Daunorubicin and the closely related adriamycin are antibiotics with a powerful cytotoxic action which is particularly effective in acute myeloblastic leukemia but is useful also in a number of other leukemias and sarcomas.
TIME OF ONSET OF HEART DISEASE
The onset of cardiac failure in patients given daunorubicin has been recognized as a hazard of the drug ever since its introduction, but the picture has not been clear since many of the patients developing heart failure had also had advanced, uncontrolled sarcoma or leukemia in relapse.
In Halazun’s study, the time interval from the first dose of daunorubicin to the onset of cardiac toxicity ranged from 105 to 1,348 days and the time intervals from the last dose to the onset of signs of cardiac toxicity ranged between 18 and 280 days but was usually less than 100 days. Transient cardiac symptoms or abnormal signs during or after administration of the drug have not been reported but should be sought.
Heart failure induced by daunorubicin develops remarkably suddenly with sinus tachycardia, hypotension, dyspnoea, tachypnoea, and gallop rhythm, but no edema at this stage. The chest radiograph may show little cardiac enlargement but
there is usually some evidence of pulmonary venous congestion. Death may be swift. Patients who survive longer may develop cardiac dilatation and fluid retention; the initial response to diuretics is good, but deterioration usually follows.
Early electrocardiographic changes are slight and easily missed: there is a fall in voltage followed by changes in the QRS and ST segments and T waves indicating an abnormality in the depolarization and repolarization forces. With continuing, heart failure changes occur in the P waves due to left atrial or biatrial dilatation, but signs of ventricular hypertrophy or infarct-like patterns are absent, probably because the patients do not survive long once cardiac failure has developed.
The mechanism of daunorubicin cardiotoxicity is not completely known but is thought to be related to binding of the drug to DNA in nuclei and mitochondria. The bound drug is only very slowly excreted from the cell, and since the cardiac muscle cell cannot reproduce itself any inhibition of protein synthesis resulting from drug-induced alteration in the DNA templates might be long-lasting. Cumulative interference with the processes of normal protein regeneration, replenishment, and growth could explain the delayed onset of toxicity and also the observation that adults are more vulnerable than children and the elderly most susceptible of all.
- Nowadays multiple drug schedules are used, doses of daunorubicin are spaced at wider intervals, and the total dose given can be less.
- Daunorubicin is less often used in the treatment of acute lymphoblastic leukemia in children but remains one of the best drugs for the treatment of acute myeloblastic leukemia.
- It may be that adriamycin, which has twice the antileukemic potency of daunorubicin, may have no more cardiac toxicity dose for dose so that cardiac toxicity would be less likely.
- Meanwhile precautions which should further reduce the incidence of cardiac toxicity would be limitation of the total dose of daunorubicin to not more than 500 mg/m in children or 200 mg/m in adults, wider spacings between individual treatments, and careful cardiac monitoring.
The most sensitive tests of cardiac function which are noninvasive and therefore repeatable are probably the measurement of the systolic time intervals of the left ventricle and ultrasonic recording of the movements of the left ventricular wall. Recognizable changes in the nuclei and mitochondria of the myocardial cell have been reported after administration of fatal doses of daunorubicin, so catheter biopsy of the septal wall of the right ventricle using the Japanese technique may possibly provide the most sensitive indication of impending cardiac damage.