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PubMed2001

Ifosfamide, paclitaxel and cisplatin first-line chemotherapy in advanced, suboptimally debulked epithelial ovarian cancer.

BACKGROUND: The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS: Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m(2), as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m(2) intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m(2) intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 microg/kg/day on Days 7-11. RESULTS: Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION: The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens.

Adult↗
PubMed1994

Ifosfamide-induced subclinical nephrotoxicity and its potentiation by cisplatinum.

Renal function was assessed in 72 children and adolescents 3.5 to 123 months after completion of chemotherapy employing ifosfamide (n = 39) or ifosfamide plus cisplatinum (n = 33). No patient had preexisting renal parenchymal disease. Whereas reduction in glomerular filtration rate was present in six of 69 patients (8.7%), impairment of tubular transport for phosphate, glucose, and amino acids was more frequent: 32.8% of the patients showed reduction in phosphate reabsorption, and glucose and amino acid reabsorption was lowered in 16.4% and 55.0%, respectively. Elevated sodium excretion was found only occasionally, and there was no evidence of renal tubular acidosis. Proximal tubular damage is related to ifosfamide chemotherapy, but correlation between ifosfamide dose and phosphate reabsorption was not linear. The most severe depletion of phosphate reabsorption was seen in patients treated with both ifosfamide and cisplatinum. On reexamination of phosphate reabsorption after a median interval of 8 months, the majority of patients with initially reduced values showed further deterioration of this function.

Adolescent↗
PubMed2007

Growth impairment after ifosfamide-induced nephrotoxicity in children.

BACKGROUND: The goal of this study was to analyze long-term consequences of ifosfamide-induced nephrotoxicity on growth and renal function in children treated for cancer. PROCEDURE: In a retrospective study, departments for pediatric oncology and nephrology in Germany, Austria, and Switzerland were asked to report patients with serious long-term nephrotoxicity after ifosfamide-treatment. Data at first appearance of renal dysfunction and at the last renal examination were collected using a standardized questionnaire. RESULTS: Fifty-nine patients with tubulopathy (35 severe, 24 moderate) following ifosfamide therapy were eligible for analysis of long-term outcome (median follow-up 4 years, range 1.1 to 12.9). Median height standard deviation score was significantly reduced at renal diagnosis, and at last renal examination (-1.7 and -2.1 respectively, P < 0.01 at each point in time). Patients with tubulopathy also had stunted growth in comparison with a control group of cancer patients without renal disease (mean difference at last examination: 7.3 cm (95% confidence interval: 2.5 to 12.1 cm). In patients with severe tubulopathy, glomerular filtration rate deteriorated significantly over time. End-stage renal disease was reported in one patient only, not solely caused by ifosfamide. CONCLUSION: Depending on the extent of tubular dysfunction, patients with ifosfamide-induced nephrotoxicity experienced significant growth impairment and a slow decline in glomerular filtration rate.

Adolescent↗
PubMed1994

A phase II trial of ifosfamide and mesna in patients with advanced or recurrent mixed mesodermal tumors of the ovary previously treated with platinum-based chemotherapy: a Gynecologic Oncology Group study.

A phase II trial of ifosfamide and mesna in women with mixed mesodermal tumors of the ovary who had previously received platinum-containing chemotherapy was conducted by the Gynecologic Oncology Group (GOG). The starting dose of ifosfamide was 1.2 g/m2 daily iv for 5 days. Mesna was given intravenously with and at 4 and 8 hr following the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Thirty-two patients were placed on the study; 31 were evaluable for toxicity and 28 for response. Twenty-seven patients (87.1%) had previously undergone surgery and three (9.3%) had received radiotherapy before this trial. GOG grade 3 or 4 granulocytopenia occurred in 11 (35.5%) patients, and one (3.2%) developed grade 4 thrombocytopenia. Two patients (6.4%) had grade 3 neurotoxicity. A complete response was observed in one patient (3.6%) and partial responses in four patients (14.3%) for a total response rate of 17.9% (95% confidence interval = 6.1-36.9%). In conclusion, ifosfamide has activity in previously mixed mesodermal tumors of the ovary.

Adult↗
PubMed2001

Phase I trial of ifosfamide and 24-h infusional paclitaxel in pelvic malignancies: a Gynecologic Oncology Group study.

OBJECTIVE: The goal of this work was to develop a combination chemotherapy regimen consisting of ifosfamide and paclitaxel to be evaluated in the management of gynecologic malignancies. METHODS: The Gynecologic Oncology Group conducted a Phase I trial of the regimen, initially with paclitaxel (24-h infusion) delivered on Day 1 and ifosfamide (1 h) administered (with Mesna) over the subsequent 4 days. All patients received granulocyte colony-stimulating factor (G-CSF) starting 24 h after the Day 5 chemotherapy. Treatment was repeated on a 28-day schedule. A cohort of patients also received the alternate sequence of ifosfamide (4 days) followed by paclitaxel. RESULTS: Twenty-two patients were evaluated. Even at the lowest dose level tested (paclitaxel 135 mg/m(2) followed by ifosfamide 1 g/m(2)/day x 4 days) grade 4 neutropenia was almost universal, despite the routine use of G-CSF. The alternate drug administration sequence resulted in marrow suppression of similar severity. CONCLUSION: The combination of 24-h infusional paclitaxel with ifosfamide delivered over 4 days results in severe neutropenia, despite the administration of G-CSF, and is not recommended for further evaluation. In view of the known activity of the two agents in several malignancies, including cervix cancer, it would be reasonable to investigate the delivery of the agents employing alternative treatment schedules predicted to result in less severe marrow suppression (e.g., 3-h infusional paclitaxel).

Adult↗
PubMed1989

A dose escalation study of carboplatin and ifosfamide in advanced ovarian cancer.

A dose escalation study of carboplatin (CBDCA) and ifosfamide was carried out in 35 patients with advanced ovarian carcinoma to determine the toxicity and therapeutic effect of this combination. In all, 13 patients had recurrent ovarian carcinoma, 11 had abdominal carcinomatosis of probable ovarian origin and 9 had newly diagnosed stage III/IV ovarian cancer. Myelosuppression was the major dose-limiting toxicity. At a dose of 400 mg/m2 CBDCA plus 5,000 mg/m2 ifosfamide, 61% of courses were associated with grade 3 leukopenia and 27%, with grade 3 thrombocytopenia. The lowest leukocyte and platelet counts occurred at a median of 14 days after treatment and cytopenia persisted for a median of 8 days. Myelotoxicity was cumulative with successive courses at this dose level, whereas at a dose of 400 mg/m2 CBDCA plus 4,000 mg/m2 ifosfamide it was possible to deliver the planned six courses of treatment. No other untoward toxicities were observed. A clinical response was achieved in 16/33 patients (49%), with 10 complete remissions (CRs), of which 3 were pathologically confirmed at laparotomy. No significant dose-response relationship was demonstrated in this heterogeneous group of patients. The predicted median duration of response is 12 months. CBDCA plus ifosfamide is an active combination therapy for ovarian cancer that merits further comparison with CBDCA alone. The recommended doses for six courses are 400 mg/m2 CBDCA plus 4,000 mg/m2 ifosfamide.

Antineoplastic Agents↗
PubMed1986

Ifosfamide by bolus as treatment for advanced non-small cell lung cancer.

Ifosfamide at 5 g/m2 was given as a bolus to 48 patients with advanced progressing non-small cell lung cancer. Mesna (5 g/m2) was also given with the ifosfamide, both over 30 min. Further mesna was then given p.o. (3 g/m2) at 4, 8, and 12 h. If oral mesna was not acceptable then one or, if necessary, two 4-h to 6-h infusions (3 g/m2) were administered. A maximum of six courses at 3-weekly intervals was prescribed. A total of 174 courses was administered, and oral mesna was given during 64 courses: discharge was considered possible within 8-10 h after 55% of courses. Haematological toxicity was mild and no renal dysfunction was noted. Two patients became drowsy shortly after ifosfamide, but recovered 24-36 h later. The objective response rate was 29%, with one complete responder. A further 31% of patients (symptomatic responders) with stable disease symptomatically improved after the chemotherapy, by 20 or more points on the Karnofsky scale. The median survival was 5 months for the whole group, and 8 months each for the objective and symptomatic responder groups. Most patients' Karnofsky and respiratory scores improved with the chemotherapy. Ifosfamide with mesna can be given by short infusions, and the mesna given p.o. prevents any urothelial toxicity. Further exploration of short-infusion ifosfamide and mesna therapy would reduce hospitalization and allow for day-case regimens.

Adult↗
PubMed1990

Treatment of metastatic breast cancer with the combination of ifosfamide, epirubicin and 5-fluorouracil.

An ongoing trial of combination chemotherapy using ifosfamide (Holoxan), epirubicin and 5-fluorouracil was started in 1987. A total of 30 patients with metastatic cancer of the breast received 1.5 g/m2 i.v. ifosfamide over 60 min on days 1-3, 50 mg/m2 i.v. epirubicin on day 1 and 500 mg/m2 i.v. 5-fluorouracil on day 1, followed by mesna (Uromitexan) given at 20% of the ifosfamide dose at 0, 4 and 8 h. The courses were repeated every 4 weeks. In all, 198 courses were given, ranging from 3 to 13 (median, 7) cycles/patient. The mean age of the 30 patients was 48 years (range, 35-66 years); 5 had not previously received chemotherapy and the others had failed prior cytotoxic and endocrine therapy. Overall, 28 patients were evaluable, 7 (25%) showed a complete response and 15 (54%) had a partial response, for an overall response rate of 22/28 (79%). Three patients showed stable disease with improved symptoms, and in three cases disease progression occurred. The median duration of response was 9 months (range, 3-20 months). Median survival was 11 months for all patients, 15 months for CRs, 10 months for PRs, 6 months for stable disease and 12 months for progressive disease (PD). Survival for the 22 responding patients was 12 months. Toxicity was acceptable and included alopecia, mucositis, nausea, vomiting, diarrhoea, mild cystitis and myelosuppression. Epirubicin did not appear to produce cardiac toxicity, and ifosfamide with mesna did not seem to result in severe urotoxicity. Chemotherapy with ifosfamide, epirubicin and 5-fluorouracil proved to be effective for treatment of advanced breast cancer and should be further studied in large, controlled trials.

Adult↗
PubMed1992

Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors.

From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m2/day with cis-platin 20 mg/m2/day for 5 days and etoposide 75 mg/m2/day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m2 IV push prior to ifosfamide and then 1200 mg/m2/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients - grade 1, 4 patients - grade 2, and 7 patients - grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 - grade 1 and 2 - grade 3) (p < 0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p < 0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.

Acetylcysteine↗
PubMed1995

A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficiency and simplified administration.

Chemotherapy with oxazaphosphorines, such as ifosfamide, is often limited by unacceptable urotoxicity. Without uroprotection hemorrhagic cystitis becomes dose-limiting. Mesna, a thiol compound, is a drug able to bind the toxic metabolites, forming nontoxic compounds in the urine. A total of 122 patients were enrolled in this study and 228 chemotherapy cycles with an ifosfamide-containing regimen were performed (225 evaluable). Mesna was given at the same total dose as the ifosfamide in all arms. On arm A, mesna was given i. v. in equal doses 15 min before and 4 h and 8 h following the ifosfamide dose. On arm B, mesna was given in three equivalent doses 15 min before (i.v.) and 4 h (i.v.) and 8 h (p.o., double dose) following ifosfamide. On arm C, mesna was given i.v. in two equal doses given 15 min before and 4 h following. The incidence of urotoxicity was very low (lower than 15%) in the three arms, 0% in A, 1.36% in B and 2.70% in C. All three arms were equally efficient. Schedule C was considered superior to the others, since it was equally effective, simpler and more convenient.

Adolescent↗
PubMed1995

Ifosfamide treatment as a 10-day continuous intravenous infusion.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Adult↗
PubMed1990

The effect of route of administration and fractionation of dose on the metabolism of ifosfamide.

The measurement of urinary ifosfamide, isophosphoramide mustard, dechloroethyl ifosfamide and carboxyifosfamide using high-performance thin-layer chromatography with photographic densitometry (TLC-PD) is described. This technique was also used to demonstrate the large inter-individual variation in the ifosfamide metabolic profile of patients receiving the drug as single-agent therapy for non-small-cell lung cancer. In addition, oral administration was shown to result in higher levels of these metabolites in the urine. Fractionation of the ifosfamide dose over several days resulted in increasing levels of metabolites in the urine, consistent with auto-induction of ifosfamide metabolism.

Administration, Oral↗
PubMedDate not supplied

Gender difference in ifosfamide metabolism by human liver microsomes.

Pharmacokinetic gender-dependent differences in cytochrome P450-mediated drug metabolism, especially CYP3A4, and their clinical implications are increasingly apparent. CYP3A4 seems to be the most important CYP isoform in both bioactivation and N-dechloroethylation of the alkylating prodrug ifosfamide, but informations about possible gender-related differences are lacking. Therefore we compared in 10 male and 10 female liver microsomal preparations the contents and activities of specific isoenzymes, involved in both metabolic pathways, especially CYP3A4, further CYP2A6, CYP2C9 and CYP2B6 and measured the in vitro activities of these microsomes in the ifosfamide 4-hydroxylation and N-dechloroethylation using high-sensitive HPLC/MS and -UV detection methods. Statistically significant differences between male and female livers were found in the mean CYP3A4 contents and activities. These differences had no consequences on the ifosfamide 4-hydroxylation activities of liver microsomes in vitro. In contrast, in the ifosfamide N-dechloroethylation reaction we found a statistically significant difference between the liver microsomes of male and female patients (0.13 +/- 0.05 nmol/min nmol P450 vs. 0.28 +/- 0.13 nmol/min x nmolP450, respectively). In conclusion, we firstly demonstrated such gender-related difference in the ifosfamide N-dechloroethylation, which could result in a higher risk of partly severe neurotoxic side effects in female patients.

Adult↗
PubMed1996

Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy.

In cancer chemotherapy with ifosfamide the occurrence of a drug-related encephalopathy represents a severe adverse-effect of unknown origin. We found that the underlying mechanism resides in the mitochondrial toxicity of ifosfamide metabolites. The electron accepting drug methylene blue can substitute for the demonstrated flavoprotein deficiency and its administration leads to resolution of the encephalopathy in patients. The prophylactic administration of methylene blue is equally effective via another principal mechanism, namely oxidation of the excessive quantity of NADH formed during ifosfamide metabolism. The inhibition by methylene blue of multiple amine oxidase activities also prevents formation of the neurotoxic chloroacetaldehyde from ifosfamide-derived chloroethyl amine. Thus, methylene blue exhibits several synergistic modes of actions which enable the dose-limiting neurotoxicity of alkylating chemotherapy with ifosfamide in cancer patients to be overcome.

Administration, Oral↗
PubMed2001

Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide and metabolites after a 72-h continuous infusion in patients with soft tissue sarcoma.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. METHODS: Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. RESULTS: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.

Adult↗
PubMed2005

Identification of biliary metabolites of ifosfamide using 31P magnetic resonance spectroscopy and mass spectrometry.

Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19+/-1.47 mM; mean+/-sd), carboxyifosfamide (2.04+/-1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05+/-2.38 mM). The unknown resonance was identified using liquid chromatography-mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW=531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of +/-drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.

Animals↗
PubMed1997

Combined intravenous and oral mesna in outpatients treated with ifosfamide.

PURPOSE: To prevent hemorrhagic cystitis, mesna is typically injected intravenously (i.v.) at the time of an ifosfamide dose and 4 and 8 h later. To simplify outpatient ifosfamide therapy, we gave the second and third mesna doses orally. METHODS: The mesna doses (400 or 600 mg/m2) were 40% (w/w) of each ifosfamide dose (1.0 or 1.5 g/m2), which was given daily for 5 days. We evaluated urinary mesna excretion and plasma concentrations in ten patients from the beginning of mesna infusion until the time of the second oral dose. The first oral dose was administered at hour 2 in the last six patients to allow time for absorption of mesna. RESULTS: The rate and amount of mesna excretion was less variable over time and among patients after oral than after i.v. administration. No macrohematuria was observed in these ten patients nor in an additional 50 patients given oral mesna at hours 2 and 8 during at least two cycles of ifosfamide therapy. CONCLUSION: These pharmacokinetic and clinical efficacy data support the use of a combined regimen of i.v. and oral mesna to simplify outpatient ifosfamide administration.

Administration, Oral↗
PubMed1998

Use of mesna to prevent ifosfamide-induced urotoxicity.

The purpose of this study was to make evidence-based recommendations regarding the mode, dosage and schedule of delivery of concomitant mesna (sodium-2-mercaptoethanesulfonate) to protect against ifosfamide-induced uroepithelial toxicity. A critical review of the literature from 1966 to 1996 was undertaken on mesna administration via the intravenous, oral, or combined modality routes. Outcome measures of urinary symptoms and macrohematuria were emphasized, since these endpoints of urotoxicity are most clinically relevant. The quality of evidence obtained from published clinical research was evaluated based on guidelines developed by the Canadian Task Force on the Periodic Health Examination. Recommendations are now made according to the strength of available evidence on the proper usage of mesna as a protective agent against ifosfamide-induced urotoxicity. There is good evidence that the use of mesna significantly reduces urinary symptoms of dysuria and frequency, as well as the incidences of macrohematuria and microhematuria, when administered concurrently with any dosage of ifosfamide regardless of tumor site. Mesna, given intravenously or orally, is superior to standard prophylaxis with vigorous hydration and alkalinization of urine. A commonly used schedule of intravenous mesna involves a dose equal to 60% of the total ifosfamide dose, divided into three aliquots and administered at 0 h, 4 h and 8 h after ifosfamide. Combined oral and intravenous mesna delivered in some tested schedules is equivalent to intravenous mesna alone, but the optimal schedule and dosage of combined formulation have not yet been established. There is fair indirect but no direct evidence that oral mesna alone is equivalent to intravenous mesna or combined modality use. Further research issues, such as patient compliance with oral mesna and other routes of mesna delivery, are discussed. Ongoing study in the appropriate use of mesna is needed to maximize its value as a uroprotective agent in the clinical setting.

Antineoplastic Agents, Alkylating↗