We describe the cardiovascular complications in a group of patients who received ifosfamide as a component of combination chemotherapy with autologous bone marrow transplantation for treatment of lymphoma or carcinoma.

Methods

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The medical records of all patients who received combination chemotherapy and autologous bone marrow transplantation at the National Institutes of Health between March 1988 and April 1991 were retrospectively reviewed.

One group of patients was enrolled in a phase I study of high-dose combination chemotherapy and autologous bone marrow transplantation for treatment of metastatic carcinoma and lymphoma. These patients received ifosfamide (total dose, 10 to 18 g/m² body surface area) with carboplatin (total dose, 900 to 1800 mg/m²) and etoposide (total dose, 600 to 1800 mg/m²). This combination is referred to as the ICE (ifosfamide, carboplatin, and etoposide) regimen [18]. The other group of patients participated in a phase I study of salvage chemotherapy followed by intensification chemotherapy and autologous bone marrow transplantation for refractory Hodgkin disease. These patients received ifosfamide (total dose, 10 to 16 g/m²) together with vinblastine (total dose, 16 to 25 mg/m²) and lomustine (also known as CCNU [N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea], total dose, 240 to 320 mg/m²). This combination is referred to as the VIC (vinblastine, ifosfamide, and CCNU) regimen [19]. In both regimens, ifosfamide was given with mesna doses ranging from 16 to 28.8 g/m².

In both phase I studies, the total amount of ifosfamide was divided into equal doses administered intravenously for 2 hours each day for 4 consecutive days. Mesna, admixed with ifosfamide, was administered as a loading dose over a 2-hour period, and this was followed immediately by a 3-hour continuous infusion. After completion of the infusion, mesna was administered intravenously every 3 hours for 15 minutes for a total of six doses. Carboplatin was administered as a 72-hour continuous infusion; etoposide was given intravenously every 12 hours in six divided doses; and vinblastine was given as an intravenous loading dose followed by a continuous infusion for 96 hours. Lomustine was given orally as two consecutive daily doses. Bone marrow that had been previously harvested was reinfused on day 7 in the ICE regimen and on day 9 in the VIC regimen.

All patients were hydrated intravenously from 24 hours before the first dose of ifosfamide until at least 7 days after completion of ifosfamide therapy. Patients on the ICE regimen received 5% dextrose and 0.9% sodium chloride at 300 mL/h, and those on the VIC regimen received 5% dextrose and 0.45% sodium chloride solution at 3 L/m² per 24 hours. Furosemide was given as needed to maintain urine output of at least 150 mL/h in all patients.

Retrospective Chart Review

The following clinical and laboratory data were reviewed: details of daily physical examinations; electrocardiograms, echocardiograms, radionuclide cineangiograms, and chest radiographs; serial measurements of serum creatinine, minerals, electrolytes, and arterial pH and blood gases; and results of all cultures obtained during hospitalization.

Hemodynamic Monitoring and Calculations

Patients admitted to the intensive care unit with congestive heart failure underwent hemodynamic monitoring with pulmonary artery catheters (Sorenson, 7.5 F, Abbott Critical Care Systems, North Chicago, Illinois) and intra-arterial catheters (20 G, 4.5 cm, Arrow International, Reading, Pennsylvania).

Hemodynamic variables assessed serially in the intensive care unit included heart rate; mean arterial pressure; central venous pressure; pulmonary artery systolic, diastolic, and mean pressures; and pulmonary artery occlusion pressure. Cardiac output was determined by thermodilution technique. The cardiac index was determined by dividing cardiac output by body surface area.

At the time of admission to the intensive care unit, left ventricular ejection fraction was obtained by bedside radionuclide cineangiography (Picker portable camera, model Dynamo, Northford, Connecticut) using standard techniques [20]. Echocardiograms were obtained using a 2.5-MHz transducer connected to a Hewlett-Packard ultrasound system. Left ventricular fractional shortening was calculated by dividing the difference between the end-diastolic and end-systolic dimensions by the end-diastolic dimension.

Histopathologic Evaluation

For cases in which autopsy material was available, gross pathologic and histopathologic findings in the heart and cardiovascular system were reviewed and noted.

Statistical Methods

Data on the following variables were collected for each of the eight patients admitted to the intensive care unit: weight, heart rate, mean arterial pressure, pulmonary artery mean pressure, pulmonary artery occlusion pressure, cardiac index, left ventricular ejection fraction, and fractional shortening. For each variable, the mean value at the time of admission to the intensive care unit was compared with that at follow-up (day 4) by a paired sample t-test. Unpaired Student t-tests were used to compare means of previous cumulative doses of doxorubicin. The Yates mean score test [21] was done to evaluate the association between ifosfamide dose and the occurrence of congestive heart failure. A Fisher exact test was used to assess the correlation of congestive heart failure with doubling of serum creatinine level, presence or absence of previous doxorubicin therapy, and presence or absence of underlying lymphoma.

Results

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During the period reviewed, 52 patients received 53 courses of chemotherapy in association with autologous bone marrow transplantation. This group included 22 women and 30 men with a mean age of 36 years (range, 15 to 65 years). Their primary diagnoses were Hodgkin disease (n = 24), diffuse large cell lymphoma (n = 10), other intermediate- or high-grade lymphomas (n = 7), breast carcinoma (n = 7), and testicular carcinoma (n = 4).

The ifosfamide dose was 10 g/m² in 6 patients, 12.5 g/m² in 12 patients, 15.6 g/m² in 20 patients, 16 g/m² in 12 patients, and 18 g/m² in 3 patients. Nineteen patients received the VIC regimen, and 34 received the ICE regimen. One patient received both regimens, initially VIC with an ifosfamide dose of 15.6 g/m², and, after relapse 13 months later, ICE with an ifosfamide dose of 16 g/m².

Before ifosfamide therapy, 45 patients had received doxorubicin in cumulative doses (mean ± SE) of 384 ± 23 mg/m² (range, 45 to 650 mg/m²). Twenty patients had received radiation therapy to the chest or mediastinum at times ranging from 1 week to 10 years before ifosfamide therapy. None of the 52 patients had a previous history of congestive heart failure, angina pectoris, or cardiac arrhythmias. At the time of admission, all patients had normal cardiovascular findings at physical examination. All patients had serum creatinine levels below 130 µmol/L (1.5 mg/dL) and creatinine clearances above 50 mL/min before initiation of therapy.

Nine of the 52 patients developed significant cardiovascular toxicity yielding an overall incidence of 17% (95% CI, 8% to 30%). Of 34 patients given the ICE regimen (23 with lymphoma and 11 with carcinoma), 6 patients with lymphoma (18%) developed congestive heart failure. Of 19 patients with lymphoma on the VIC regimen, 3 (16%) developed congestive heart failure. A significant dose-response trend was observed in the incidence of congestive heart failure as the ifosfamide dose was increased (P = 0.02): Congestive heart failure developed in 0 of 6 patients receiving 10 g/m², 1 of 12 patients (8%) receiving 12.5 g/m², 2 of 20 patients (10%) receiving 15.6 g/m², 4 of 12 patients (33%) receiving 16 g/m², and 2 of 3 patients (67%) receiving 18 g/m².

Eight of the nine patients developed severe congestive heart failure and required admission to the intensive care unit. Demographic data for these eight patients are shown in Table 1. Three patients had received mediastinal radiation therapy. All eight patients had received previous doxorubicin therapy (mean cumulative dose, 340 mg/m²; range, 190 to 550 mg/m²) at a median interval of 1 month (range, 0.5 to 36 months) before the administration of ifosfamide. Another 26 patients who received ifosfamide doses of 15.6 to 18 g/m² had also received previous therapy with doxorubicin at a similar mean cumulative dose (326 mg/m² [range, 45 to 650 mg/m²]; P > 0.2) and at a similar median interval of 1 month (range, 0.33 to 4.6 months) before ifosfamide therapy; however, these patients did not develop serious cardiac complications.

The onset of symptoms of heart failure occurred at a mean of 12 days (range, 6 to 23 days) after the initiation of ifosfamide therapy. By the time of admission to the intensive care unit, all eight patients had dyspnea, tachycardia, tachypnea, peripheral edema, weight gain (mean, 5.2 kg), hypoxemia (mean alveolar-arterial oxygen gradient, 32 kPa [236 mm Hg]), and evidence of pulmonary edema or pleural effusion on chest radiographs. Right-sided heart catheterization in these eight patients confirmed the clinical impression of congestive heart failure and helped to guide therapy (Table 2).

In four of these eight patients, left ventricular ejection fraction was measured by radionuclide cineangiography both before and after ifosfamide administration. The mean (± SE) left ventricular ejection fraction for these four patients decreased relative to the baseline value, from 47% ± 3% to 28% ± 4% (P = 0.005). In our laboratory, left ventricular ejection fraction of 45% or higher is considered normal. In seven patients, echocardiographic fractional shortening was measured both at the time of admission to the intensive care unit and a mean of 7 days later (see Table 1). Over this time, fractional shortening improved from 11% ± 1% to 22% ± 2% (P = 0.005). All seven patients had normal septal and left ventricular posterior wall thicknesses.

Various arrhythmias were documented (Table 3). One patient required cardioversion for pulseless ventricular tachycardia and subsequently was given intravenous lidocaine. Another patient required procainamide to treat re-entrant supraventricular tachycardia associated with hemodynamic instability. All of the eight patients had nonspecific ST-segment or T-wave abnormalities on their electrocardiograms. Two patients had decreased QRS complex voltage relative to baseline electrocardiographic findings.

Congestive heart failure was treated with various agents, including diuretics (eight patients), nitroglycerine (five patients), dopamine (five patients), dobutamine (four patients), digitalis (three patients), levarterenol (two patients), epinephrine (two patients), amrinone (one patient), and nitroprusside (one patient).

In addition to the eight patients admitted to the intensive care unit, another patient with lymphoma developed moderate congestive heart failure that did not require intensive care unit admission. He was on the ICE regimen and was receiving an ifosfamide dose of 12.5 g/m². He had not received mediastinal radiation therapy, but 6 months earlier he had completed a course of doxorubicin (cumulative dose, 600 mg/m²). His left ventricular ejection fraction before the ICE regimen was 46%. Symptoms of congestive heart failure began 6 days after the first dose of ifosfamide. He developed dyspnea, orthopnea, jugular venous distention, and peripheral edema and had a weight gain of 4.4 kg. His serum creatinine had doubled relative to the admission level. An electrocardiogram showed sinus tachycardia and nonspecific ST-segment and T-wave abnormalities. An echocardiogram obtained 15 days after the onset of symptoms showed left ventricular fractional shortening of 11%, normal septal and left ventricular wall thicknesses, and a dilated left atrium. He responded to therapy with diuretics, digitalis, and captopril, and 2 months later his left ventricular ejection fraction was 43%.

Of the nine patients who developed congestive heart failure, only one patient (Patient 5) died of cardiac causes, succumbing to intractable cardiogenic shock 12 days after the first ifosfamide dose. The other seven patients admitted to the intensive care unit showed significant decreases in weight, heart rate, mean arterial pressure, pulmonary artery mean pressure, and pulmonary artery occlusion pressure (see Table 2) as well as clinical resolution of pulmonary edema and improvement in fractional shortening within 4 to 7 days after admission. Five patients died of noncardiac causes, a mean of 40 days after the first ifosfamide dose (range, 11 to 72 days), despite showing improvement in cardiovascular function. The three survivors subsequently regained normal or near-normal left ventricular ejection fraction.

Autopsy data were available in four of the six patients who died. Both the gross and the histologic cardiac abnormalities are listed in Table 4. All patients had increased heart weight and small pericardial effusions, one had fibrinous pericarditis, two had right atrial subendocardial hemorrhages, one had scant lymphocytic infiltration of the myocardium, and two had pulmonary vascular congestion. Patient 5, who died of cardiogenic shock, had right and left ventricular dilatation, numerous petechial lesions in the epicardium, substantial epicardial fibrosis, and moderate adipose infiltration of the myocardium. This patient also had marked edema of the myocardial interstitium, with accumulation of lipofuscin pigment and perinuclear vacuolization within many of the myocytes, as well as endocardial thickening and fibrosis. No histopathologic evidence of occlusive coronary artery disease or myocardial infarction was found in any of these four patients.

Development of congestive heart failure correlated significantly (P = 0.0001) with doubling of serum creatinine from pre-ifosfamide levels. Serum creatinine doubled after ifosfamide therapy in 18 of 52 patients. These 18 patients included all 9 patients who developed congestive heart failure (see Table 1). Although all nine patients who developed congestive heart failure had lymphoma rather than carcinoma, the correlation between lymphoma and development of congestive heart failure was not statistically significant.

None of the nine patients who developed congestive heart failure had electrocardiographic evidence of myocardial ischemia or elevation of serial cardiac enzyme levels. Blood cultures and other studies were done in all nine patients, and no evidence of systemic infection was found. All of these patients had evidence of renal tubular acidosis, presumably related to ifosfamide therapy, requiring correction of electrolyte and acid-base abnormalities.

Discussion

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High-dose ifosfamide should be added to the list of antineoplastic therapies associated with major cardiac complications [22-26]. In our series of 52 patients who received combination chemotherapy and autologous bone marrow transplantation, 9 patients developed clinical congestive heart failure. One case was moderate, and the patient was managed without invasive monitoring; the other eight patients presented with fulminant pulmonary edema and required management in an intensive care unit. All eight patients had evidence of depressed left ventricular function as documented by right-sided heart catheterization and, in most cases, by radionuclide cineangiography and echocardiography. Good responses to diuretic, inotropic, and vasodilator agents were seen in all but one patient, who died of intractable cardiogenic shock. Also observed among these eight patients were malignant arrhythmias, some requiring cardioversion or antiarrhythmic drugs.

The observation that only the patients with lymphoma developed cardiac toxicity is intriguing, although the association was not statistically significant. All patients with carcinoma received the ICE regimen; however, there is no evidence that the incidence of congestive heart failure in patients on the ICE regimen (18%) was lower than that in patients on the VIC regimen (16%). No difference was observed between patients with lymphoma and those with carcinoma in the mean previous anthracycline doses. Consequently, it is unclear why only the lymphoma patients developed congestive heart failure.

In our series of patients, ifosfamide appears likely to have been the causative agent of myocardial depression in a dose-dependent fashion. The other chemotherapeutic agents used in the ICE and VIC regimens—carboplatin, etoposide, vinblastine, and CCNU—have been used in similar doses and have not been associated with myocardial depression. Etoposide, when infused too rapidly, may produce arrhythmias and hypotension [27]. A few case reports suggest a possible association of myocardial ischemia with etoposide [28] and vinblastine [29]. However, the patients in our series did not receive rapid etoposide infusions and did not have evidence of myocardial ischemia.

Previous studies on animals have suggested that ifosfamide might be cardiotoxic. In animals, high-dose ifosfamide has been reported to cause severe myocardial damage with loss of striation and sometimes fragmentation of ventricular muscle fibers [30]. Questions have also been raised about the possibility of ifosfamide cardiotoxicity in humans. Elias and colleagues [6] described two patients, both of whom had received previous doxorubicin therapy, who developed congestive heart failure after receiving an ifosfamide dose of 18 g/m². In patients receiving ifosfamide doses of 6.5 to 10 g/m², Kandylis and colleagues [17] reported a 15% incidence of supraventricular arrhythmias and electrocardiographic ST-segment and T-wave abnormalities.

Ifosfamide is structurally similar to cyclophosphamide, an alkylating agent that is associated with a well-defined cardiomyopathy and in some cases may be refractory to inotropic support and cause death acutely [25, 26]. Cazin and colleagues [31] reported a 43% incidence of cardiac complications after chemotherapy with 6-thioguanine, cytosine arabinoside, CCNU, and cyclophosphamide in patients undergoing bone marrow transplantation. In our patients, we found no histopathologic evidence of hemorrhagic myocarditis, the hallmark of cyclophosphamide cardiomyopathy [25]. Given the close chemical resemblance between ifosfamide and cyclophosphamide, however, it remains possible that both drugs induce myocardial depression through similar mechanisms. Given the times of death of the nonsurvivors, in relation to the times of the ifosfamide doses, it is possible that acute changes induced by ifosfamide had already resolved and were no longer identifiable histopathologically. The lack of endomyocardial biopsy specimens at the time of acute decompensation limits our ability to comment on the pathogenesis of the cardiac toxicity of ifosfamide.

The nephrotoxicity of ifosfamide has been well characterized. Reduction of glomerular filtration rate, tubular defects, renal tubular acidosis, a syndrome of inappropriate secretion of antidiuretic hormone, and diabetes insipidus all have been reported [10, 11]. That a rise in serum creatinine invariably preceded the onset of congestive heart failure and that reversal of the congestive heart failure occurred with time suggest that the ifosfamide-related cardiotoxicity may be related to delayed elimination of cardiotoxic metabolites of the drug. It may be that fluid retention or acid-base and electrolyte disturbances related to tubular defects were factors contributing to the observed cardiac complications. It is also possible that the fluid and sodium loads given with the chemotherapeutic regimen contributed to decompensation in patients who developed myocardial depression. Thus, careful monitoring of fluid balance is important in patients receiving ifosfamide therapy, especially in those with rising serum creatinine levels.

Previous exposure to doxorubicin may have potentiated the cardiotoxicity of ifosfamide. However, the mean cumulative doxorubicin dose did not differ significantly between the 9 patients with and the 43 patients without congestive heart failure. In the patients who were on the VIC regimen, CCNU may have potentiated the cardiac toxicity of ifosfamide. Nitrosoureas have been shown to induce depletion of cellular glutathione [32, 33], and some studies in mice [34] have shown that cytoplasmic glutathione is protective against the cardiac toxicity of cyclophosphamide.

In summary, our retrospective study of 52 patients suggests that high-dose ifosfamide is associated, usually in the setting of decreased glomerular filtration rate, with reversible myocardial depression, which manifests by overt congestive heart failure and malignant arrhythmias. A high index of suspicion of this toxicity is warranted when managing patients on ifosfamide therapy. Other causes of congestive heart failure should be considered, but the reversible nature of ifosfamide-associated heart failure mandates aggressive therapeutic support of all patients who develop this complication.