Doxorubicin therapy should not be started in patients who have marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy.Doxorubicin treatment is contraindicated in patients who received previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenes.
Special attention must be given to the cardiotoxicity induced by doxorubicin.
Irreversible myocardial toxicity, manifested in its most severe form by life-threatening or fatal congestive heart failure, may occur either during therapy or months to years after termination of therapy.
The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2 and 6 to 20% at a dose of 500 mg/m2 given in a schedule of a bolus injection once every 3 weeks (data on file at Pharmacia & Upjohn).
In a retrospective review by Von Hoff et al, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2 and 3/14 (21%) at 728 mg/m2.
The cumulative incidence of CHF was 2.2%.
In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the cumulative incidence of congestive heart failure was 5 to 6%.
The probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2 and 20.5% at 500 mg/m2. Cardiotoxicity may occur at lower doses in patients with prior mediastinal irradiation, concurrent cyclophosphamide therapy exposure at an early age and advanced age.
Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity.
In such cases, cardiac toxicity may occur at doses lower than the respective recommended cumulative dose of doxorubicin.
Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers may increase the risk of doxorubicin cardiotoxicity.
The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone.
Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy. The risk of congestive heart failure and other acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults.
Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood.
As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up.
This late cardiac toxicity may be related to the dose of doxorubicin.
The longer the length of follow-up the greater the increase in the detection rate. Treatment of doxorubicin induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest.Such intervention may relieve symptoms and improve the functional status of the patient.