|Year : 2019 | Volume
| Issue : 2 | Page : 63-68
Assessment of anthracycline-induced long-term cardiotoxicity in patients with hematological malignancies
Aws Sabah Al-Rubaye1, Ahmed S Noori2, Tareq Abdullah Saleh3, Ibrahim Khalil Ibrahim4
1 Lecturer and Specialist in Internal Medicine, College of Medicine, Al-Nahrain University, Baghdad, Iraq
2 Clinical Hematologist, Department of Medecine, Al-Imamein Al-Kadhimein Medical Ciy, Hematology/Oncology Unit, Baghdad, Iraq
3 Consultant Hematologist, Medical City Complex, Bone Marrow Transplant Center, Baghdad, Iraq
4 Consultant Hematologist, Al-Imamein Al-Kadhimein Medical City, Hematology/Oncology Unit, Baghdad, Iraq
|Date of Submission||21-Feb-2019|
|Date of Acceptance||10-Jun-2019|
|Date of Web Publication||17-Oct-2019|
Dr. Tareq Abdullah Saleh
Consultant Hematologist, Medical City Complex, Bone Marrow Transplant Center, Baghdad
Source of Support: None, Conflict of Interest: None
BACKGROUND: Anthracyclines are antibiotic antineoplastic drugs used in the treatment of various hematological and solid malignancies. They are well-known for their cardiotoxic side effects which are related to their cumulative dosages. Many investigations are used to detect such cardiotoxicity, the gold standard of which is the endomyocardial biopsy that has a limited use because it is an invasive procedure. The aims of this study were to explore the cardiotoxicity induced by anthracyclines in patients with hematological malignancies by using electrocardiography (ECG) and echocardiography and to determine relationship between the detected changes in ECG and echocardiography, with some demographic and clinical variables.
PATIENTS AND METHODS: A cross-sectional study of fifty patients was recruited at Al-Imamein Al-Kadhemein Medical City from March 2014 to January 2015. ECG and echocardiography were done to the patients to study several parameters such as ejection fraction (EF), diastolic dysfunction, QRS voltage, QRS duration, and corrected QT (QTc) both at baseline and reassessment. Reassessment was done after completing induction for leukemia patients and at mid-term reassessment for lymphoma patients.
RESULTS: ECG showed reduction in QRS voltage, increase in QRS duration, and increase in QTc, all of which showed statistical significance and may reflect the effect on the depolarization and repolarization on the myocardium. The echo study showed the development of systolic left ventricular (LV) dysfunction (EF <55%) in 12% of patients and a statistically significant reduction in the mean of EF of the study group. It also showed statistically significant development of new diastolic dysfunction. Statistically significant association between reduction of QRS voltage (>30% from baseline) with the development of LV dysfunction was also found.
CONCLUSIONS: Significant changes in QRS voltage, QRS duration, QTc, as well as the occurrence of LV systolic dysfunction and diastolic dysfunction were noted. The mean cumulative dose at which LV systolic dysfunction occurred was about 250 mg/m2.
Keywords: Anthracycline, cardiotoxicity, hematological malignancies
|How to cite this article:|
Al-Rubaye AS, Noori AS, Saleh TA, Ibrahim IK. Assessment of anthracycline-induced long-term cardiotoxicity in patients with hematological malignancies. Iraqi J Hematol 2019;8:63-8
|How to cite this URL:|
Al-Rubaye AS, Noori AS, Saleh TA, Ibrahim IK. Assessment of anthracycline-induced long-term cardiotoxicity in patients with hematological malignancies. Iraqi J Hematol [serial online] 2019 [cited 2019 Nov 12];8:63-8. Available from: http://www.ijhonline.org/text.asp?2019/8/2/63/269410
| Introduction|| |
Anthracyclines are antibiotic antineoplastic agents that were discovered in 1963 when a red fluorescent dye was isolated from fermentation of broth of the bacteria Streptomyces peucetius.
Anthracycline-induced cardiotoxicity is termed type I chemotherapy-induced cardiotoxicity which is characterized by the presence of free-radical formation. These radicals may be responsible for lipid peroxidation and DNA breaks.
Anthracycline's cardiac effects were initially categorized into two distinct forms: early and late toxicity. Early cardiac manifestations of anthracycline administration probably represent the actual insult, which later progresses to overt cardiomyopathy. These manifestations may be sufficiently subtle as not to be considered a serious medical concern. The importance of the initial injury is usually underappreciated as it almost never requires treatment.
The most common findings seen are electrocardiographic changes, usually in the form of repolarization changes involving the ST-segment and the T-wave, and dysrhythmia usually in the form of supraventricular or ventricular ectopics, which are seen often and are only rarely sustained or malignant.
Early toxicity is more common in the elderly and is probably related to underlying and unrelated heart disease that exists in the aging population and the associated likelihood of increased oxidative stress. Early toxicity is also more common with large single doses of doxorubicin.
Late toxicity is related to the cumulative doxorubicin dose, with the injury resulting from the death of myocytes. The more recent data from Swain et al. and MD Anderson Cancer Center suggest that doxorubicin is substantially more cardiotoxic than was originally believed.
It was observed that the estimated cumulative percentage of congestive heart failure was 5% of patients at cumulative dose of 400 mg/m2, 26% of patients at dose of 550 mg/m2, and 48% of patients at dose of 700 mg/m2.
There is no sensitive or specific test that reliably predicts which patient might develop cardiac dysfunction after treatment with anthracycline.
The noninvasive tests have suboptimal predictive value that is manifestation of false-positive and false-negative results. At low cumulative dosages, when the likelihood of a decreased ejection fraction (EF) due to anthracycline is small, false-positive results may exceed the incidence of true-positive results. Noninvasive testing can result in the recognition or confirmation of early or subclinical abnormalities in selected patients. Two-dimensional (2D) echocardiography is the most widely available method for monitoring left ventricular ejection fraction. Advantages include portability and capability of assessing other measures of myocardial dysfunction as well as other cardiac lesions (such as valve disease). Measurement of resting global left ventricular (LV) function using either first pass or equilibrium multigated blood pool imaging (MUGA (multigated acquisition scan) scan) is an established technique for monitoring anthracycline cardiotoxicity. However, it is used less often than echocardiography. Conduction abnormalities are also a nonspecific finding; they are a manifestation of congestive heart failure but may be related to other factors as well; they are also not helpful as a predictive parameter for following up patients receiving doxorubicin.
All patients should undergo a baseline measurement of EF using echocardiography or a nuclear technique. The baseline results are useful for later comparisons and identify patients with cardiac risk factors and thus require closer monitoring. Patients with normal systolic function and no risk factors will usually tolerate 550 mg/m2 of doxorubicin or the maximum recommended cumulative dose of other anthracyclines. Toxicity at cumulative doses below 2/3 of the maximal recommended dosage (300 mg/m2 in the case of doxorubicin) is unusual. In the cumulative dose range from 2/3 to the maximally recommended dose (300–550 mg/m2 for doxorubicin), patients should be evaluated by obtaining a clinical history and follow-up echocardiogram, either at that time of or approximately 3 months after therapy.
Aim of the study
- To explore the cardiotoxicity induced by anthracyclines in patients with hematological malignancies using electrocardiography (ECG) and echocardiography as simple noninvasive techniques
- To determine the presence of any association between the detected changes in ECG and echocardiography, with some demographic and clinical variables.
| Patients and Methods|| |
This is a cross-sectional study.
Hematology ward at Al-Imamein Al-Kadhemein Medical City from March 2014 to January 2015.
- Diagnosed with the following types of hematological malignancies: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma (NHL)
- They received protocol of chemotherapy containing anthracyclines according to their condition [Table 1]
- All patients had EF of 55% or more by echocardiography at baseline assessment
- Verbal consent was taken from all patients regarding the study
- Patients receiving drugs that prolong QT were excluded from the study.
|Table 1: Chemotherapy protocols used in the treatment of the study group|
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ECG and echocardiography were done for all patients at baseline before starting chemotherapy. They were repeated at the time of clinical reassessment. Reassessment was done after completing the induction for leukemia patients and at mid-term reassessment for lymphoma patients. Reassessment was also done whenever there was a cardiovascular concern.
Corrected QT (QTc) was obtained directly from the device. ST-T changes were identified if ST depression or T-wave changes were noted. QRS voltage was calculated as the voltage of the net number of small squares in the vertical length of lead II (R wave–S wave). QRS duration was measured directly by the device. The patients were treated with various chemotherapy protocols according to the type of hematologic malignancy [Table 1], some of ALL (acute lymphocytic leukemia) patients were treated with protocol of UKALL XII, other ALL patients were treated with Hyper CVAD protocol, AML (acute myeloid leukemia) patients were treated with daunorubicin+cytarabine protocol, M3 subtype of AML was treated with all trans retinoic acid ATRA + doxorubicin, Hodgkin disease was treated with ABVD protocol, Non hodgkin lymphoma patients were treated with RCHOP protocol.
The statistical analysis was done using IBM SPSS Statistics for Windows, Version 20.0. (Armonk, NY, IBM Corp).
Demographic and clinical categorical characteristics were simply present in frequency; Chi-square test was used to compare the qualitative variables; and parametric tests such as t-test (paired or unpaired) and ANOVA were used for quantitative variables.
| Results|| |
Fifty patients were included in this study. Twenty-three patients (46%) were males and 27 patients (54%) were females.
The mean (standard deviation [SD]) age of the patients included in this study was 35.4 (17.1) years, with no significant difference between the age means of both sexes, P > 0.05.
Acute myeloid leukemia was the diagnosis in 14 patients (28%), acute lymphoblastic leukemia was the diagnosis in 13 patients (26%), NHL in 13 patients (26%), and Hodgkin's disease in 10 patients (20%).
Six patients (12%) had hypertension. Six patients (12%) had diabetes. One patient (2%) had renal disease. Two patients (4%) had hypothyroidism. Eight patients (16%) received radiotherapy during the course of treatment. Only four patients (8%) were smokers, four patients (8%) were exsmokers, and no one had alcohol consumption. All patients had no family history of hematological malignancy.
Twelve patients (24%) were treated by UKALL XII protocol. One patient (2%) was treated by hyper-CVAD. Ten patients (20%) were treated by 3 + 7 protocol, four patients (8%) were treated by ATRA + ADM, and ten patients (20%) were treated by ABVD. Thirteen patients (26%) were treated by R-CHOP.
The mean (SD) cumulative dose of doxorubicin was 204.7 (91.16) mg/m2 and ranging between 100 and 450 mg/m2.
The mean (SD) cumulative dose of daunorubicin was 244.18 (76.1) mg/m2 and ranging between 180 to 480 mg/m2 [Table 2].
Assessment of cardiac toxicity
Having been treated with anthracyclines, one patient (2%) who was previously asymptomatic developed orthopnea, basal crackles on chest auscultation, gallop rhythm, and leg edema. While another four patients (8%) developed exertional dyspnea and exercise intolerance.
[Table 3] shows the changes in the studied ECG parameters and the significance of that change.
[Table 4] shows the changes in the studied echocardiographic parameters and the significance of that change.
Association with treatment protocols
Majority of LV dysfunction was detected among patients treated by R-CHOP protocol comprising 5 patients 83.3% of those who developed LV dysfunction and the association was statistically significant [Table 5].
|Table 5: Cross tabulation of left ventricular systolic dysfunction with treatment protocol of the study group|
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Association with the diagnosis
Cross tabulation of LV dysfunction with the diagnosis of the treated diseases showed high frequency of LV dysfunction among patients with NHL which was statistically significant (P< 0.05) [Table 6].
|Table 6: Cross tabulation of left ventricular systolic dysfunction with diagnosis of the study group|
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Treatment-related left ventricular dysfunction
Only patients treated with doxorubicin developed LV dysfunction, while those treated with daunorubicin did not develop LV dysfunction [Table 7].
|Table 7: Cross tabulation of left ventricular systolic dysfunction with the type of anthracycline used for the treatment of the study group|
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| Discussion|| |
In this study, there was no significant difference between both sexes regarding inclusion criteria, so that they were all suffering from hematological malignancies. There was no significant difference in mean (SD) of their ages either.
Patients were classified according to their diagnosis so that more than 1 type of hematological malignancies were included. Horacek et al. in their study included leukemia patients, but they did not classify them. Uchikoba et al. included hematological malignancies as well as solid tumors in their study. They also included a control group as their study was a case–control one, while this study is a prospective case series.
In the present study, different associated diseases were noticed. None of the patients showed signs and symptoms of heart failure prior to chemotherapy, this was similar to Uchikoba et al.
Treatment protocols used in the present study were UKALL XII, hyper-CVAD, doxorubicin + cytosar (3 + 7), ATRA + ADM, ABVD, and R-CHOP. The choice of the protocol was according to the guidelines of treatment of the included hematological malignancies. For this reason, the type of anthracycline and the cumulative dosages varied according to the type of malignancies and their treatment protocols. Horacek et al. included the treatment protocols of acute leukemia. The mean cumulative dose of anthracyclines used in the present study did not differ much from those used in the study of Horacek et al. They reported the mean (SD) cumulative dose to be 264.3 (117.5). In the present study, 1 (2%) patient developed symptoms and signs of congestive heart failure in the form of orthopnea, basal crackles on auscultation, gallop rhythm, and leg edema. Four patients (8%) developed increasing dyspnea on exertion and decreased exercise tolerance. The latter symptoms can also be explained by causes other than heart failure such as anemia or pulmonary diseases.
In a study of Limat et al., 10% of patients treated by R-CHOP developed clinical features of congestive heart failure.
On the other hand, there was a significant increase in QRS duration. However, none of the patients had QRS complex >120 ms. Nousianen et al. found no significant difference in QRS duration among patients with NHL treated by CHOP.
QTc interval increased significantly from the baseline reading but with only one patient having QTc >450 ms. Horacek et al. also reported a significant prolongation in QTc from 414.7 ± 16 to 430 ± 18.4 at the end of the study. In their study, five patients (19.2%) developed QTc >450 ms.
In the present study, significant new ST-T changes were found as compared to baseline ECG (after exclusion of patients with electrolyte abnormalities). Elme et al. reported ST-T changes in the ECGs of patients with left-sided breast cancer treated by doxorubicin.
LV dysfunction developed in 6 (12%) with significant reduction of EF from the baseline. Statistically significant new diastolic dysfunction developed in 7 (14%) patients. Horacek et al. reported LV dysfunction in 19.2% of patients at the end of their study. Their result also recorded diastolic dysfunction in 19.2% of patients.
Majority of patients in the present study who developed LV dysfunction had NHL. Nousianen et al. found a significant reduction in EF in patients with NHL treated by anthracycline-containing protocol.
In the present study, the majority of patients who developed LV dysfunction were treated by R-CHOP protocol. In a study performed by Jurczak et al. whereby patients with NHL lymphoma were treated by RCHOP protocol, RCHOP was associated with a significant reduction in EF. Limat et al. found a significant occurrence of cardiovascular events (mostly due to congestive heart failure) in patients treated by CHOP. Coiffier et al. found no significant difference in toxicity caused by R-CHOP as compared to CHOP. No further studies could be found to compare cardiotoxicity associated with R-CHOP treatment with other protocols.
In the present study, the occurrence of LV dysfunction was linked to the use of doxorubicin, while no patient treated with daunorubicin developed LV dysfunction. An explanation could be suggested for this difference; doxorubicin may be more cardiotoxic.
In the present study, the mean (SD) of cumulative dosages of doxorubicin in those patients who developed LV dysfunction was higher than the mean (SD) of those who did not develop LV dysfunction but with no statistical significance. However, LV dysfunction developed in patients who received doses as low as 150 mg/m2. Nousiainen et al. also found a significant decline in EF at low doses (about 200mg/m2). Jurczak et al. found death due to cardiovascular causes in patients who received doses not exceeding 200 mh/m2.
In the present study, there was a significant association between the reduction of QRS voltage >30% from baseline and the development of LV dysfunction.
Shapira et al. and Ali et al. suggested that the reduction in QRS voltage >30% from baseline in limb leads can serve as a predictor of anthracycline-induced cardiomyopathy.
Horacek et al. also found a significant correlation between the reduction in QRS voltage and LV systolic dysfunction.
| Conclusions|| |
- The study showed significant changes in QRS voltage, QRS duration, and QTc associated with treatment with doxorubicin
- The study showed a significant reduction in EF and development of LV systolic dysfunction and diastolic dysfunction among the studied patients
- LV dysfunction occurred more in patients with NHL treated by R-CHOP protocol
- There was a significant association between the reduction of QRS voltage (>30% from baseline) and the development of LV dysfunction
- The cumulative dose of doxorubicin at which LV dysfunction occurred was about 250 mg/m2.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Gianni L, Meyers C. The role of free radical formation in the cardiotoxicity of anthracycline. In: Muggia F, Green M, Speyer J, editors. Cancer Treatment and the Heart. Baltimore, MD: The John Hopkins University Press; 1992.
Sinha BK. Free radicals in anticancer drug pharmacology. Chem Biol Interact 1989;69:293-317.
Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N
Engl J Med 1998;339:900-5.
Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC, et al.
Early anthracycline cardiotoxicity. Am J Med 1978;65:823-32.
Wortman JE, Lucas VS Jr., Schuster E, Thiele D, Logue GL. Sudden death during doxorubicin administration. Cancer 1979;44:1588-91.
Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003;97:2869-79.
Ewer MS, Gibbs HR, Swafford J, Benjamin RS. Cardiotoxicity in patients receiving transtuzumab (Herceptin): Primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin Oncol 1999;26:96-101.
Saletan S. Mitoxantrone: An active, new antitumor agent with an improved therapeutic index. Cancer Treat Rev 1987;14:297-303.
Robert NJ, Vogel CL, Henderson IC, Sparano JA, Moore MR, Silverman P, et al.
The role of the liposomal anthracyclines and other systemic therapies in the management of advanced breast cancer. Semin Oncol 2004;31:106-46.
Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al.
Induction therapy for adults with acute lymphoblastic leukemia: Results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005;106:3760-7.
Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al.
Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547-61.
Horacek JM, Jakl M, Horackova J, Pudil R, Jebavy L, Maly J, et al.
Assessment of anthracycline-induced cardiotoxicity with electrocardiography. Exp Oncol 2009;31:115-7.
Uchikoba Y, Fukazawa R, Ohkubo T, Maeda M, Ogawa S. Early detection of subclinical anthracycline cardiotoxicity on the basis of QT dispersion. J Nippon Med Sch 2010;77:234-43.
Limat S, Demesmay K, Voillat L, Bernard Y, Deconinck E, Brion A, et al.
Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin's lymphoma. Ann Oncol 2003;14:277-81.
Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer 2002;86:1697-700.
Elme A, Saarto T, Tötterman KJ, Utrianen M, Kautiainen H, Järvenpää S, et al.
Electrocardiography changes during adjuvant breast cancer therapy: Incidence and risk factors. Anticancer Res 2013;33:4933-9.
Jurczak W, Szmit S, Sobociński M, Machaczka M, Drozd-Sokołowska J, Joks M, et al.
Premature cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen – A national multicenter study. Int J Cardiol 2013;168:5212-7.
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al.
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N
Engl J Med 2002;346:235-42.
Shapira J, Gotfried M, Lishner M, Ravid M. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 1990;65:870-3.
Ali MK, Buzdar AU, Ewer MS, Cheng RS, Haynie TP. Noninvasive cardiac evaluation of patients receiving adriamycin-containing adjuvant chemotherapy (FAC) for stage II or III breast cancer. J Surg Oncol 1983;23:212-6.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]