Ifosfamide-induced encephalopathy.

ABSTRACT

A 46-year-old man with a history of metastatic transitional cell carcinoma of the bladder received treatment with ifosfamide/mesna. He had reversible encephalopathy after the first cycle of chemotherapy. Adequate clinical response was achieved, with an obvious decrease in tumor size. Subsequently, an identical treatment was given without adverse central nervous system effects. Few data exist about retreatment with intravenous ifosfamide/mesna after induced encephalopathy, but this case suggests that this adverse effect may not recur m some patients.

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IFOSFAMIDE is an alkylating agent used in the treatment of several solid tumors. Side effects of this drug include central nervous system (CNS) toxicity in 20% to 30% of treated patients. The CNS toxicity is characterized by metabolic encephalopathy that includes confusion, mutism, seizures, and coma. Some metabolic conditions may enhance the risk of encephalopathy. The available information about retreatment with ifosfamide in patients who have had encephalopathy is virtually nonexistent. We report a case of a 46-year-old patient who had uneventful retreatment after the development of encephalopathy during the first cycle of chemotherapy.

CASE REPORT

A 46-year-old man had been diagnosed with extensive carcinoma in situ of the bladder 2 years before the reported admission. He had been treated with numerous cystoscopies and local excisions. When invasive tumor was detected, he had cystectomy and neobladder construction. Six months after that surgery, the patient presented with chronic pain in the rectal area, and although he received large doses of opioids, he still did not achieve adequate pain relief. Local anesthetic injections helped; the patient had detoxification at a chemical-dependence unit but continued to have pain. When he was admitted to our center because of fever, a rectal mass was detected on physical examination. Imaging workup was done; computed tomography (CT) showed a new mass in the pelvis and several densities in the liver. Despite negative results of blood cultures and treatment with intravenous (IV) antibiotics, he continued to be febrile. Results of fine needle aspiration of the liver lesions showed metastatic carcinoma. On the fourt h hospital day, the patient remained febrile and was found to have an acute abdomen. Exploratory laparotomy revealed that the tumor had grown and perforated the rectosigmoid colon. Bowel resection and colostomy were done; during the postoperative period, the patient's fever continued without evidence of infection. Repeated CT of the abdomen showed an interval increase in the size of the pelvic tumor and the liver lesions. It was thought that the fever was related to the tumor, and chemotherapy was started.

Pertinent pretreatment laboratory values were leukocytes, 26,700/[micro]L; platelet count, 522,000/[micro]L; hemoglobin, 8.7 g/dL; blood urea nitrogen (BUN), 10 mg/dL; creatinine, 0.8 mg/dL; sodium, 134 mEq/L; potassium, 4.0 mEq/L; magnesium, 2.1 mg/dL; albumin, 2.4 g/dL; alkaline phosphatase, 140 IU/L; bilirubin, 1.1 mg/dL; and prothrombin time, 13.6 seconds.

Chemotherapy was initiated with paclitaxel, 200 mg/[m.sup.2] IV, infused over 3 hours on day 1; cisplatin, 70 mg/[m.sup.2] IV, infused over 1 hour on day 1; and ifosfamide, 1.5 g/[m.sup.2] IV, infused over 1 hour; with mesna uroprotection, 500 mg/[m.sup.2] given before, 4 hours after, and 8 hours after treatment with ifosfamide on days 1, 2, and 3 of therapy.

The patient's other medications included granisetron hydrochloride, 1 mg IV, once a day; dexamethasone, 20 mg orally, 12 hours before, 6 hours before, and during paclitaxel administration; famotidine, 20 mg orally, twice a day; oxycodone hydrochloride, 30 mg orally, twice a day; and ketorolac tromethamine IV for pain. He received 2 IV doses. of 10 mg of prochlorperazine because of nausea during the first 48 hours of the chemotherapy cycle and had no secondary effects after the medication was administered.

On day 2 of the ifosfamide therapy, the patient became sleepy and confused; he had generalized myoclonic jerks, muscle spasticity, and asterixis. He was responsive but not oriented. There were no localizing CNS signs, the cranial nerves were intact, and the plantar response was normal. A CT scan of the brain was normal. Laboratory studies revealed the following values: leukocytes, 26,2004/[micro]L; platelet count, 405,00O/[micro]L; hemoglobin, 8.4 g/dL; magnesium, 2.2 mg/dL; calcium, 7.6 mg/dL; sodium, 132 mEq/L; potassium, 4.1 mEq/L; carbon dioxide, 22 mmol/L; chloride, 105 mEq/L; glucose, 153 mg/dL; creatinine, 1.1 mg/dL; BUN, 21 mg/dL; lactate dehydrogenase (LDH), 729 U/L; aspartate aminotransferse (AST), 22 U/L; alanine aminotransferase (ALT), 34 U/L; total protein, 4.6 g/dL; albumin, 2.0 g/dL; alkaline phosphatase, 159 mg/dL; total bilirubin, 0.6 mg/dL; uric acid, 4.7 mg/dL.

The total dosage of ifosfamide given to the patient was 5.4 g (2.7 g per day). When neurologic symptoms developed, all medications were discontinued, including the last dose of chemotherapy. The patient was started on lorazepam, morphine sulfate patient-controlled analgesia, and droperidol, with improvement of the myoclonic jerks. Total parenteral nutrition was started the next day, and the patient returned to his baseline clinical status 72 hours after the encephalopathy had started. During the next 5 days, the patient's laboratory test results were normal, except for a low albumin level. Physical examination and CT scan showed that the size of the pelvic tumor and the liver lesions had decreased dramatically. Upon his recovery from the acute side effects and after extensive discussion with the patient, the decision was made to continue the same antineoplastic chemotherapy.

The patient received 6 more cycles of chemotherapy with the same doses of ifosfamide/mesna, paclitaxel, and cisplatin, which were tolerated with no adverse effects other than bone marrow depression. The tumor response continued to be adequate, and the patient's albumin level rose to within normal limits.

DISCUSSION

The mechanism by which ifosfamide causes encephalopathy is not yet clearly understood, but it may be related to the accumulation of the metabolite chloroacetaldehyde, which is believed to be neurotoxic. The most common manifestations of neurotoxicity include confusion, depressive psychosis, somnolence, and hallucinations; other symptoms include dizziness, incontinence, seizures, mutism, weakness, cranial-nerve dysfunction, extrapyramidal symptoms, and, rarely, coma. The signs of CNS toxicity can occur from 2 to 48 hours after infusion with ifosfamide, and, when reversible, usually clear within 1 to 3 days after discontinuance of the drug. (1-3) Central nervous system dysfunction occurs in 0% to 50% of patients undergoing ifosfamide therapy, with most studies reporting a rate between 10% and 30%. A clear dose-toxicity relationship has not been defined, and there is no clear relationship between the development of neurotoxicity and either the rate of ifosfamide infusion or the dosage fractionation. Abnormalitie s in the electroencephalogram (EEG) are consistent with a diffuse encephalopathy. Neurologic abnormalities associated with ifosfamide appear to be reversible in the majority of cases, though encephalopathy resulting in death has been reported. (3-5)

A serum albumin level lower than 3.5 g/dL, hyponatremia, elevated serum creatinine level, bulky abdominal disease (and especially bulky pelvic disease), previous nephrectomy, previous treatment with cisplatin, and poor performance status have been implicated in the development of CNS toxicity in patients receiving ifosfamide therapy. (4,6-12) There are also medications that may enhance the risk of encephalopathy. In their report of a case of encephalopathy in an epileptic 15-year-old patient, Ghosn et al (13) suggested that the administration of ifosfamide/mesna should be carefully monitored in patients receiving phenobarbital. The encephalopathy in such a case may be related to the induction of hepatic microsomal activity by this medication.

Our patient had encephalopathy during the first 48 hours of treatment and recovered 72 hours after the medication was discontinued. He presented with several signs of severe metabolic CNS toxicity, mainly myoclonic jerks, severe lethargy, and asterixis. The CT scan of his brain was normal. The suspected risk factors for encephalopathy were low levels of albumin and sodium, bulky abdominal disease, and the concomitant administration of cisplatin. He was taking no other medications that might have enhanced his risk for CNS toxicity.

Several intervention techniques have been used to prevent and treat CNS toxicity due to ifosfamide. Dosage fractionation to obtain more rapid clearance of the toxic metabolites (4,14) and continuous infusion over 3 to 5 days may minimize the risk of encephalopathy. (15,16) Anderson et al (17) used IV diphenhydramine to treat a patient who presented with extrapyramidal myoclonus, and this produced immediate relaxation.

Guilliam et al (18) cited 2 cases of patients with complex partial seizures, in which the symptoms and the EEG changes resolved after IV diazepam administration; this finding was confirmed by Simonian et al, (2) who reported ifosfamide-related encephalopathy as diazepam-sensitive encephalopathy. Kupfer et al (1) suggested that the electron-accepting drug methylene blue could be used as an antidote for ifosfamide-induced encephalopathy, reporting several cases in which the EEG abnormalities resolved with this therapy. It was also used prophylactically in other patients with previous episodes of encephalopathy. (1,19)

Cerny and Kupfer (20) state that to prevent systemic toxicity resulting from presystemically-formed metabolites with hypophilic and neurotrophic properties, orally-administered mesna may be, in appropriate doses and schedule, a potentially CNS-protective drug.

In addition to these interventions, though not yet clinically proven to be of benefit, the normalization of serum electrolytes and albumin, as well as appropriate hemodialysis, may be considered for those patients with life-threatening neurotoxicity. If for clinical reasons retreatment is considered, a prolonged IV continuous infusion of ifosfamide with equidose mesna admixed into the same infusion and, if necessary, restoration of hypoalbuminemia and bicarbonate supplementation, could help prevent further CNS toxicity.

There is a paucity of information in the medical literature describing patients retreated with ifosfamide after the development of encephalopathy because, in most of these cases, the CNS toxicity recurs and the patients may die. Encephalopathy did not recur, however, in a few of the patients treated with oral ifosfamide. (17,20,21) ( We propose that if the risk factors and the metabolic problems of these patients are identified and corrected in time, the possibility of encephalopathy in patients who are retreated with ifosfamide after previous CNS toxicity may be decreased or even avoided.

References

(1.) Kupfer A, Aeschlimann C, Wermuth B, et al: Prophylaxis and reversal of ifosfamide encephalopathy with methyleneblue. Lancet 1994; 343:763-764

(2.) Simonian NA, Gilliam FG, Chiappa KH: Ifosfamide causes a diazepam-sensitive encephalopathy. Neurology 1993; 43:2700-2702

(3.) Tuxen MK, Hansen SW: Neurotoxicity secondary to antineoplastic drugs. Cancer Treat Rev 1994; 20:191-214

(4.) Zalupski M, Ryan JR, Ensley J, et al: Ifosfamide. J Natl Cancer Inst 1988; 80:556-566

(5.) Verdeguer A, Castel V, Esquembre C, et al: Fatal encephalopathy with ifosfamide mesna (Letter). Pediatr Hematol Oncol 1989; 6:383-385

(6.) Antman KH, Elias A: Dana-Farber Institute studies in advanced sarcoma. Semin Oncol 1990; 17:7-15

(7.) Pratt CB, Goren MP, Meyer WH, et al: Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors. J Clin Oncol 1990; 8:1399-1404

(8.) Cantwell BM, Idle M, Millward MJ, et al: Encephalopathy with hyponatremia and inappropriate arginine vasopressin secretion following the intravenous ifosfamide infusion (Letter). Ann Oncol 1990; 1:232

(9.) Curtin JP, Koonings PP, Gutierrez M, et al: Ifosfamide induced neurotoxicity. Gynecol Oncol 1992; 42:193-196

(10.) Watkin SW, Husband DJ, Green JA, et al: Ifosfamide encephalopathy: a reappraisal. Eur J Clin Oncol 1989 25:1303-1310

(11.) Merimsky O, Reider-Groswasser I, Wigler N, et al: Encephalopathy in ifosfamide treated patients. Acta Neurol Scand 1992; 86:521-525

(12.) Meanwell GA, Blake AE, Kelly KA, et al: Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol 1986; 22:815-819

(13.) Ghosn M, Carde B, Flamant F, et al: Ifosfamide/mesna related encephalopathy: a case report with a possible role of phenobarbital in enhancing toxicity. Bull Cancer 1988; 75:391-392

(14.) Merimsky O, Imbar M, Reider-Groswasser I, et al: Ifosfamide related acute encephalopathy: clinical and radiological aspects. Eur J Cancer 1991; 27:1188-1189

(15.) Antman KH, Elias A, Ryan L: Ifosfamide/mesna: response in toxicity at standard and high dose schedules. Semin Oncol 1990; 17:68-73

(16.) Cerny T, Castiglione M, Brunner K, et al: Ifosfamide by continuous infusion to prevent encephalopathy. Lancet 1990; 335:175

(17.) Anderson NR, Tandon DS: Ifosfamide extrapyramidal neurotoxicity. Cancer 1991; 68:72-75

(18.) Gilliam F, Simonian N, Chiapa K: Complex partial status epilepticus associated with ifosfamide infusion. Epilepsia 1992; 33(suppl 3):3

(19.) Zulian GB, Tullen E, Maton B, et al: Methylene-blue for ifosfamide-associated encephalopathy. New Engl J Med 1995; 332:1239-1240

(20.) Cerny T, Kupfer A: The enigma of ifosfamide encephalopathy (Editorial). Ann Oncol 1992; 3:679-681

(21.) Cantwell BM, Harris AL: Ifosfamide/mesna and encephalopathy (Letter). Lancet 1985; 1:752

RELATED ARTICLE: KEY POINTS

* Ifosfamide-induced encephalopathy is a serious complication of this medication. The causes of this complication are unknown.

* Retreatment with ifosfamide in a patient who previously had ifosfamide-induced encephalopathy is possible, without recurrence of the encephalopathy.

* It is unlikely that a genetic or constitutional defect is responsible for the development of ifosfamide-induced encephalopathy.

From the Departments of Medicine and Hematology-Oncology, Mount Sinai Medical Center, Miami Beach, Fla.

Reprint requests to Enrique Davila, MD, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL 33140.