Cyclophosphamide adverse effects

Mechlorethamine was the first nitrogen mustard. It is directly toxic. With its half-life of only a few minutes infusion directly into arteries supplying the tumor is the preferred mode of administration. Its spectrum of adverse effects is similar to that of 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. 

CYCLOPHOSPHAMIDE H2 RECEPTOR BLOCKERS-CIMETIDINE t adverse effects of alkylating agent, e.g. myelosuppression 1. Additive toxicity 2. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9 Avoid co-administration of cimetidine with cyclophosphamide... 

If life-threatening, prednisolone up to 70 mg, or its equivalent of another steroid. The dose is then increased if necessary until the disease is controlled or adverse effects occur as much as prednisolone 2-3 mg/kg/d can be needed. Cyclophosphamide or azathioprine (see p. 292) are valuable adjuncts they may enhance the initial control of the disease and have a sparing effect on the maintenance dose of prednisolone required. 

Nephrotic syndrome. Patients with minimal change disease respond well to daily or alternate day therapy. With a total of prednisolone 60 mg/d, 90% of those who will lose their proteinuria will have done so within 4-6 weeks, and the dose is tapered off over 3-4 months. Longer courses only induce adverse effects. Relapses are common (50%) and it is then necessary to find a minimum dose of steroid that will keep the patient well. If a steroid is for any reason undesirable, cyclophosphamide or chlorambucil may be substituted. Membranous nephropathy may respond to high dose corticosteroid with or without chlorambucil. 

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. 

Leukemic patients receiving marrow from HLA-identi-cal sibling donors were randomized to either oral busulfan 16mg/kg (n = 8S) or total body irradiation (n — 79), plus cyclophosphamide 120mg/kg (2). Over 5-9 years the following adverse effects occurred in the two groups ... 

Common adverse effects observed at low doses of cyclophosphamide are similar to, but less frequent than, those observed in oncology patients. They include gastrointestinal disturbances (mostly nausea), hematological toxicity (mostly leukopenia), alopecia, and infectious complications (4,5). 

Hemorrhagic cystitis and bladder cancer are well-known complications of cyclophosphamide. The damage to the urinary bladder epithelium is caused by acrolein, a metabolite of cyclophosphamide that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk (23). Mesna (2-mercaptoethane sodium sulfonate) is used to prevent this adverse effect. It is excreted by the kidney, and it binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. Intravesical prostaglandin E2 has been suggested as an alternative treatment (23). 

In 155 patients with Wegener s granulomatosis, of whom 142 took daily oral cyclophosphamide, the most frequent long-term cyclophosphamide-related adverse effects were cystitis despite mesna therapy (12%) and myelodysplasia (8%) (25). Patients who took a cumulative dose of over 100 g had a two-fold greater risk of cystitis and/or myelodysplasia than patients who took under 100 g. The authors emphasized that cyclophosphamide therapy should be as short as possible, with mesna and close surveillance in order to reduce treatment-associated morbidity. 

In a retrospective analysis in 51 children with glucocorticoid-dependent nephrotic sjmdrome, the ability of levamisole to reduce the relapse rate and to spare prednisone therapy was compared with that of cyclophosphamide (21). Apart from one patient who had a spontaneously resolving skin rash with levamisole and three patients who had transient neutropenia with cyclophosphamide, there were no other clinically significant adverse effects. 

Treatment is largely supportive. Cyclophosphamide is adsorbed to activated charcoal and charcoal should be used for substantial, recent ingestions. Patients may require aggressive fluid support. Standard supportive therapies, such as vasopressors, should be utilized as clinically indicated. Patients may require prolonged observation due to the delay in the development of adverse effects. Antibiotics may be needed due to development of immunosuppression. MESNA has been used for management of cyclophosphamide-induced hemorrhagic cystitis. 

Cyclophosphamide and azathioprine were found to have no beneficial effect. Cyclosporine was evaluated iu a limited uumber of pa-tieuts with MPGN with some beueficial effect however, the trials were uot coutrolled or raudoruized. Iu additiou, the risks for devel-opiug adverse effects were high. Figure 47-9 preseuts an algorithm for treatment and follow-up. 

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