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328 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 329

the anthracycline of choice in the treatment of AML. To minimize the infarction, and CHF) in their adult years. The incidence of may be
cardiotoxic effects of daunorubicin, in standard “3+7” therapy in AML decreased by coadministering dexrazoxane, an iron chelator, during
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the daunorubicin dosage (45 to 60 mg/m for adults <60 years) is given chemotherapy. It is recommended that the total doxorubicin dose
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daily for 3 days to avoid high peak concentrations, although larger doses be limited to 300 mg/m in children. In addition, children treated with
(90 mg/m /day), may produce higher complete remission rates. In the anthracyclines should have long-term cardiology followup. 110
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elderly, a lower dose of 30 mg/m daily for 3 days is typically used in Ejection fraction measurements have been helpful in detecting a
combination therapy. decline in myocardial function, a sign of impending myocardial failure.
Ejection fraction measurements, usually by multigated acquisition scan
Adverse Effects (MUGA), should be performed to verify normal cardiac function prior
Myelosuppression is the primary acute toxicity of this class of drugs, to starting anthracycline-based chemotherapy, and should be repeated
with a nadir occurring 7 to 10 days after single-dose administration and at the earliest clinical sign of cardiac dysfunction, and before every two
recovery by 2 weeks. Mitoxantrone produces less nausea and vomiting cycles of treatment when the total dose of doxorubicin exceeds 300 mg/
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than does either daunorubicin or doxorubicin. Doxorubicin may cause m . Anthracyclines should be discontinued if the ejection fraction falls
mucositis, especially when used in maximally tolerated divided doses below 40 percent, or if the ejection fraction drops a total of 20 percent
given over 2 to 3 days or when used in combination with other drugs from pretreatment levels.
that cause mucositis. Anthracyclines can also cause radiation recall As cardiotoxicity of anthracyclines results from the generation of
in previously irradiated tissues, especially when the drug is adminis- free radicals by an anthracycline–iron complex, dexrazoxane, an iron
tered just prior to or in the weeks following irradiation. Alopecia often chelator, decreases free radical formation in vitro and decreases the
occurs. Extravasation of these drugs can result in tissue necrosis so they risk of cardiotoxicity in children receiving treatment for ALL, and in
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should be administered through an indwelling central venous cathe- adults with metastatic breast cancer. Fortunately, dexrazoxane does
ter. Dexrazoxane injected subcutaneously, lessens tissue damage after not cause any apparent diminution of antitumor activity. Adding dex-
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extravasation. Patients receiving doxorubicin should also be warned razoxane to an anthracycline-based regimen represents an alternative
that their urine may turn red. to discontinuing anthracyclines in patients who are approaching total-
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Cardiotoxicity is the major late toxic effect of anthracyclines. dose thresholds of drug, but who still require treatment. Two trials have
Cardiotoxicity most likely results from free radical formation catalyzed shown a higher rate of secondary leukemia and MDS in patients receiv-
by the anthracycline’s quinone moiety, although cardiac Topo IIb (not ing doxorubicin and dexrazoxane. 111,112 In adult patients, dexrazoxane
the major topoisomerase involved in DNA replication) may play a role should be added only in patients who have received a total dose of at
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in mediating this effect. Iron as a reduction-oxidation (redox) cofactor least 300 mg/m doxorubicin or 540 mg/m epirubicin.
contributes to toxicity, as it accumulates in mitochondria during treat- Treatment with Topo II inhibitors, including anthracyclines,
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ment. Cardiac proteins, including the cardiac myosin-binding pro- mitoxantrone, and the epipodophyllotoxins (see “Epipodophyllotoxins”
tein C, show evidence of alkylation and degradation after anthracycline below), increases the risk of AML. AML typically develops 6 months
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treatment. 107 to 5 years after exposure to the Topo II inhibitor. This heightened
Clinically, anthracycline-induced cardiotoxicity presents after risk derives from the increased DNA double-strand breaks generated
repeated cycles of treatment. Rarely, acute effects are manifest as by the Topo II inhibitor. These double-stranded DNA breaks can give
arrhythmias, conduction abnormalities, or a “pericarditis–myocarditis rise to balanced chromosomal translocations involving the MLL or
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syndrome.” The more common long-term consequence is congestive PML genes. Anthracyclines and mitoxantrone have affinity for spe-
heart failure (CHF), which can develop during or several months after cific DNA sequences and cause translocations at specific hot spots in
treatment. Studies in breast cancer have demonstrated a 0.5 to 1 per- the genome, including a 6-base pair breakpoint region in the PML gene
cent risk of cardiomyopathy in patients treated with adjuvant anthra- causing the 15;17 translocation, the 11q23 translocation involving the
cyclines. The risk is higher in patients receiving trastuzumab or MLL gene, and the 11;20 translocation involving the NUP98 gene. 113,114
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paclitaxel in combination with doxorubicin.
The risk of anthracycline-induced cardiotoxicity increases with
total dose, but is difficult to estimate for any individual patient. In EPIPODOPHYLLOTOXINS
patients with normal cardiac function prior to treatment, the subse- Two semisynthetic derivatives of podophyllotoxin, VP-16 (etoposide)
quent rate of doxorubicin-induced CHF reaches less than 1 percent at and VM-26 (teniposide), inhibit Topo II and have significant clinical
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total doses of 400 mg/m , but climbs steeply thereafter to 7 to 20 percent activity in hematologic malignancies. Etoposide has been incorporated
at total doses of 550 mg/m . The threshold for cardiotoxicity varies into combination therapy regimens for Hodgkin lymphoma, large cell
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among the different anthracyclines. For example, the inflection thresh- non-Hodgkin lymphomas, leukemias, and various solid tumors, and is a
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old for daunorubicin (600 to 700 mg/m ) is significantly higher than frequent component of high-dose chemotherapy regimens. Teniposide
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for doxorubicin (400 mg/m ). However, it should be remembered that has limited value in clinical oncology. Its use is generally restricted to
these thresholds are based on population studies, and for any individual childhood acute leukemia, where it appears to be synergistic with ara-
patient the risk is impossible to predict. The clinician must pay close C. These compounds induce double-stranded breaks in DNA through
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attention to symptoms of CHF, such as dyspnea, cough, orthopnea, and their sequence-specific binding to DNA in complex with Topo II.
weight gain or ankle edema, throughout a course of treatment and irre- One mechanism of resistance is increased expression of the MDR drug
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spective of total dose. exporter. A second mechanism results from decreased Topo II activity
Besides the cumulative dose of anthracycline, other risk factors for or mutation of the enzyme, resulting in decreased drug binding. 116,117
anthracycline-induced cardiomyopathy include mediastinal (mantle)
radiation, preexisting heart disease, and patient age, the risk being high- Clinical Pharmacology
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est in children younger than the age of 4 years. Children who receive Etoposide is administered in doses of 100 to 120 mg/m per day for
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greater than 300 mg/m have a significant risk of having decreased myo- 3 days, either consecutively or every other day. Approximately 30 to
cardial contractility, decreased ventricular dimension, and an increased 40 percent of an intravenous dose of etoposide is excreted intact in
incidence of cardiac events (such as conduction defects, myocardial the urine, while the remainder is cleared by hepatic glucuronidation

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