Early and late arrhythmogenic effects of doxorubicin.

Background: To determine the incidence of early and late arrhythmogenic effects of doxorubicin-containing chemotherapy regimens.

Patients and Methods: A prospective study including 29 patients who were treated with doxorubicin-containing regimens. Cardiac evaluation was based on 24-hour electrocardiographic monitorization (Holter), which was performed during the first cycle of doxorubicin-containing regimens, as well as after the last cycle of chemotherapy.

Results: The mean age of the patients was 45.8 [+ or -] 15.1 (range 18-69). Holter records obtained during the first cycle of treatment revealed varying arrhythmias in 19 patients (65.5%) and in 18 (62.1%) patients after completion of therapy. One patient presented with syncope and both Mobitz Type 2 atrioventricular block and complete atrioventricular block were demonstrated. The patient subsequently underwent permanent pacemaker implantation.

Conclusions: Doxorubicin may result in arrhythmias both in early and late periods of treatment. These arrhythmias are rarely life threatening.

Key Words: cardiotoxicity, doxorubicin, arrhythmia 

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Cardiotoxicity is a well-known side effect of doxorubicin, a chemotherapeutic agent used in cancer treatment, and is frequently a dose-limiting factor. It may occur in both the early and late periods after administration. Dilated cardiomyopathy, which is the most serious complication, usually presents at least one year after doxorubicin infusion. (1) Doxorubicin can result in decreased left ventricular function, decreased exercise capacity or even congestive heart failure. For the diagnosis, echocardiography, serum cardiac troponin-T and -I levels may be useful. (1-3) Rhythm abnormalities have also been reported to occur as a result of acute and chronic toxicity of anthracyclines. (4,5) Early effects occur during or immediately following infusion and are usually transient. Late effects can occur a few years after completion of the therapy. Doxorubicin-induced arrhythmia may be ventricular or supraventricular, and can even present as a nonspecific electrocardiographic abnormality. (5) Life-threatening arrhythmias rarely develop. (6) In this study, the arrhythmogenic effects of doxorubicin in cancer patients who were treated with doxorubicin-containing chemotherapy regimens were evaluated using 24-hour ambulatory electrocardiographic monitoring.

Patients and Methods

Patients who received doxorubicin-containing regimens at the Hacettepe University Faculty of Medicine between September 2002 and September 2003 formed the initial patient population. Eligibility criteria were (1) age greater than 18 years; (2) histologically confirmed malignancy; (3) Karnofsky performance status of [greater than or equal to]70%; (4) creatinine and bilirubin levels [less than or equal to] 1.5 times the upper limit of normal (ULN); (5) alkaline phosphatase and AST/ALT levels [less than or equal to]2.5 times the ULN. Criteria for ineligibility were (1) prior exposure to anthracycline chemotherapy; (2) clinically significant cardiac disease or myocardial infarction; (3) hypertension; (4) abnormal electrocardiogram; (5) pericardial effusion; (6) electrolyte disturbances; (7) tumoral invasion of the mediastinum. Each doxorubicin dose was infused with 150 cc of 5% dextrose over 30 minutes for all patients enrolled in the study. Patients were monitored in an ambulatory setting by a 7-lead Delmar Holter apparatus. Holter was started one hour before the first course of the doxorubicin-containing regimen and lasted 24 hours. Control recordings were obtained from 1 to 3 days after the last doxorubicin dose. The subjects were evaluated at least 6 weeks after the doxorubicin infusion. Doxorubicin-induced arrhythmias were analyzed during the early period (23 hours following the doxorubicin infusion) and the late period (after the completion of doxorubicin-containing treatment). The Holter records were evaluated by an experienced cardiologist. All patients were informed about the potential toxicity of chemotherapy, including cardiotoxicity, at the onset of treatment. Written informed consent was obtained from all patients enrolled in the study. This study was designed and conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee.

Results

A total of 29 patients, twelve (41.4%) of whom were men, were enrolled in this study. Patient characteristics and diagnoses involved, as well as chemotherapy protocols assigned, are summarized in Table 1. Mean age was 45.8 [+ or -] 15.1 (18-69 years). Median cumulative doxorubicin dose was 278.0 [+ or -] 112.5 mg/[m.sup.2] (50-480 mg/[m.sup.2]). Five patients (17.2%) had a history of radiotherapy to the mediastinum. The most common diagnosis was lymphoma (12 patients, 41.4%). Other diagnoses were breast cancer (13.8%), nasopharyngeal carcinoma (10.3%), leiomyosarcoma (6.9%), hepatocellular carcinoma (6.9%), liposarcoma (3.4%), rhabdomyosarcoma (3.4%), multiple myeloma (3.4%), primitive neuroectodermal tumor (3.4%), and primary of unknown origin (3.4%). A summary of the arrhythmias recorded by Holter is provided in Table 2. The first Holter records revealed a variety of arrhythmias in 19 patients (65.5%). Supraventricular extrasystole (41.4%) was the most common rhythm disturbance. Other rhythm abnormalities observed were ventricular extrasystole (31.0%), sinus tachycardia (13.8%), sinus bradycardia (3.4%), and paroxysmal atrial fibrillation (10.3%). In one case, 24-hour electrocardiographic monitorization revealed Mobitz Type 2 atrioventricular block, as well as complete atrioventricular block lasting for 12 seconds. The patient subsequently underwent permanent pacemaker implantation. There was more than one rhythm disturbance in 9 patients (31%). A second Holter recording was obtained for the remaining 28 patients after completion of doxorubicin therapy. Abnormal rhythms were observed in 18 patients (64.2%). Thirty-six percent of the subjects had more than one documented arrhythmia. Supraventricular extrasystole was the most common arrhythmia occurring in 10 patients (35.7%). Only 13 patients (44.8%) had rhythm abnormalities in both Holter records. Gender, diagnosis, age, and previous radiotherapy history were not associated with an increased risk for developing arrhythmias, either in the early or the late period.

Discussion

The most serious side effect of anthracyclines is dilated cardiomyopathy. This toxicity is usually seen a few years after completion of therapy. (1,7) Doxorubicin-related rhythm disturbances, including nonspecific electrocardiographic (ECG) changes, ventricular and supraventricular arrhythmias, may occur both in the acute and chronic phase after therapy. The mechanisms involved in the development of rhythm disturbances differ in both periods. The actual nature of doxorubicin-induced electrocardiographic abnormalities and arrhythmias occurring at the early stage remains a cause for speculation. It has been hypothesized that electrophysiologic changes induced by vasoactive substances released into the circulation during or after doxorubicin infusion may be responsible. (8-10) Others support the idea that electrocardiography changes and rhythm disturbances can be attributed to drug-related allergic reactions and hypotension occurring during and after the infusion of doxorubicin. Furthermore, sympathetic discharge is established to be enhanced with the administration of doxorubicin, which may help explain its acute arrhythmogenic effects. (11-13) However, the role of different cytokines released from malignant cells induced by doxorubicin infusion must also be considered. Acute cardiotoxicity may occur in 11 to 41% of patients treated with doxorubicin, either during or after infusion. (2,13,14) Though uncommon, transient and dose-independent life-threatening arrhythmias and even death have been reported in association with the drug. (15,16) In one study, authors described seven out of 30 patients who developed severe ventricular ectopy following administration of the first dose of doxorubicin. (5) Other electrocardiographic abnormalities documented include T-wave inversion, ST segment elevation or depression, decreased QRS voltage, prolonged QT interval and several arrhythmias such as AV block and supraventricular and ventricular arrhythmias. (1,2,5) Chronic phase arrhythmias associated with doxorubicin occur many years after the completion of therapy and are usually related to dilated cardiomyopathy. These arrhythmias are generally serious, permanent and dose-dependent. The incidence of doxorubicin cardiotoxicity varies from 1 to 5% if the cumulative dose is limited to less than 550 mg/[m.sup.2]. (17) However, drug-associated arrhythmias have been reported to occur even at lower doses. (18)

In this study, we investigated doxorubicin-related arrhythmias, both in the early and late periods. Rhythm abnormalities recorded in both periods were similar, with the most common arrhythmia being supraventricular extrasystole. One patient in particular developed complete atrioventricular block during doxorubicin infusion. Permanent pacemaker implantation was performed before treatment was recommenced. Our study is not without its limitations. Other chemotherapeutics utilized in combination with doxorubicin, such as fluorouracil and cyclophosphamide, may have also played a role in the development of arrhythmias in early Holter records. (19) Moreover, adverse effects of chemotherapeutics such as nausea and vomiting may stimulate vagal tonus resulting in hypotension and sympathetic discharge, which may induce arrhythmias. Certain anti-emetic drugs are known to be arrhythmogenic as well. (20)

Doxorubicin should be carefully used due to its cardiotoxic effects. The risk of doxorubicin-induced cardiomyopathy warrants regular follow-up of patients receiving combined chemotherapy regimens containing doxorubicin. In conclusion, doxorubicin is a cardiotoxic agent that can cause rhythm disturbances during or after its infusion, and it should be used with great caution, even in patients without preexisting cardiovascular risk factors. Patients should be monitored closely for signs of arrhythmias.

References

1. Keefe DL. Anthracycline-induced cardiomyopathy. Semin Oncol 2001; 28(Suppl 12):2-7.

2. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol 2005;16:798-804.

3. Meinardi MT, van der Graff WTA, van Veldhuisen DJ, et al. Detection of anthracycline-induced cardiotoxicity. Cancer Treat Rev 1999;25:237-247.

4. Steinberg JS, Cohen AJ, Wasserman AG, et al. Acute arrhythmogenicity of doxorubicin administration. Cancer 1987;60:1213-1218.

5. Friess GG, Boyd JF, Geer MR, et al. Effects of first-dose doxorubicin on cardiac rhythm as evaluated by continuous 24-hour monitoring. Cancer 1985;56:2762-2764.

6. Kilickap S, Akgul E, Aksoy S, et al. Doxorubicin-induced second degree and complete atrioventricular block. Europace 2005;7:227-230.

7. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996;125:47-58.

8. Bristow MR, Kantrowitz NE, Harrison WD, et al. Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release. J Cardiovasc Pharmacol 1983;5:913-919.

9. Bristow M, Thompson P, Martin R, et al. Early anthracycline cardiotoxicity. Am J Med 1978;65:823-832.

10. Speyer JL, Ewer MS, Freedberg RS. Cardiac effects of cancer therapy. In: Abeloff MD, Armitage JO, Niederhuber JE, et al, eds. Clinical Oncology. Philadelphia, Churchill Livingstone, 2004, pp. 1251-1268.

11. Robison TW, Giri SN. Effects of chronic administration of doxorubicin on myocardial beta-adrenergic receptors. Life Sci 1986;39:731-6.

12. Benedict CR, Weiner DH, Johnstone DE, et al. Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. J Am Coll Cardiol 1993;22(4 Suppl A):146A-153A.

13. Ali MK, Soto A, Maroongroge D, et al. Electrocardiographic changes after adriamycin chemotherapy. Cancer 1979;43:465-471.

14. Lenaz L, Page JA. Cardiotoxicity of adriamycin and related anthracy-clines. Cancer Treat Rep 1976;3:111-120.

15. Wortman JE, Lucas VS, Schuster E, et al. Sudden death during doxorubicin administration. Cancer 1979;44:1588-1591.

16. O'Bryan RM, Luce JK, Talley RW, et al. Phase II evaluation of adriamycin in human neoplasia. Cancer 1973;32:1-8.

17. Lefrak EA, Pitha J, Rosenheim S, et al. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32:302-314.

18. Larsen RL, Jakacki RI, Vetter VL, et al. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. Am J Cardiol 1992;70:73-77.

19. Keefe DL. Cardiovascular emergencies in the cancer patient. Semin Oncol 2000;27:244-255.

20. Kasinath NS, Malak O, Tetzlaff J. Atrial fibrillation after ondansetron for the prevention and treatment of postoperative nausea and vomiting: a case report. Can J Anaesth 2003;50:229-231.

Saadettin Kilickap, MD, Ibrahim Barista, MD, Ebru Akgul, MD, Kudret Aytemir, MD, Sercan Aksoy, MD, and Gulten Tekuzman, MD

From the Departments of Medical Oncology and Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Reprint requests to Dr. Saadettin Kilickap, Hacettepe University Institute of Oncology, Department of Medical Oncology, Sihhiye, 06100, Ankara, Turkey. Email: [e-mail]

Accepted July 25, 2006.

RELATED ARTICLE: Key Points

* Cardiotoxicity is a well-known side effect of doxorubicin, a chemotherapeutic agent used in cancer treatment, and is frequently a dose-limiting factor.

* Doxorubicin-induced arrhythmia may be ventricular or supraventricular and can even present as a nonspecific electrocardiographic abnormality. Life-threatening arrhythmias rarely develop.

* In this study, we investigated doxorubicin-related arrhythmias, both in the early and late periods. Rhythm abnormalities recorded in both periods were similar, with the most common arrhythmia being supraventricular extrasystole.

* Doxorubicin is a cardiotoxic agent that can cause rhythm disturbances during or after its infusion and should be used with great caution.

Table 1. Summary of patient characteristics

                                                Cumulative dose
No.  Sex  Age  Diagnosis              Protocol  (mg/[m.sup.2])   Med-RT

 1   M    46   Lymphoma               CHOP      300              -
 2   F    35   Rhabdomyosarcoma       IMA       360              -
 3   F    64   M. myeloma             VAD       196              -
 4   F    23   Lymphoma               CHOP       60              -
 5   F    56   Lymphoma               CHOP      360              -
 6   M    38   Lymphoma               ABVD      150              -
 7   F    39   Breast cancer          CAF       300              +
 8   F    38   MMT                    IMA       360              -
 9   M    56   HCC                    PIAF      480              -
10   F    62   PUO                    CAP        50              -
11   F    18   PNET                   AC        285              -
12   M    44   Lymphoma               CHOP      300              -
13   M    69   Lymphoma               CHOP      100              -
14   F    45   Lymphoma               CHOP       50              -
15   F    37   Leiomyosarcoma         IMA       120              -
16   F    20   MMT                    IMA       450              -
17   F    39   Leiomyosarcoma         IMA       360              -
18   F    56   Lymphoma               CHOP      300              +
19   M    19   Lymphoma               ABVD      300              -
20   F    37   Breast cancer          CAF       300              +
21   M    52   Lymphoma               CHOP      300              -
22   M    50   Nasopharyngeal cancer  IMA       300              -
23   M    41   Nasopharyngeal cancer  IMA       360              -
24   F    46   Breast cancer          CAF       300              +
25   F    64   Breast cancer          CAF       300              -
26   M    31   Lymphoma               CHOP      300              +
27   F    65   Lymphoma               CHOP      300              -
28   M    66   Nasopharyngeal cancer  IMA       360              -
29   M    42   Liposarcoma            IMA       360              -

CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IMA,
ifosfamide, mesna, doxorubicin; VAD, vincristine, doxorubicin,
dexamethasone; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine;
CAF, cyclophosphamide, doxorubicin, fluorouracil; PIAF, cisplatin,
interferon, doxorubicin, fluorouracil; CAP, cyclophosphamide,
doxorubicin, cisplatin; AC, doxorubicin, cyclophosphamide; MMT,
malignant mesenchymal tumor; HCC, hepatocellular cancer; PNET, primitive
neuroectodermal tumor; PUO, Primary of unknown origin; Med-RT,
Mediastinal radiotherapy.

Table 2. Summary of rhythm disturbances recorded by Holter

Patient no.  First Holter  Second Holter

 1           2,3           2,3
 2           3             3,6
 3           3,5           6
 4           1             1
 5           2,3           3
 6           2,3           2,3
 7           2             2
 8           6             2,6
 9           1             3,6
10           3             1
11           1             1
12           4             1
13           1             2,3
14           4             4
15           8             Pacemaker
16           1             1
17           1             1
18           2,3,6         2,3,5
19           2             1
20           3             5
21           1             2,3
22           1             3,7
23           1             2,3
24           1             1
25           3,4           3
26           2,3           1
27           4             1
28           2,3           3
29           2,3,6         3

1, normal; 2, ventricular extrasystole; 3, supraventricular
extrasystole; 4, sinus tachycardia; 5, sinus bradycardia; 6, paroxysmal
atrial fibrillation; 7, paroxysmal supraventricular tachycardia; 8,
atrioventricular block.