Cyclophosphamide

Observational studies

Cyclophosphamide has been investigated in a wide range of diseases, but results in aplastic anemia and idiopathic pulmonary fibrosis have been disappointing. In a low dose (2 mg/kg/day), it produced minimal efficacy in 19 patients with idiopathic pulmonary fibrosis who had failed to respond to a glucocorticoid or who had had adverse effects [ ]. Moreover, 13 patients had cyclophosphamide-induced adverse effects, which required drug withdrawal in nine. The most frequent were severe gastrointestinal effects, leukopenia, and skin rashes. In another study, high-dose cyclophosphamide plus ciclosporin (50 mg/kg/day for 4 days) was compared with antithymocyte globulin plus ciclosporin in patients with severe aplastic anemia, but the trial was prematurely stopped after only 31 patients had been enrolled because of three early deaths in patients taking cyclophosphamide [ ]. Subsequent analysis showed excess morbidity and mortality in patients taking cyclophosphamide, with six proven or suspected cases of systemic fungal infection (including the three deaths) compared with no cases in the other group, but no significant difference in the hematological response rates between the groups. In addition, the durations of hospital stay, neutropenia, and antibacterial treatment were longer with cyclophosphamide. Based on these results, the authors concluded that cyclophosphamide should not be used in aplastic anemia.

Comparative studies

The beneficial effects of cyclophosphamide must be weighed against its considerable toxicity during long-term therapy in patients with proliferative lupus nephritis. Patients with lupus nephritis (n = 59; 12 of WHO class III, 46 of class IV, and one of class Vb) received induction therapy with up to seven monthly intravenous boluses of cyclophosphamide 0.5–1.0 g/m ² plus glucocorticoids [ ]. They were subsequently randomized to quarterly intravenous cyclophosphamide, oral azathioprine 1–3 mg/kg/day, or oral mycophenolate mofetil 0.5–3 g/day for 1–3 years. During maintenance therapy, five patients died (four taking cyclophosphamide and one taking mycophenolate mofetil), and five developed chronic renal insufficiency (three taking cyclophosphamide, one taking azathioprine, and one taking mycophenolate mofetil). The 72-month event-free survival rate for the composite end-point of death or chronic renal insufficiency was significantly higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group. The rate of relapse-free survival was significantly higher in the mycophenolate mofetil group than in the cyclophosphamide group. The incidences of hospitalization, amenorrhea, infections, nausea, and vomiting were significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group. Therefore, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.

General adverse effects and adverse reactions

Common adverse effects and reactions 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 [ , ].

Cardiovascular

Cardiac toxicity can be observed at high doses of cyclophosphamide (usually over 1.5 g/m ² /day), and acute myocardial necrosis or severe cardiac failure have been anecdotally reported after smaller dosages [ ].

High-dose cyclophosphamide (120–200 mg/kg) can cause lethal cardiotoxicity, and severe congestive heart failure can develop 1–10 days after the first dose [ ]. Severe congestive heart failure is accompanied by electrocardiographic findings of diffuse voltage loss, cardiomegaly, pulmonary vascular congestion, and pleural and pericardial effusions. Pathological findings include hemorrhagic myocardial necrosis, thickening of the left ventricular wall, and fibrinous pericarditis.

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 [ ]. Six died from congestive heart failure. Older patients were at greatest risk of developing cardiotoxicity.

In six patients who developed heart failure after high-dose conditioning therapy before stem cell transplantation, cyclophosphamide was suspected, despite the possible involvement of four drugs [ ]. The authors suggested monitoring high-risk patients.

Corrected QT dispersion was a predictor of acute heart failure after high-dose cyclophosphamide chemotherapy (5.6 g/m ² over 4 days) in 19 patients [ ].

Respiratory

Cyclophosphamide-induced pneumonitis has been described in 29 cases [ ]. Considering the widespread use of this drug over many years, this is a rare adverse effect. It does not clearly correlate with dosage [ ]. From a review of 12 case reports and a retrospective analysis of six other patients (including four with Wegener’s granulomatosis), in whom cyclophosphamide was thought to be the only causative factor, two distinct clinical patterns of pneumonitis with different prognoses were identified [ ]. Early-onset pneumonitis (n = 8) occurred acutely within 1–8 months of treatment, and complete recovery was noted after cyclophosphamide withdrawal and prednisone treatment. In contrast, late-onset pneumonitis (n = 10) developed insidiously over several months (eventually after cyclophosphamide withdrawal) in patients maintained taking low daily doses for months to years. These patients had progressive pulmonary fibrosis unresponsive to glucocorticoid therapy, and six died of respiratory failure. Radiological pleural thickening may be an early sign of late-onset lung toxicity.

Cyclophosphamide-induced lung disease may be more common in patients who have used other potentially pneumotoxic drugs (e.g. amiodarone) [ ].

• A 73-year old Caucasian woman with follicular center non-Hodgkin’s lymphoma (grade 2, stage III) was given R-CHOP—intravenous rituximab 375 mg/m ² , cyclophosphamide 750 mg/m ² , doxorubicin 50 mg/m ² , and vincristine 1 mg/m ² on day 1 plus oral prednisone 100 mg/day on days 1–5. She had also been taking amiodarone 300 mg bd for 4 years, simvastatin 40 mg/day, atenolol 100 mg/day, and warfarin. Two days after the first treatment cycle she developed acute respiratory distress and profound hypoxia, with an oxygen saturation of 77%. She required intubation and underwent bronchoscopy. No pathogen was identified and she was given dexamethasone 8 mg every 6 hours for presumed cyclophosphamide-induced acute lung injury. However, 2 weeks later, she developed septicaemia with Pseudomonas and vancomycin-resistant Enterococcus and died.

Nervous system

Progressive multifocal leukoencephalopathy is sometimes associated with Wegener’s granulomatosis, but one case occurred in a patient who was taking low-dose cyclophosphamide, with subsequent significant improvement on withdrawal of the drug [ ].

Sensory systems

Blurred vision is sometimes reported after high intravenous doses of cyclophosphamide, and there has been one report of transient myopia that recurred after each monthly intravenous pulse [ ].

The mechanism of cyclophosphamide-induced facial discomfort or upper respiratory symptoms, including facial burning, sneezing, oropharyngeal tingling, rhinorrhea, and lacrimation, has not been elucidated, but may be at least in part vagally mediated. Some authors have suggested that rapid administration predisposes to facial discomfort. However, prolonging the duration of administration during high-dose cyclophosphamide, e.g. by infusing over 2 hours rather than 1 hour, led to some improvement in 20 patients but not consistently [ ]. Further considerations include the use of anticholinergic agents.

• A 72-year old woman received carboplatin and intravenous cyclophosphamide 930 mg over 15 minutes for ovarian carcinoma [ ]. Immediately after cyclophosphamide administration, she experienced nasal burning, nasal stuffiness, and profuse lacrimation. The symptoms resolved spontaneously within 15 minutes. The preceded supportive use of intranasal ipratropium bromide markedly reduced the intensity of symptoms in the following cycles.

Endocrine

Even low-dose intravenous cyclophosphamide can cause a syndrome that resembles inappropriate secretion of antidiuretic hormone, with severe hyponatremia and symptoms of water intoxication [ , ]. A direct effect on the renal tubules is likely, but no other nephrotoxic effects have been documented.

Hematologic

Leukopenia, and less commonly thrombocytopenia or anemia, due to cyclophosphamide are typically dose-related in the therapeutic range. Cyclophosphamide-induced anemia has led to retinopathy presenting as striated hemorrhage of the retina [ ].

Relative eosinophilia and increased interleukin-4 secretion were found in one study, suggesting that an immune deviation toward a type-2 T helper cell (Th2) response can occur [ ]. The clinical relevance of these findings as regards hypersensitivity reactions is unknown.

The idea that the degree of leukocyte suppression can be used to predict the success of adjuvant chemotherapy has been applied to combined treatment with cyclophosphamide, methotrexate, and 5-fluorouracil for breast cancer; the lower the nadir leukocyte count, the greater the incidence of metastatic disease-free survival [ ].

Mouth

Unilateral necrosis of the tongue has been attributed to cyclophosphamide [ ].

• A 62-year-old woman with invasive ductal carcinoma of the breast was treated with epirubicin and cyclophosphamide. She rapidly developed swelling and necrosis of the tongue and consequent airway obstruction necessitating tracheostomy. After excision of the necrosis, the swelling of the tongue and the airway obstruction resolved.

Because of the temporal connection between the necrosis and the chemotherapy, the authors suspected an adverse effect, although they could not exclude a paraneoplastic pathogenesis.