a ventricular dysrhythmia was observed was 44 mg/m2. However, the correlation between ECG abnormalities and histologically confirmed cardiomyopathy was not evident in all of the dogs.
In humans, the cardiac abnormalities reported can vary from slight ECG abnormalities to fatal congestive heart failure.26 The reported incidence of ECG abnormalities in humans with doxorubicin-induced cardiomyopathy is 11–30%.8,26–28 Nonspecific ECG changes observed in humans include ST-T wave abnormalities, premature atrial contractions and ventricular beats, prolonged Q-T intervals, supraventricular arrhythmias, and QRS axis shifts.26,28,29 These ECG abnormalities are usually dismissed as being transient in human patients, and treatment with doxorubicin is not halted. It has been suggested that some ECG abnormalities such as QRS voltage changes can indicate early myocardial damage.8,26,27
In dogs, the incidence of doxorubicin-induced cardiomyopathy with subsequent congestive heart failure has been reported in one study as 4% (7/175) with a median cumulative dose for all seven dogs of 150 mg/m2 (range, 90–210 mg/m2)8. Another study reported the incidence as 8.6% (4/46) with a cumulative median dose of the affected dogs of 155 mg/m2 (range, 150–180 mg/m2)17. More recently, a third study reported the incidence as 2.3% (3/133).9 Congestive heart failure in dogs has been reported secondary to cumulative doses of doxorubicin ranging from 90 mg/m2 to 265 mg/m2.2,6,8,9 The median survival of canine patients that develop 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 cardiomyopathy, developed in 2.1% of this patient population. All of these patients had a preadministration echocardiogram and a recheck echocardiogram at the onset of clinical signs consistent with heart failure. Echocardiographic findings consistent with doxorubicin-induced cardiomyopathy included increased left ventricular end systolic internal dimensions, decreased FS, decreased left ventricular ejection time, and reduced left ventricular posterior wall thickness.6 In this study, all of the patients that were diagnosed with doxorubicin-induced cardiomyopathy had an increase in left ventricular systolic dimensions and a mean decrease in FS of 16.5%. One limitation of this study was that these patients were only presumptively diagnosed with doxorubicin-induced cardiomyopathy 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., n=86), but a small number were performed by another cardiologist (R.P., n=15). 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 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 (n=15) 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 a low-yield test; however, in a small population of animals it can detect life-threatening abnormalities. Further studies are needed to determine if serial echocardiography can reduce the incidence of doxorubicin-induced cardiomyopathy in dogs. Ideally, prospective, controlled, studies comparing additional parameters such as echocardiographic measurements of diastolic function, tissue Doppler, or circulating levels of cardiac biomarkers would be valuable.
Contributor Notes
