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PubMed2006

Nonconvulsive status epilepticus due to ifosfamide.

OBJECTIVE: To report 2 cases of nonconvulsive status epilepticus (NCSE) following infusion of ifosfamide. CASE SUMMARIES: Two patients who received ifosfamide-containing chemotherapy developed NCSE. One woman received ifosfamide 1000 mg/m2 (1 h infusion on days 1-5); confusion, lethargy, and speech deterioration developed on day 3. The second patient developed similar symptoms on day 3 of treatment with 2500 mg/m2. Both patients responded to intravenous administration of diazepam 10 mg and were given levetiracetam as maintenance therapy. DISCUSSION: The severity and presentation of central nervous system toxicity due to ifosfamide varies greatly and involves a spectrum ranging from subclinical electroencephalogram changes to coma. NCSE, an epileptic disorder in which typical convulsive activity is absent, has previously been reported in only 4 patients receiving ifosfamide. Levetiracetam may be used for maintenance antiepileptic therapy after diazepam administration. CONCLUSIONS: Among the many presentations of ifosfamide neurotoxicity, clinicians should consider NCSE as a possible explanation for changes in consciousness in a patient receiving this agent. An objective causality assessment by use of the Naranjo probability scale revealed that NCSE due to ifosfamide was probable.

Anticonvulsants↗
PubMed2006

Results of a phase II clinical trial on the use of ifosfamide for treatment of cats with vaccine-associated sarcomas.

OBJECTIVE: To determine clinical activity and toxic effects of ifosfamide when used to treat cats with vaccine-associated sarcoma (VAS). ANIMALS: 27 cats with a nonresectable, recurrent, or metastatic VAS. PROCEDURE: Each cat received ifosfamide (900 mg/m(2) of body surface area) as an IV infusion during a 30-minute period. Diuresis by infusion of saline (0.9% NaCl) solution and administration of mesna were used to prevent urothelial toxicosis. Treatments were administered every 3 weeks, and tumor response was assessed after the second treatment. All ifosfamide-associated toxic effects were graded in accordance with predetermined criteria. RESULTS: 61 treatments were administered to 27 cats (median, 2 treatments/cat; range, 1 to 4 treatments/cat). After ifosfamide treatment, 1 cat had a complete response and 10 had partial responses for an overall response rate of 11 of 27 (41%; 95% confidence interval [CI], 25% to 59%). Responses lasted from 21 to 133 days (median, 70 days; 95% CI, 60 to 113 days). The acute dose-limiting toxicosis was neutropenia, which was detected 5 to 28 days (median, 7 days) after treatment. Median nadir neutrophil count was 1,600 cells/muL (range, 200 to 5,382 cells/microL). Nine (33%) cats had adverse gastrointestinal effects (primarily salivation during the ifosfamide infusion and inappetence after treatment). Two cats were euthanatized because of severe nephrotoxicosis, and 1 cat developed pulmonary edema during diuresis. CONCLUSIONS AND CLINICAL RELEVANCE: Ifosfamide has antitumor activity against VAS in cats and is tolerated well by most cats. Ifosfamide should be evaluated as an adjuvant treatment for cats with VAS.

Animals↗
PubMed2002

Tumor necrosis factor-alpha and interleukin-1beta mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice.

PURPOSE: We investigated the participation of nitric oxide in ifosfamide induced hemorrhagic cystitis in mice, and the involvement of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in the induction of nitric oxide production in this model. MATERIALS AND METHODS: Hemorrhagic cystitis was induced in mice by 100 to 400 mg./kg. ifosfamide and evaluated 6, 12, 24 or 48 hours thereafter by certain parameters, including vesical edema measurements, microscopic analysis and immunohistochemical testing for inducible nitric oxide synthase. Ifosfamide injected mice were pretreated with 10 to 40 mg./kg. of the nitric oxide synthesis inhibitor L-NG-nitroarginine methyl ester, 80 mg./kg. of mesna, a chemical antagonist of acrolein and the urotoxic metabolite of ifosfamide, 50 microl. antiserum against TNF-alpha and IL-1beta per mouse, 45 mg./kg. of the selective TNF-alpha synthesis inhibitor thalidomide or 200 mg./kg. of the TNF-alpha and IL-1beta synthesis inhibitor pentoxifylline. RESULTS: Ifosfamide induced vesical edema, which peaked 12 hours after ifosfamide injection. Microscopic analysis revealed vascular congestion, edema, hemorrhage, fibrin deposition, neutrophil infiltration and epithelial denudation. Inducible nitric oxide synthase immunolocalization demonstrated intense reactivity to inducible nitric oxide synthase in the cytoplasm of bladder epithelial cells, which showed diffuse necrosis. Pretreatment with mesna reduced the increases in vesical edema, while treatment with L-NG-nitroarginine methyl ester, antiserum to TNF-alpha or IL-1beta, thalidomide or pentoxifylline inhibited vesical edema and microscopic alterations. Antiserum treatments also inhibited the expression of inducible nitric oxide synthase in the urothelium. CONCLUSIONS: Nitric oxide produced by inducible nitric oxide synthase is involved in urothelial damage and in the inflammatory events leading to hemorrhagic cystitis after ifosfamide administration in mice. The induction of inducible nitric oxide synthase in the urothelium appears to depend on the synergistic effect of IL-1beta and TNF-alpha.

Animals↗
PubMed1992

Activity of ifosfamide in breast cancer.

Ifosfamide is an alkylating agent that has clearly demonstrated efficacy against advanced breast cancer. In broad phase II trials, ifosfamide produced response rates of approximately 15% to 20%, and up to 30% in patients without exposure to previous chemotherapy. In subsequent studies, in which ifosfamide was evaluated in higher doses with mesna uroprotection in advanced breast cancer patients with or without prior chemotherapy, the combined complete and partial response rate was 28%. Ifosfamide has also been used in combination regimens. The ifosfamide/methotrexate/5-fluorouracil (IMF) combination has produced efficacy similar to that of the cyclophosphamide/methotrexate/5-fluorouracil (CMF) combination in both previously treated and untreated metastatic breast cancer. Combinations of ifosfamide/epirubicin, ifosfamide/mitoxantrone, and ifosfamide/etoposide have shown encouraging results. Response rates of approximately 70% have been obtained with regimens that include ifosfamide/doxorubicin or ifosfamide/epirubicin. The dose-limiting toxic reactions of ifosfamide, with administration of mesna uroprotection, are myelosuppression, renal tubular acidosis, and renal insufficiency. Additional studies are needed to determine the role of ifosfamide in well-defined patient subsets, to assess its cross-resistance with other alkylating agents, and to determine the slope of the dose-response curve in patients with breast cancer. Further, the role of ifosfamide in front-line combinations needs to be defined.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1976

[Chemotherapeutic activity of ifosfamide in 6 different isologously transplanted experimental tumours of BD-rats (author's transl)].

The chemotherapeutic activity of ifosfamide, applied i.v. at a high single dose, was tested on some transplantable tumours of BD-rats. As standard substance cyclophosphamide was used. The margin of safety of ifosfamide in DS-carcinosarcoma and TA-nephroblastoma was found to be wider than that of cyclophosphamide. Therefore, using massive single doses of ifosfamide, rats could be cured of DS-carcinosarcoma in higher percentage than by an analogous treatment with cyclophosphamide. Further, with a single i.v. dose of 280 mg/kg ifosfamide was it possible to cure all TA-nephroblastoma-bearing animals. The ANH-nephroblastoma, however, could not be cured even with the highest tolerable doses of ifosfamide. It was, nevertheless, possible to attain higher increase of life span over the controls than by cyclophosphamide-treatment. In some other isologous tumours ifosfamide proved to be less effective or without any activity, respectively. Pretreatment by repeated small doses of ifosfamide resulted in resistance of DS-carcinosarcoma against curative action of subsequent high single doses of this drug.

Animals↗
PubMed1989

European experience with ifosfamide in lymphomas.

In malignant lymphomas, ifosfamide-containing regimens were at first used mainly in second-line therapy and response-adapted protocols. Currently, in combination with other drugs, ifosfamide is being used in several phase-III trials. As salvage therapy in non-Hodgkin's lymphoma (NHL), IMV-Bleo (ifosfamide, methotrexate, etoposide, bleomycin) produced a complete remission (CR) rate of 41% and seemed to be particularly effective in patients with suboptimal response to first-line treatment. IBEP (ifosfamide, bleomycin, etoposide, procarbazine), in combination with procarbazine and bleomycin was an effective non-cross-resistant alternative in CHOP (cyclophosphamide, hydroxydauomycin/doxorubicin, vincristine, prednisone)-refractory NHL. In a trial of response-oriented therapy in high-grade malignant lymphoma patients, the investigators concluded that consolidation therapy was necessary even in patients with rapid response to CHOP. Patients with NHL resistant to or relapsing from conventional chemotherapy or with MOPP-ABVD (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, decarbazine)-resistant Hodgkin's disease (HD) were treated with BMV-VIP [bleomycin, plus high-dose methylprednisolone plus ifosfamide, etoposide, plus methylprednisolone]. In high-grade malignant NHL, patients received three cycles of COP-BLAM (cyclophosphamide, vincristine, procarbazine, prednisone, bleomycin, doxorubicin). Those who achieved CR received two more cycles of COP-BLAM and IMV (ifosfamide, methotrexate, etoposide) as consolidation therapy. Patients in partial remission (PR) or with less of a response to COP-BLAM were switched to IMV. After reaching CR, patients received two additional cycles as consolidation therapy. After the second restaging, patients were randomized to observation v additional radiotherapy. Of 191 patients, 148 have passed first restaging with 51% in CR; 85 went through the second restaging with 61% in CR. Of 32 patients who only reached PR after the first restaging, 15 (47%) achieved CR with IMV. For primary treatment of HD, the German Hodgkin Study Group added a third non-cross-resistant regimen, IMEP (ifosfamide, methotrexate, etoposide, prednisone), to supplement COPP (cyclophosphamide, vincristine, procarbazine, prednisone) and ABV in the primary treatment of HD. In a pilot study, 87% of 63 evaluable patients reached CR. The current phase-III protocol is comparing COPP/ABVD with fast alternating cycles of COPP/ABV/IMEP.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

European experience with ifosfamide in non-small cell lung cancer.

Ifosfamide is one of the most effective cytostatics for the treatment of lung carcinomas. For non-small cell lung cancer (NSCLC), in particular, the administration of 1.5 to 2.0 g/m2 on five successive days at intervals of 3 to 4 weeks has been found optimal. Used in combination with one or two cytotoxic agents, ifosfamide has achieved higher remission rates and longer periods of remission than single-drug chemotherapy. This result also is reflected in the longer median survival of successfully treated patients. The results of chemotherapy with ifosfamide combinations are comparable with those using cisplatin combinations. Because of considerably better tolerance, ifosfamide combinations are preferred, particularly when cisplatin is used in a moderate to high dose. At our institution, 192 untreated patients with histologically verified NSCLC were treated in three phase-II studies with different chemotherapy regimens: ifosfamide, 2 g/m2 days 1 to 5, and cisplatin, 75 mg/m2 on day 1 (study I); ifosfamide, 2 g/m2 days 1 to 5, and etoposide, 120 mg/m2 days 1 to 3 (study II); and ifosfamide, 2 g/m2 days 1 to 5, and vindesine, 3 mg/m2 on days 1 and 8 (study III). All chemotherapy combinations were repeated every 4 weeks. At least two courses of therapy were necessary to evaluate remission rate. We observed complete remissions in five patients and partial remissions in 54, for a total remission rate. of 31%. The median duration of remission was 7 months, and the time to progression was 5 months. Median survival time of all 192 patients was 8.5 months. Performance status significantly influenced the remission rate and survival time. Sex and age as well as the tumor extent and histologic type had no influence on remission. No significant differences among the three therapy regimens were seen in remission rate and survival time. The ifosfamide/etoposide combination was the preferred regimen in terms of toxicity.

Adult↗
PubMed1976

Evaluation of a cooperative clinical study of the cytostatic agent ifosfamide.

In cooperative studies performed in 21 German clinics, the new cytostatic agent 3-(2-chloroethyl)-2-[(2-chloroethyl)-amino]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (ifosfamide; trade name: Holoxan) was administered as massive-dose treatment. The studies aimed at confirming the results obtained in pharmacological and Phase I clinical trials with a fractionated administration of ifosfamide on a large scale. The study was carried out in 390 patients suffering from various malignant conditions. The majority of patients had had pretreatment without response or were admitted at an advanced stage of disease. Despite this negative selection, 25.5% of the patients showed an initial full remission and 42.3% partial remission; in 32.2% of the patients, reduction of the tumour signs by at least 50% was not attained. After an average observation period of 6 1/2 months, 53.8% of the patients were still alive. The study clearly shows the superiority of fractionated administration of ifosfamide when compared to its use as a single administration. In addition, the rates of remission and survival, and of survival times, were clearly dependent on dosage, independent of the tumour type. A daily dosage of 50 to 60 mg/kg ifosfamide on 5 consecutive days produced the best results. In spite of the fact that ifosfamide was not always given at optimum dosage, it proved to be definitely superior to conventional chemotherapy in testicular tumours, particularly teratomas and also in hypernephromas. Retrospective comparison with results of conventional chemotherapy for ovarian, bronchial and mammary cancer has shown ifosfamide to produce the same therapeutic effect in these tumour types. In this study group, leukopenia was not regarded as a limiting factor to the administration of ifosfamide. Side effects in the efferent urinary tract, particularly cystitis, were controlled with adequate preventive measures.

Adenocarcinoma↗
PubMed1996

Preliminary report on a phase I study of ifosfamide and vinorelbine (navelbine) in advanced non-small cell lung cancer.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid, and ifosfamide have each shown activity as a single agent and in various combination-chemotherapy regimens against non-small cell lung cancer. Vinorelbine usually has been given on a once-weekly schedule. We designed a phase I study adding escalating doses of vinorelbine on a novel schedule of 3 consecutive days to ifosfamide in a dose-intensive regimen with granulocyte colony-stimulating factor. The goals were to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine and to document the toxicity profile and the overall response and survival rates observed. Eligibility criteria included histologically or cytologically documented stage IIIB or stage IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 15 mg/m2) on days 1, 2, and 3 and ifosfamide at 2 g/m2 and decreased to 1.6 g/m2 on days 1, 2, and 3. Granulocyte colony-stimulating factor was administered subcutaneously at 5 micrograms/kg on days 5 through 11 in all patients. Cycles were repeated every 21 days. Forty-two patients were treated. The median age was 58 years (age range, 34 to 75 years); 41 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in two of three patients at the initial dose level of ifosfamide 2 g/m2 and vinorelbine 15 mg/m2. Ifosfamide was therefore decreased to 1.6 g/m2, and vinorelbine was subsequently escalated, with a maximum administered dose of 35 mg/m2. The recommended phase II dose was ifosfamide 1.6 g/m2 on days 1, 2, and 3 with vinorelbine 30 mg/m2 on days 1, 2, and 3, given with granulocyte colony-stimulating factor support, on a 21-day cycle. At the recommended phase II dose myelosuppression remained the most common toxic effect, with grade 3 or 4 neutropenia of brief duration occurring in 20 patients. Final analysis has not yet been completed, but responses have been observed at several dose levels. The maximum tolerated dose of vinorelbine given on days 1, 2, and 3 is 30 mg/m2 when given with ifosfamide at 1.6 g/m2 on days 1, 2, and 3 and granulocyte colony-stimulating factor support. Myelosuppression is the dose-limiting toxic effect. Future analyses of the data will report the overall response and survival rates in these patients.

Adult↗
PubMed1996

Ifosfamide in the treatment of non-Hodgkin's lymphoma.

Ifosfamide has been used extensively for the treatment of patients with non-Hodgkin's lymphoma (NHL). This review is limited to published series in which 30 or more evaluable patients were treated in a prospective, uniform fashion either with ifosfamide alone or in combination with other chemotherapeutic agents. Studies in which ifosfamide was used solely as part of a high-dose chemotherapy preparative regimen with autologous hematopoietic progenitor cell transplantation are not included. Three different applications of ifosfamide are addressed: (1) ifosfamide as a single agent and in combination chemotherapy for patients with previously treated NHL, (2) ifosfamide in combination chemotherapy for patients with newly diagnosed, aggressive NHL; and (3) ifosfamide in combination chemotherapy as consolidation for patients with aggressive NHL in first complete remission.

Antineoplastic Agents, Alkylating↗
PubMed1996

Ifosfamide in non-small cell lung cancer.

Ifosfamide is an analogue of cyclophosphamide that is active against a variety of solid tumors, including non-small cell lung cancer. In preclinical studies, ifosfamide had yielded an average response rate of 20% to 25% and a median length of survival of 4 to 5 months. With the introduction of mesna, hematologic toxicity is the major toxicity associated with ifosfamide use. Response is not affected by the schedule of drug administration, nor is the response rate compromised by oral delivery of ifosfamide. Neurotoxicity is greater with oral administration, however. Ifosfamide has been used in combination with many different agents, including cisplatin and etoposide and newer drugs like vinorelbine and paclitaxel. The results of the combination studies indicate improved response rates. However, results of randomized phase II trials suggest there may be no survival benefit with the addition of ifosfamide to establish drug combinations. Further study of ifosfamide in combination with newer drugs is appropriate.

Antineoplastic Agents, Alkylating↗
PubMed1996

Ifosfamide in the treatment of pediatric malignancies.

Neuroblastomas, nephroblastomas, malignant mesenchymal tumors, including rhabdomyosarcomas, Ewing's sarcomas, osteosarcomas, brain tumors, and non-Hodgkin's lymphomas respond to ifosfamide monotherapy. Ifosfamide has found an established place in the treatment of these pediatric malignancies. Ifosfamide has been shown to be an especially valuable agent in brain tumors in patients with a poor-prognosis medulloblastoma. The combination of ifosfamide with other cytotoxic drugs is more effective than ifosfamide medication alone. Ifosfamide has to be given with mesna to prevent bladder toxicity, but other toxic side effects, such as neurotoxicity, nephrotoxicity, and gonadal damage, are more difficult to prevent. Ifosfamide has proven to be an important asset in the treatment of cancer in children.

Antineoplastic Agents, Alkylating↗
PubMed1996

Inhibition of (mono)amine oxidase activity and prevention of ifosfamide encephalopathy by methylene blue.

The clinical application of ifosfamide is hampered by a central nervous side effect, the so-called ifosfamide encephalopathy. Methylene blue is effective in prophylaxis and reversal of this side effect. In the present study, the in vitro inhibition of (mono)amine oxidases by methylene blue is demonstrated in two different experimental systems. The results provide an explanation for the preventive action of methylene blue in ifosfamide neurotoxicity, because the generation of chloroacetaldehyde (a potential neurotoxin of ifosfamide metabolism) is prevented in liver mitochondria and extrahepatic tissues. Generation of alkylating metabolites was also studied in rat liver perfusions, and methylene blue did not show any inhibition of ifosfamide activation. From these data, we conclude that the clinical effectiveness of methylene blue in treatment and prevention of ifosfamide encephalopathy might be based on inhibition of (mono)amine oxidases. Hepatic bioactivation of ifosfamide is not influenced by methylene blue.

Alkylation↗
PubMed1996

Phase I dose-escalation trial of paclitaxel and ifosfamide in patients with advanced non-small cell lung cancer.

This phase I dose-escalation study was undertaken to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide that could be administered without growth factors to previously untreated patients with non-small cell lung cancer. Forty patients with advanced non-small cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide, repeated every 3 weeks. Groups of three patients each entered at escalating dose levels in a traditional phase I design. Starting doses were paclitaxel 100 mg/m2 and ifosfamide 3 g/m2; all patients received premedication with dexamethasone and diphenhydramine, and some also received a 5-HT3 blocker. Dose escalation was permitted only after full toxicity assessment had been completed for two cycles for all patients at a dose level. Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this dosage. Instead, ifosfamide was increased to 4 g/m2 for the final dose level. At these doses, dose-limiting myelosuppression was not seen, and there was only one episode of febrile neutropenia in 162 treatment cycles. Drug-related ifosfamide toxicities included gross hematuria and confusion in one patient each; paclitaxel-related symptoms included flu-like syndrome in most patients, arthralgia and/or myalgia in eight and 25 patients, respectively, and paresthesia in 14 patients. Despite premedication, 15 patients experienced grade 1 hypersensitivity reactions. Partial response was seen in 21% of patients (confidence interval, 9.3% to 36.5%), and the median duration of response was 5.9+ months (range, 3 to 14 months). The median survival was 9.1 months (range, 1 to 12 months). In summary, outpatient paclitaxel given over 3 hours and single-dose ifosfamide given over 1 hour may be combined safely without hematopoietic growth factors for the treatment of patients with non-small cell lung cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and ifosfamide 4 g/m2, every 3 weeks.

Adult↗
PubMed1998

Excretion kinetics of ifosfamide side-chain metabolites in children on continuous and short-term infusion.

Ifosfamide (IFO) requires metabolic activation by hydroxylation of the ring system to exert cytotoxic activity. A second metabolic pathway produces the cytostatically inactive metabolites 2-dechloroethyl-ifosfamide (2-D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release of chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion of ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m2 to 3 g/m2. The kinetics of the excretion were compared following short-term and continuous ifosfamide infusion at a dosage of 3 g/m2. IFO and side-chain metabolites were analyzed by gas chromatography, the active metabolites by indirect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59+/-15% of the applied dose could be recovered in the urine, 23+/-9% as unmetabolized IFO. The main metabolite was 3-D-IFO (14+/-4%) followed by isophosphoramide mustard (IFO-M) (13+/-4%) and 2-D-IFO (8+/-3%). Neither the total amount recovered nor the excretion kinetics of ifosfamide and side-chain metabolites showed obvious schedule dependency. The excretion kinetics of side-chain metabolites as well as unmetabolized IFO were nearly superimposable on short-term and continuous infusion. Even after 1-hour infusion there was a lag of 3 - 6 hours until dechloroethylation became relevant. Therefore, differences in toxicity and efficacy cannot be explained by an influence of the application time on the metabolic profile of ifosfamide.

Acetaldehyde↗
PubMed1991

Ifosfamide extrapyramidal neurotoxicity.

Ifosfamide-associated central nervous system toxicity has been reported in 5% to 30% of patients treated with ifosfamide. Its pattern is characterized by metabolic encephalopathy with confusion, blurred vision, mutism, auditory or visual paranoid hallucinations, seizures, and rarely coma. The biochemical cause of the neurotoxicity is not understood completely, but it is thought to result from an accumulation of drug metabolites with direct central nervous system effects. A case of ifosfamide neurotoxicity is reported that had unusual extrapyramidal features in a patient treated with a 5-day course of infused ifosfamide. Although usually spontaneously reversible with cessation of drug administration, ifosfamide neurotoxicity occasionally has been associated with prolonged psychopathologic sequelae. Death from irreversible encephalopathy has also been reported rarely. The authors believe that classic extrapyramidal symptoms should be considered to be a part of the neurotoxic profile of ifosfamide.

Adenocarcinoma↗
PubMed1992

Intradermal carboplatin and ifosfamide extravasation in the mouse.

BACKGROUND: Carboplatin and ifosfamide are new antineoplastic agents with vesicant properties that have not been determined. Vesicant activity was investigated in Balb-c mice by administering carboplatin or ifosfamide intradermally in clinically relevant concentrations. METHODS: Carboplatin concentrations tested were 15, 10, and 1 mg/ml; those of ifosfamide were 50, 20, and 1 mg/ml. Five female mice were tested with each concentration; and five animals were used as controls and received only saline. RESULTS: Carboplatin concentrations of 15 mg/ml and 10 mg/ml produced mean peak ulcer areas of 10 square millimeters (mm2) and 21 mm2 within 2-3 days of injection, respectively. The 1 mg/ml carboplatin injection was not associated with any ulcer formation. Ifosfamide at 50 mg/ml induced skin ulcerations in four of five mice, with maximal effect (19.6 mm2) by 1-2 days. Lower concentrations of ifosfamide produced no ulcerations. All ulcerative lesions healed completely within 21 days. CONCLUSIONS: These results suggest that extravasation of carboplatin at concentrations of greater than or equal to 10 mg/ml or ifosfamide at concentrations of greater than or equal to 50 mg/ml is likely to cause ulcers in humans.

Animals↗
PubMed1993

A phase II trial of ifosfamide in previously untreated children and adolescents with unresectable rhabdomyosarcoma.

BACKGROUND: Children and adolescents with unresectable rhabdomyosarcoma fare poorly when treated with contemporary chemotherapeutic regimens. Evaluation of newly developed agents in these patients is important to improve their outcome. Based on a preclinical rhabdomyosarcoma xenograft model that accurately predicted the activity of new agents, the safety and efficacy of ifosfamide was evaluated as part of a Phase II clinical trial in previously untreated children with unresectable rhabdomyosarcoma. METHODS: Twenty-two children and adolescents (median age, 9 years) with newly diagnosed unresectable rhabdomyosarcoma (Intergroup Rhabdomyosarcoma Study Group III [n = 15] or IV [n = 7]) received two courses of ifosfamide at a dose of 1.6 g/m2 intravenously for 5 days over a 6-week period. Then the patients were evaluated for response, and additional treatment with surgery, radiation therapy, and multiagent chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin) was administered. RESULTS: Nineteen of 22 patients (86%) had a partial response to ifosfamide given as a single agent. No complete responses to this agent alone were observed. After administration of additional chemotherapy and local control measures (radiation therapy and surgery), the estimated proportion of patients surviving progression-free at 2 years was 63% (95% confidence interval, 37-80%). Ifosfamide was tolerated well; the most frequent toxicity was nondose-limiting myelosuppression. Transient mild renal toxicity infrequently was observed, and no central nervous system toxicity occurred in this group of patients. CONCLUSIONS: Ifosfamide appears to have significant clinical activity in untreated patients with unresectable rhabdomyosarcomas. These findings provide an accurate estimate of the response rate to single-agent ifosfamide in this group of previously untreated patients and thus provide a foundation for its rational incorporation into multiagent clinical trials. In addition, the potential benefits of this type of new drug development were demonstrated.

Adolescent↗