Toxicity

The dose-limiting acute toxicities are:

♦ Myelosuppression and mucositis, both occuring 5-10 days after treatment.

♦ Alopecia occurs but is reversible.

♦ Extravasation injury can be severe and there is no proven, effective treatment.

Cumulative cardiotoxicity is specific to anthracyclines and appears to be caused by accumulation of free radicals in the heart. It is characterized by dilatation of sarcoplasmic reticulum and loss of myofibrils. Children appear more sensitive to these effects.

Cardiotoxicity typically presents with heart failure, the risk of which is dose-related. At doxorubicin doses below 450 mg/m2, the risk is less than 5%, but increases substantially at higher doses. In most cases this threshold allows a full course of anthracycline to be given without risk. Irradiation of the heart, which may occur with radiotherapy to the left breast or chest, increases risk of cardiotoxicity, as does preexisting cardiac disease.

Cardiotoxicity appears to be related to peak drug levels as doxo-rubicin is less cardiotoxic when given as a 96-hour infusion than by bolus administration. Liposomal encapsulation of doxorubicin also reduces cardiotoxicity.

Epirubicin is less cardiotoxic than doxorubicin, the 'threshold' dose being 900 mg/m2. This two-fold difference in cardiotoxicity compares with 1.2-fold difference in therapeutic activity. In terms of cardio-toxocity, epirubicin has a 1.6-fold higher therapeutic index than doxorubicin, so more prolonged treatment may be possible with epirubicin before there is an unacceptable risk of cardiotoxicity. Daunorubicin and idarubicin also have less effect on the myocardium than doxorubicin.

Serial estimation of cardiac ejection fraction by gated isotope scanning or echocardiography detects changes in cardiac function before becoming clinically significant. Where patients do develop cardiac failure it often responds to standard treatment. Iron appears to generate free radicals that are associated with anthracycline treatment. The iron chelator ICRF 187 may protect against cardiotoxicity.

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