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Utility of Prechemotherapy Evaluation of Left Ventricular Function for Patients With Lymphoma

Clinical Lymphoma Myeloma and Leukemia

Micro-Abstract

We reviewed the records of patients with lymphoma to determine whether a prechemotherapy evaluation of left ventricular function led to a change in patient management. We determined that testing rarely alters the choice of chemotherapy and that testing is a poor predictor of subsequent cardiac damage. Guidelines that recommend a cardiac evaluation for all patients with lymphoma who receive anthracyclines should be reexamined.

Abstract

Background

Published guidelines recommend baseline cardiac function testing before initiating anthracycline-based chemotherapy. These recommendations are based largely on consensus, and there is little information regarding how often testing leads to alterations in therapy or whether testing is able to predict subsequent cardiac toxicity.

Patients and Methods

We performed a retrospective analysis of patients with Hodgkin lymphoma and non-Hodgkin lymphoma to determine whether there was a prechemotherapy evaluation of left ventricular function and whether findings from the evaluation led to alterations in therapy. Records also were reviewed to evaluate subsequent test results of cardiac function.

Results

We identified 309 patients with lymphoma between 2004 and 2012 with a planned anthracycline- or anthracenedione-based regimen. Of this total, 232 patients (75%) had a pretreatment cardiac evaluation. There were 201 patients (87%) in this group with no history of cardiac disease. Although 22 of these patients (11%) had abnormal echocardiograms, none had a change in therapy and no subsequent cases of cardiomyopathy were identified. Five of the remaining 179 patients with a normal cardiac evaluation developed a cardiomyopathy. Thirty-one patients had a history of cardiac disease, and only 4 patients had a change in therapy. There were 77 patients (25%) who did not have a prechemotherapy cardiac evaluation. No subsequent cases of cardiomyopathy were identified in this group.

Conclusions

Pretreatment evaluation rarely leads to a change in management and is not helpful in predicting subsequent cardiomyopathy. Guidelines that recommend evaluation of left ventricular function in all patients before anthracycline-based chemotherapy should be reexamined.

Keywords: Anthracycline, Cardiomyopathy, Doxorubicin, Echocardiogram, Lymphoma.

Introduction

Doxorubicin-based chemotherapy is widely used in a variety of regimens for Hodgkin lymphoma and non-Hodgkin lymphoma. Unfortunately, administration of this agent is associated with cardiotoxicity. Acute toxicity occurs during or immediately after infusion and usually consists of supraventricular or ventricular arrhythmias, heart block, pericarditis, or myocarditis. Chronic or late toxicity is characterized by a cardiomyopathy leading to subclinical or overt left ventricular dysfunction and congestive heart failure that may be seen within a year or several years after finishing chemotherapy.

A variety of mechanisms may be responsible for the development of anthracycline-induced cardiotoxicity.1, 2, and 3 The most frequently proposed mechanism is thought to be related to the formation of reactive oxygen species generated by the interaction of doxorubicin with iron. This results in subsequent damage to myocytes, causing myofibrillar loss, cytoplasmic vacuolization, and apoptosis.

A number of risk factors have been associated with the development of anthracycline-induced cardiomyopathy, including age, coronary artery disease, valvular heart disease, hypertension, combination treatment with other chemotherapy agents, and the use of radiation therapy. There is also evidence that single nucleotide polymorphisms may alter susceptibility to cardiomyopathy from these agents. 4 However, the most important risk factor for toxicity is the cumulative dose of anthracycline.5 and 6

Because of the risk of cardiotoxicity, the package insert for doxorubicin recommends that treatment should be preceded by a careful baseline assessment of cardiac function as measured by left ventricular ejection fraction. 7 Current National Comprehensive Cancer Network (NCCN) guidelines state that it is essential for patients with diffuse large B-cell lymphoma, mantle cell lymphoma, lymphoblastic lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma to have a multiple gated acquisition (MUGA) scan or echocardiogram to evaluate left ventricular function if therapy with an anthracycline- or anthracenedione-containing regimen is indicated. 8 The NCCN has identical recommendations for patients with Hodgkin lymphoma who receive anthracycline-containing chemotherapy regimens. 9 In addition to the NCCN, the European Society for Medical Oncology guidelines for management of diffuse large B-cell lymphoma state that left ventricular ejection fraction should be assessed before treatment. 10 Hodgkin lymphoma guidelines from the European Society for Medical Oncology also state that cardiac function tests are mandatory before treatment. 11 In addition, baseline evaluation of left ventricle function by echocardiography for patients receiving cardiotoxic chemotherapy was given a class I recommendation in updated guidelines from the American College of Cardiology and American Heart Association. 12 Guidelines that also include the American Society for Nuclear Cardiology state that ejection fraction should be measured in all patients before receiving doxorubicin. 13 Finally, recommendations from the cardiology committee of the Children's Cancer Study Group state that all patients expected to receive doxorubicin or daunorubicin should have baseline cardiac evaluation with electrocardiography, echocardiography, and, when available, radionuclide angiocardiography. 14

The recommendations to evaluate left ventricular function before initiating therapy with anthracyclines are based primarily on consensus. Echocardiography and radionuclide angiography are insensitive measures of cardiac damage, and a decline in left ventricular ejection fraction may not occur until long after the completion of chemotherapy. There is limited literature about the ability of a single baseline test of left ventricle function to estimate the probability of developing anthracycline-related cardiotoxcity. 15 In addition, there is little information on whether routine testing of left ventricular function before initiating chemotherapy influences the outcome of patients with lymphoma. Because of this, we performed a retrospective analysis in an attempt to determine the value of measuring left ventricular function before initiating anthracycline-based therapy for lymphoma.

Patients and Methods

A list of patients with Hodgkin lymphoma or non-Hodgkin lymphoma treated with anthracycline- or anthracenedione-based chemotherapy at the University of Nebraska Medical Center between August 2004 and May 2012 was obtained from the Nebraska Lymphoma Study Group database.

Baseline characteristics were collected, including age, histology, gender, and history of cardiac diagnosis. Prior cardiac diagnoses consisted of a history of atrial fibrillation/flutter, supraventricular tachycardia, heart block requiring pacemaker implantation, coronary artery disease, valvular disease, pulmonary hypertension, or cardiomyopathy.

Charts were reviewed to determine whether there was a prechemotherapy evaluation of left ventricular function and the method of evaluation (echocardiogram, MUGA, or magnetic resonance imaging [MRI]). In addition, records of post-treatment evaluation of cardiac function were evaluated for any change in cardiac function. Inpatient and outpatient records were reviewed to determine whether the findings from the cardiac evaluation influenced the selection of the initial chemotherapy regimen.

A left ventricular ejection fraction less than 50% was considered abnormal. Echocardiogram findings of moderate to severe valvular disease, diastolic dysfunction (grade 1-3), and moderate or severe pulmonary hypertension (moderate = pulmonary artery systolic pressure 45-60 mm Hg, severe = pulmonary artery systolic pressure > 60 mm Hg) also were collected.

Characteristics of patients were summarized using descriptive statistics. Comparisons of patient characteristics were analyzed using the Wilcoxon test or chi-square test for continuous or categoric variables, respectively.

Results

We identified 309 patients with lymphoma who started chemotherapy with an anthracycline- or anthracenedione-based regimen during the study period. Of these, 232 (75%) had an evaluation of left ventricular function performed before therapy. The majority of patients in this group (94%) were evaluated with echocardiograms, whereas the remaining 13 patients (6%) were evaluated with MUGA scans (n = 9) or MRI (n = 4). The characteristics of the patients who had a baseline prechemotherapy evaluation of left ventricular function and those who were not evaluated are shown in Table 1 . Patients who received a pretreatment cardiac evaluation were more likely to be older (median age, 56 vs. 42 years; P < .001). Patients who had pretreatment cardiac evaluations also were more likely to have a history of cardiac disease (14% vs. 4%, P = .01). Otherwise, the groups were similar with respect to patient-, disease-, and treatment-related characteristics.

Table 1 Patient Characteristics

  With Pretreatment

Cardiac Evaluation
Without Pretreatment

Cardiac Evaluation
P Value
N 232 77  
Median age (range) 56 (17-89) 42 (18-87) <.001
Gender     .87
 Female 114 (49) 37 (48)  
 Male 118 (51) 40 (52)  
Diagnosis     .24
 Hodgkin lymphoma 62 (27) 26 (34)  
 Non-Hodgkin lymphoma 170 (73) 51 (66)  
Type of treatment      
 Hodgkin lymphoma     .54
 ABVD 36 (58) 15 (58)  
 Stanford V 21 (34) 7 (27)  
 Others 5 (8) 4 (15)  
 Non-Hodgkin lymphoma     .36
 CHOP/CNOP ± rituximab 141 (83) 45 (88)  
 Others 29 (17) 6 (12)  
History of cardiovascular disease     .01
 No 199 (86) 74 (96)  
 Yes 33 (14) 3 (4)  
Method of testing      
 Echocardiogram 219 (94)  
 MUGA 9 (4)  
 MRI 4 (2)

Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, dacarbazine; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition; Stanford V = doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone.

The outcomes of patients are shown in Figure 1 . Among the 232 patients who had pretreatment evaluation of left ventricular function, 201 (87%) had no history of cardiac disease. No patients evaluated with MUGA scans or MRI had left ventricular function abnormalities. Twenty-two patients (9%) had prechemotherapy echocardiograms that demonstrated 1 or more of the following abnormalities: moderate-severe valvular disease (n = 4), diastolic dysfunction (n = 14), moderate-severe pulmonary hypertension (n = 3), patent foramen ovale (n = 1), or left ventricular ejection fraction < 50% (n = 1). However, none of these findings led to a change in the choice of chemotherapy regimen or a change in dose for these patients. Thirty-one (13%) of the patients with a prechemotherapy evaluation had a history of cardiac disease, as described earlier. Only 4 of these patients had an alteration of chemotherapy regimen that consisted of substitution of mitoxantrone in place of doxorubicin. The reasons for altering the regimens were severe aortic stenosis, wall motion abnormalities in a patient with an ejection fraction of 50%, moderate pulmonary hypertension with an ejection fraction of 35%, and grade III diastolic dysfunction with aortic stenosis. However, the decision to change the chemotherapy regimen for these patients was made because of known preexisting heart disease and not because of the abnormal echocardiogram findings. Echocardiograms after completion of chemotherapy did not show a significant change in any of these patients.

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Figure 1 Patient Outcome

Five (2%) of the 232 patients with prechemotherapy cardiac evaluations were diagnosed with doxorubicin-induced cardiomyopathy after completion of treatment. None of these patients had a history of cardiac disease, and all had normal prechemotherapy echocardiograms.

Only 3 (4%) of the 77 patients who did not have a pretreatment echocardiogram had a history of cardiac disease. One patient with a history of coronary artery disease received mitoxantrone instead of doxorubicin. The second patient had a history of atrial fibrillation, and the third patient had a history of coronary artery disease. Both patients received doxorubicin-containing regimens. No patients had a subsequent diagnosis of cardiomyopathy, although 2 had follow-up echocardiograms revealing diastolic dysfunction.

There were no significant overall survival differences when patients with a pretransplant cardiac evaluation were compared with those who did not have a cardiac evaluation. The actuarial 5-year overall survival was 89% for those with Hodgkin lymphoma with a pretreatment cardiac evaluation, compared with 100% for those who were not evaluated (P = .35). The corresponding survival rates for the patients with non-Hodgkin lymphoma were 63% and 82%, respectively (P = .07).

Discussion

At the University of Nebraska Medical Center, 75% of patients with lymphoma had an evaluation of left ventricular function before initiation of chemotherapy. These patients were significantly older and statistically more likely to have a preexisting diagnosis of cardiac disease than patients who did not have an evaluation of cardiac function before chemotherapy. Although routine testing identified a significant number of cardiac abnormalities among patients without a history of cardiac abnormalities, these results did not lead to alterations in the planned chemotherapy regimen for any patient. Furthermore, testing failed to identify patients at risk for subsequent anthracycline-associated cardiomyopathy.

Our results are similar to those reported by Conrad et al, 16 who retrospectively evaluated practice patterns regarding measurement of left ventricular ejection fraction before initiating chemotherapy for diffuse large B-cell lymphoma. In their series, left ventricular function was evaluated in 65% of patients before therapy. As seen in our analysis, patients who did not have cardiac evaluations were more likely to be younger and had fewer risk factors for congestive heart failure. Only 7 patients (5%) had abnormal left ventricular function, and 3 of these patients had prior clinical evidence of congestive heart failure. Five of these patients were subsequently treated with doxorubicin-based chemotherapy anyway, including the 4 patients with incidentally detected asymptomatic left ventricular function abnormalities. None of the patients without a history of congestive heart failure had their treatment modified on the basis of pretreatment cardiac testing. There was no difference in the development of congestive heart failure between these patients and the patients who did not have evaluation of left ventricular function.

Another analysis from the University of Iowa evaluated the use of pretreatment MUGA scans for patients receiving doxorubicin-based chemotherapy. 17 Sixty-seven percent of the patients had lymphomas. Seventy-six percent of patients had pretreatment cardiac evaluations, and the remaining patients were treated without evaluation of left ventricular ejection fraction. Only 4 patients (2.4%) did not receive doxorubicin as a result of an abnormal ejection fraction. None of these patients had a history of cardiac disease, and 1 patient had an ejection fraction of 48%. There were no significant survival differences when patients who had MUGA scans were compared with patients who received chemotherapy without a pretreatment cardiac evaluation.

Sabel et al 18 reviewed the utility of pretreatment evaluation of left ventricular ejection fraction in women before receiving doxorubicin-based chemotherapy for breast cancer; 62% had pretreatment MUGA scans. Four women (6.5%) had low-normal cardiac ejection fractions between 49% and 51% without wall motion abnormalities. There were no instances in which the results of the MUGA scan influenced decisions on management, and no cardiac complications were observed.

Karanth et al 19 performed a retrospective analysis of patients who had prechemotherapy echocardiograms performed over a 3-year period at a single institution. Approximately 75% of the patients had breast cancer. One or more abnormalities were noted in 13.4% of patients, and these led to a change in management in 2.8% of patients.

An analysis from Nova Scotia also examined the utility of MUGA scans before adjuvant chemotherapy for patients with breast cancer. 20 Eighty percent of women had baseline MUGA scans before chemotherapy. Only 2.5% of woman had abnormal scan results, and only 2% of patients had a change in therapy because of MUGA scan results. One of these patients had a left ventricular ejection fraction of 47%, and 1 had an ejection fraction of 51% with an asymptomatic wall motion abnormality.

Similar analyses in the pediatric population also show that routine echocardiograms before anthracycline-based chemotherapy for leukemia and other malignancies almost never leads to a change in treatment.21, 22, and 23

The results from our series and from published literature lead to questions regarding the widespread recommendations to evaluate left ventricular ejection fraction before the administration of anthracycline-based chemotherapy for lymphoma. It is interesting to note that 20% to 38% of patients do not have this type of evaluation despite the recommendations.16, 17, 18, and 20 Although routine testing may identify a significant number of asymptomatic abnormalities, these abnormalities usually are not clinically significant and rarely lead to alterations in the choice of chemotherapy, even in patients with cardiac risk factors.

It is also noteworthy that patients with limited-stage lymphoma often are treated with abbreviated courses of chemotherapy. For example, some patients with Hodgkin lymphoma may require only a total of 100 mg/m2 of doxorubicin. 24 It seems that the value of pretreatment left ventricular function evaluation would be particularly low for this population. It is also interesting that NCCN guidelines do not recommend evaluation of left ventricle function before doxorubicin-based chemotherapy for breast cancer. These patients commonly receive dose-dense doxorubicin-cyclophosphamide treatment resulting in a cumulative dose of 240 mg/m2 of doxorubicin. This total is comparable to the 300 mg/m2 that patients with lymphoma receive with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), the most commonly used regimens for diffuse large B-cell lymphoma and Hodgkin lymphoma. Furthermore, this total is higher than the dose patients with lymphoma receive with abbreviated courses of chemotherapy.

Echocardiography and radionuclide angiography are insensitive tests to predict the development of anthracycline-related cardiac damage. A prospective study by Jensen et al 25 failed to show that evaluation of left ventricular function before therapy was able to predict subsequent cardiomyopathy for patients with breast cancer who were treated with epirubicin. However, monitoring cardiac function after treatment was of clinical benefit. Other analyses also have concluded that pretreatment evaluation of left ventricular function does not correlate with the development of subsequent cardiomyopathy.6 and 26

It cannot be overemphasized that initial therapy for patients with lymphoma is usually administered with curative intent and that doxorubicin has an essential role in these regimens. Late-onset congestive heart failure from anthracycline-induced cardiomyopathy is a devastating complication for a patient who is cured of lymphoma. Nevertheless, it also may be a mistake to use a less-effective chemotherapy regimen, or a regimen with a risk of other late toxicity, in a patient without clinical evidence of heart disease because of a diminished ejection fraction. Although guidelines recommend that left ventricular ejection fraction should be evaluated before chemotherapy, these guidelines are not accompanied by recommendations regarding what to do with the results of an abnormal examination. There are no established guidelines on when to eliminate doxorubicin, and it may be inappropriate to withhold doxorubicin because of minor decrements in left ventricular ejection fraction of unknown clinical significance.15, 17, 18, and 20

Conclusions

Our results are retrospective and limited by the fact that patients were not followed in a consistent manner for the development of subsequent cardiac toxicity. Nevertheless, our results reflect standard practice patterns with respect to the use of prechemotherapy evaluation of cardiac function. Results from our study are in agreement with others that show that evaluation of left ventricular ejection fraction before treatment is a poor predictor of subsequent cardiac toxicity. This form of testing rarely influences management decisions and has the potential to alter treatment in a potentially harmful manner. In addition, elimination of testing has the potential for significant cost savings.16 and 17 Although some high-risk groups might benefit from pretreatment cardiac evaluation, current guidelines that mandate evaluation of all patients should be reconsidered. This recommendation may be especially applicable to asymptomatic patients without risk factors and those who receive abbreviated courses of chemotherapy with reduced cumulative doses of anthracycline. Better predictive tests for anthracycline toxicity are needed rather than a single pretreatment evaluation of left ventricular function.

Clinical Practice Points

 

  • Although guidelines from several sources recommend evaluation of left ventricular ejection fraction before initiation of anthracycline-based chemotherapy for patients with lymphoma, there is little published evidence to support this recommendation.
  • Our retrospective analysis showed that evaluation of left ventricular ejection fraction before chemotherapy for patients with lymphoma rarely results in a change in therapy.
  • A single test of left ventricular ejection fraction before chemotherapy is an insensitive test for the prediction of subsequent anthracycline cardiotoxicity.
  • Guidelines that mandate evaluation of cardiac function before initiation of anthracycline-based chemotherapy for all patients with lymphoma should be reexamined.

Disclosure

JS, RB, DM, MB, SS, and PB: None. FL receives unrestricted educational support from Pfizer. JA is a consultant for GlaxoSmithKline, Seattle Genetics, Genentech, Roche, Spectrum, and Ziopharm, and is on the Board of Directors for Tesaro Bio, Inc. JV receives research grant support from Allos Therapeutics/Spectrum, Amgen, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte Corp, Janssen Biotech, OncoMed Pharmaceuticals, Onyx Pharmaceuticals, Pharmacyclics, and US Biotest, Inc. TP receives research support from Lantheus, Astellas, and GE Healthcare, and instrumentation support from Philips Healthcare.

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Footnotes

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE

Address for correspondence: Philip J. Bierman, MD, University of Nebraska Medical Center, Department of Internal Medicine, 987680 Nebraska Medical Center, Omaha, NE 68198-7680