Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma

Abstract

Two hundred and seventy-four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48-hour (79 patients) or 96-hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinical cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48-hour or 96-hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P less than 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P less than 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a greater than 75% decrease in the frequency of clinical congestive heart failure at cumulative dosages greater than or equal to 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48-hour or 96-hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.

NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity

“…44 The lower incidence of heart damage after doxorubicin infusion as opposed to bolus injection suggests a role for peak levels of the drug in doxorubicin-induced cardiotoxicity. 45 Significant interindividual differences in doxorubicin pharmacokinetics have been reported previously, 46,47 and they could result from genetic variants in transporters such as MRP2. The 2 missense variants associating with ACT, Val1188Glu (rs8187694), and Cys1515Tyr (rs8187710), were initially described in the Japanese.…”

New approaches in the management of advanced breast cancer – role of combination treatment with liposomal doxorubicin

“…As a result the toxicity profile of PLD is closer to that of doxorubicin administered by continuous infusion than it is to doxorubicin administered by the more common bolus method. 30 Thus, myelosuppression, alopecia and cardiotoxicity are reduced but mucositis and palmar-plantar erythrodysesthesia (PPE), a toxicity rarely encountered with bolus doxorubicin, are increased. Preferential delivery of PLD to tumor tissue has been confirmed in animal models as well as in biopsy studies in patients with MBC and Kaposi's sarcoma.…”

Liposomal Anthracyclines: Adjuvant and Neoadjuvant Therapy for Breast Cancer

“…In the metastatic setting, the risk of cardiac toxicity may be reduced by limiting the cumulative anthracycline dose, by using a 48-or 96-hour continuous infusion schedule [19], by using a cardioprotectant (e.g., dexrazoxane) [20,21], or by choosing an anthracycline formulation with a lower potential for cardiac toxicity, such as a liposomal anthracycline.…”