Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpectedly frequent complication.
BACKGROUND
In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects.


METHODS
Sixteen patients with metastatic melanoma were treated with high dose interleukin-2 (IL-2) and alpha-interferon (alpha-IFN). Each treatment cycle consisted of IL-2 at a dose of 12 MIU/m2 and alpha-IFN at a dose of 3 MIU/m2, given as intravenous bolus injections every 8 hours on Days 1-5, every 3 weeks for a total of three cycles. Before treatment, careful cardiologic screening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiography. During therapy, patients were monitored with daily ECG and creatine phosphokinase measurements. Once cardiac damage was suspected, IL-2 and alpha-IFN were discontinued, and echocardiography, stress test and MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed.


RESULTS
Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. Acute myocardial infarction occurred in one patient, cardiomyopathy developed in four, asymptomatic ECG changes appeared in one, and 1 patient died of acute cardiac arrest. Echocardiography showed hypokinesis and decreased left ventricular ejection fraction. These abnormalities disappeared within 6 months. Cardiac catheterization in four affected patients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, swelling of mitochondria and loss of mitochondrial cristae.


CONCLUSIONS
This intensive treatment schedule of IL-2 and alpha-IFN is prohibited by severe and life-threatening cardiac toxicity.
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek, The Netherlands.
W H
WH
Kruit
K J
KJ
Punt
S H
SH
Goey
P H
PH
de Mulder
D C
DC
van Hoogenhuyze
S C
SC
Henzen-Logmans
G
G
Stoter
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000009:adverse effects; D007376:Interleukin-2 / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged
D016898:Interferon-alpha; D007376:Interleukin-2