mesna and Brain-Diseases

The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen.. Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity.. One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months.. The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Dacarbazine; Doxorubicin; Drug Administration Schedule; Drug Resistance; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Kidney; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Sarcoma

In two sequential trials, 154 patients were treated with dosages of ifosfamide, ranging between 8 and 18 g/m2 divided over 4 days, with mesna uroprotection. The first was a phase II efficacy trial in 125 advanced sarcoma patients (Antman et al: J Clin Oncol 7:126-131, 1989), while the second was a dose escalation trial involving 29 patients (Elias et al: J Clin Oncol 8:170-178, 1990). In the first trial, patients received 8 to 10 g/m2 ifosfamide either by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (P = .09). Of the 154 patients, 144 had sarcoma and had failed at least one previous regimen. Of these 144, 4% responded completely and 23% had a complete or partial response. The maximum tolerated dose of ifosfamide was 16 g/m2 in the second trial. Dose-limiting renal toxicity was observed at 18 g/m2 ifosfamide (Elias et al: J Clin Oncol 8:170-178, 1990). The duration of myelosuppression and the frequency and severity of mucositis and renal tubular acidosis were dose-dependent. A median of 11 days (range, 8 to 18) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion was not required. Severe central nervous system toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. The first four patients on the standard-dose study did not receive mesna because it was unavailable; three developed gross hematuria. In patients who received mesna, hematuria was uncommon. Hematuria in the group as a whole was significantly associated with a lack of uroprotection, but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus versus a continuous infusion schedule. Patients receiving ifosfamide with mesna uroprotection can tolerate considerable dose escalation over the usual prescribed doses before nonhematologic toxicity becomes dose-limiting. Ifosfamide, with its broad activity in solid tumors, may prove to be an important addition to high-dose combination-chemotherapy regimens (Elias et al: J Clin Oncol 8:170-178, 1990).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Child; Child, Preschool; Cystitis; Drug Administration Schedule; Drug Evaluation; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Mesna; Middle Aged; Pulmonary Fibrosis; Sarcoma

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.

Topics: Adult; Amino Acids; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Brain Diseases; Dicarboxylic Acids; Humans; Ifosfamide; Kidney Cortex; Kidney Diseases; Kidney Function Tests; Kidney Medulla; Magnetic Resonance Spectroscopy; Mesna; Methylene Blue; Molecular Weight; Neoplasms; Protons; Retinol-Binding Proteins; Urinalysis

Acute encephalopathy following treatment with ifosfamide and mesna was observed in 5 (4 women and 1 men) of 28 patients (17.8%), with advanced sarcoma, lymphoma or ovarian carcinoma. This appeared within 2 to 7 days following the first dose of ifosfamide treatment, and included mental status changes, urinary incontinence, weakness, seizure activity, altered consciousness and psychiatric manifestations. Three cases were fatal, while two patients recovered completely. Brain CT and morphometric studies were normal in all the patients. Associated findings were myelosuppression, renal failure and electrolyte alterations.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Diseases; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoplasms; Neurologic Examination; Substance-Related Disorders; Tomography, X-Ray Computed

Topics: Brain Diseases; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Humans; Ifosfamide; Infusions, Intravenous; Mesna

Topics: Brain Diseases; Child; Drug Therapy, Combination; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Rhabdomyosarcoma

Topics: Adult; Brain Diseases; Drug Therapy, Combination; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged

A case of reversible encephalopathy after one dose of ifosfamide/mesna in an epileptic 15-year-old girl is reported. No other pathology could be responsible for the symptoms. An epilepsy or a toxicity induced by vincristine were discussed. Nevertheless, the possible role of phenobarbital, known to induce hepatic microsomal activity, seems the more probable mechanism.

Topics: Adolescent; Brain Diseases; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Phenobarbital

Topics: Brain Diseases; Drug Therapy, Combination; Humans; Ifosfamide; Infusions, Intravenous; Mercaptoethanol; Mesna

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Child, Preschool; Dactinomycin; Female; Humans; Ifosfamide; Maxillary Neoplasms; Mercaptoethanol; Mesna; Rhabdomyosarcoma; Vincristine

Topics: Adolescent; Adult; Aged; Brain Diseases; Drug Therapy, Combination; Female; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Probability

Ifosfamide and mesna were administered to 77 patients with advanced malignancies. Seven (9%) experienced a severe but reversible encephalopathy. In 56% of patients in whom EEG data was available, characteristic changes were seen with or without mild clinical toxicity. Discriminant analysis identified low serum albumin concentration, high serum creatinine concentration and the presence of pelvic disease as variables which predispose patients to the development of severe encephalopathy. A nomogram has been constructed which can be used to determine the probability that an individual patient may be given ifosfamide and mesna safely. This has important implications for the clinical use of a highly active chemotherapy regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Electroencephalography; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Soft Tissue Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Cyclophosphamide; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Uterine Neoplasms

Topics: Brain Diseases; Carcinoma, Small Cell; Cyclophosphamide; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Child; Cyclophosphamide; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna