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Doxorubicin 60 mg/m 2 IV Dilute with normal saline (NS) to a final concentration of 2 mg/mL and administered as an IV bolus over three to five minutes into a free flowing IV infusion of NS or 5 percent dextrose in water (D5W). If needed, doxorubicin can be further diluted after reconstitution in NS or D5W and given as a slow IV infusion administered over 15 to 60 minutes [2] . Day 1

Hydration: Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day during administration and for one to two days thereafter) and void frequently to reduce the risk of hemorrhagic cystitis [3] . •

Vesicant/irritant properties: Doxorubicin is a vesicant and can cause significant tissue damage if an extravasation occurs. For peripheral infusions, the IV line should be recently placed into a large, intact vein, with good blood return established immediately prior to starting the infusion. The IV or catheter site should be continuously monitored throughout drug administration infusion. If extravasation occurs, apply ice to the site and consider use of dexrazoxane. Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-neoplastic vesicants". •

Dose adjustment for baseline liver or renal dysfunction: Dose adjustment is not necessary for doxorubicin in renal impairment. The need for cyclophosphamide dose reduction in renal insufficiency is controversial. For patients with preexisting hepatic impairment, dose adjustments in doxorubicin and cyclophosphamide may be needed. Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease". •

Cardiac issues: A baseline assessment of LVEF is recommended, with periodic reassessment of during therapy. The risk of doxorubicin-associated cardiac dysfunction is related to cumulative dose. The risk is increased in patients with underlying heart disease, when anthracyclines are used concurrently with other cardiotoxic agents or radiation, and in patients previously treated with mediastinal or chest wall irradiation. Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin [2] . Further information on anthracycline-associated cardiotoxicity, including discussion about prevention and treatment, is available. Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents". Monitoring parameters: • CBC with differential and platelet count every two weeks prior to each treatment cycle. • Serum electrolytes and liver and renal function tests every two weeks prior to each treatment cycle. • Cumulative doxorubicin dose should be monitored. As appropriate, assess cardiac function prior to initiation of AC then periodically during treatment. For patients receiving AC for metastatic disease, consider the addition of dexrazoxane after 300 mg/m 2 total dose. Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents". Suggested dose alterations for toxicity: •

Myelotoxicity: Subsequent cycles should be delayed until the absolute neutrophil count is greater than 1000/mm 3 and platelet count greater than 100,000/mm 3 . If there is more than a three week delay in treatment, a dose reduction of 25 percent is recommended [1] . Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". •

Dose adjustment for hepatic or renal dysfunction: Guidelines for managing doxorubicin and cyclophosphamide in patients who have changes in kidney or liver function during therapy are addressed in detail separately. Refer to UpToDate topics on "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease". •

Cardiotoxicity: Guidelines for managing doxorubicin in patients with symptomatic cardiac dysfunction or asymptomatic changes in LVEF during therapy are addressed in detail separately. Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents". If there is a change in body weight of at least 10 percent, dose should be recalculated for all drugs. This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances to make adjustments, as necessary. IV: intravenous; LVEF: left ventricular ejection fraction; CBC: complete blood count. References: Fisher B, et al. J Clin Oncol 1990; 8:1483. Adriamycin (doxorubicin hydrochloride) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 19, 2011). Cytoxan (cyclophosphamide) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 19, 2011).