Cardiotoxicity cyclophosphamide

Adverse Effects. Cyclophosphamide is used very cautiously as an immunosuppressant because of the possibility of severe side effects, including carcinogenic effects during long-term use. Other side effects include hematologic disorders (leukopenia, thrombocytopenia), cardiotoxicity, nephrotoxicity, and pulmonary toxicity. 

Batist, G., Ramakrishnan, G., and Rao, C. S. (2001), Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer,/. Clin. Oncol., 19,1444-1454. 

An interaction of doxorubicin with the anti-HER2 receptor humanized monoclonal antibody, trastuzumab (Herceptin), has been reported. Most patients who received trastuzumab in early trials had been pretreated with anthracyclines. Despite this, preliminary information suggested that reduced systolic cardiac function was an adverse effect of trastuzumab (119). More recently, this problem has been further highlighted in a study of women with metastatic breast cancer (120). Patients who had not received prior anthracycline-containing adjuvant chemotherapy were at greater risk of cardiotoxicity when they received trastuzumab in combination with doxorubicin or cyclophosphamide (27 and 75% respectively), compared with only 11% of patients who received trastuzumab in combination with pachtaxel (120,121). The risk of cardiac events in patients treated with doxorubicin, cyclophosphamide, and trastuzumab increased markedly after a cumulative doxorubicin dose of 360 mg/m. This suggests synergistic cardiotoxicity with trastuzumab and doxorubicin. Trastuzumab is therefore currently licensed only for use in conjunction with pacli-taxel or docetaxel and not with conventional doxorubicin. 

Of 80 patients who received cyclophosphamide 50 mg/ kg/day for 4 days in preparation for bone marrow grafting 17% had symptoms consistent with cyclophosphamide cardiotoxicity (6). Six died from congestive heart failure. Older patients were at greatest risk of developing cardiotoxicity. 

Goldberg MA, Antin JH, Guinan EC, Rappeport JM. Cyclophosphamide cardiotoxicity an analysis of dosing as a risk factor. Blood 1986 68(5) 1114-18. 

Cardiotoxicity is a major concern with trastuzumab, particularly as it is often used in patients who are receiving or who have previously received anthracychne antibiotics (2). It occurs in 5% of patients given trastuzumab alone, in 13% of patients given trastuzumab with paclitaxel, and in 27% of patients given trastuzumab in combination with anthracyclines and cyclophosphamide (3). 

AR is a 48-year-old woman who was treated for Hodgkin s disease 15 years ago with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). She now presents with breast cancer and her oncologist feels that chemotherapy with FAC (fluorouracil, doxorubicin [Adriamycin], and cyclophosphamide) is the most appropriate regimen. Her previous chemotherapy included a total of 300 mg/m doxorubicin exposure. Which of the following agents may be utilized to reduce risk of cardiotoxicity associated with the anthracycline therapy she is about to receive ... 

Braverman AC, Antin JH, and Plappert MT (1991) Cyclophosphamide cardiotoxicity in bone marrow transplantation. Journal of Clinical Oncology 9 1215-1223. 

Batist et reported results from an early trial using Myocet for the treatment of MBC and concluded that Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and Grade 4 neutropenia and provides comparable antitnmor efficacy, when used in combination with cyclophosphamide for the first line treatment of MBC. However, these conclnsions were not accepted by FDA as they concluded that the trial had insufficient patients, hence insnfficient power, to infer this based on statistical analysis. ... 

Folinic acid (leucovorin) reduces the toxicity of methotrexate because it provides an active form of folate to normal (nonneo-plastic) cells, resulting in leucovorin rescue. Dexrazoxane is a free radical trapping agent that is thought to reduce the cardiotoxicity of anthracyclines (eg, doxorubicin). Mercaptoethanesulfonate (mesna), which inactivates acrolein, is available for protection against hemorrhagic cystitis in patients treated with cyclophosphamide and related drugs. 

Cardiac irradiation or administration of high doses of cyclophosphamide or another anthracycUne may increase the risk of cardiotoxicity. There is evidence that cardiac damage is reduced by the concomitant administration of the iron chelator dexrazoxane (ADR-529) or by amifostine (WR-2721) or its active metabolite (WR-1065). 

A clinical study that was started to find out if pentostatin would improve the immunosuppressive effects of cyclophosphamide, carmustine and etoposide in bone marrow transplant patients was stopped when acute and fatal cardiovascular collapse developed in the first 2 patients. Both patients had been given cyclophosphamide 800mg/m and etoposide 200 mg/m, both every 12 hours for 8 doses, and carmustine 112 mg/m daily for 4 doses. On day 3 pentostatin 4 mg/m, given over 4 hours, was added. Within 8 to 18 hours after completion of chemotherapy both patients developed confusion, hypothermia, hypotension, respiratory distress, pulmonary oedema, and eventually fatal ventricular fibrillation within 45 to 120 minutes of the first symptoms. A later study in rats similarly found that pentostatin markedly increased the acute toxicity of cyclophosphamide. The reasons for this cardiotoxicity are not understood. Neither of the 2 patients had previously shown any evidence of cardiac abnormalities. ... 

Unlike paclitaxel, docetaxel does not appear to affect the metabolism of doxorubicin. Thus, the combination of docetaxel arul doxorubicin does not increase the risk of cardiotoxicity, compared with doxorubicin alone [145 ] or doxorubicin + cyclophosphamide combination chemotherapy [146 ]. 

NPLD has been observed to have low cardiotoxicity, with only three of 63 patients (aged 32-85) treated with 60mg/m NPLD in combination with 75mg/m cyclophosphamide (or 75mg/m NPLD alone) experiencing LV fraction reduction [36 ]. 

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