Administration Of Ifosfamide Research Articles

Pharmacokinetics and efficacy of ifosfamide or trofosfamide in patients with intraocular lymphoma

Background: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has not yet been defined. The study assesses ifosfamide (IFO) and trofosfamide (TRO) for treating IOL.Patients and methods: We prospectively evaluated the efficacy and aqueous penetration of intravenous IFO, oral TRO and their active 4-hydroxy (4-OH) metabolites in 10 patients with IOL. Doses varied from 1500 to 2000 mg/m2/day on days 1–3 for IFO and from 150 to 400 mg/day (continuous or intermittent administration) for TRO. Four patients had newly diagnosed disease, and six had relapsed after pretreatment.Results: All patients responded to first treatment with IFO or TRO, and both of two patients responded to re-treatment with IFO on ocular relapse. Progression-free survival from the first treatment with IFO or TRO was ≥6–18 months. In six of six patients, 4-OH metabolites were detected in the aqueous humor at a concentration of 0.32–1.56μm immediately after IFO infusion with an aqueous/serum ratio of 0.19–0.54. 4-OH metabolites could be detected in one of three patients at a concentration of 7.2μm 3–16 h after ingestion of TRO.Conclusions: IFO and TRO are active in IOL. IOL patients evidence aqueous penetration of 4-OH metabolites after intravenous administration of IFO.

Subsieve-size agarose capsules enclosing ifosfamide-activating cells: a strategy toward chemotherapeutic targeting to tumors

Localized activation of the prodrug ifosfamide in or close to tumors by implanting encapsulated ifosfamide-activating cells is an efficacious strategy for tumor therapy. The aim of this study was to evaluate the feasibility of subsieve-size agarose capsules for enclosing the cells in this application. Compared with many conventional microcapsules, subsieve-size agarose capsules are about one-tenth the size and have both higher mechanical stability and allow better molecular exchangeability than other systems. Cells that have been genetically modified to express cytochrome P450 2B1 enzyme were encapsulated in subsieve-size agarose capsules of approximately 90 microm in diameter and implanted into preformed tumors in nude mice. Living cells were detected for >1 month after encapsulation in vitro and showed enzymatic activity (i.e., they were able to activate ifosfamide). More significant regression of preformed tumors was observed in the recipients implanted with cell-enclosing capsules compared with those implanted with empty capsules. These results suggest that the strategy of using subsieve-size agarose capsules enclosing cytochrome P450 2B1-expressing cells is feasible for tumor therapy by chemotherapeutic targeting in combination with ifosfamide administration.

Cerebral formation in situ of S-carboxymethylcysteine after ifosfamide administration to mice: A further clue to the mechanism of ifosfamide encephalopathy

The clinical use of the alkylating oxazaphosphorine ifosfamide is hampered by a potentially severe encephalopathy. S-carboxymethylcysteine (SCMC), a metabolite of ifosfamide (IF), activates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor, causes neuronal acidification, and could thus be responsible for the encephalopathy. Since the presence of SCMC in brain has not been documented following administration of IF, SCMC was measured in the brain of mice following both the individual i.p. administration of IF and SCMC. SCMC was found in a concentration of 108.2 ± 29.7 nmol/g following IF, but was detectable at much lower levels following the administration of SCMC (21.1 ± 21.2 nmol/g). Together with the observation that the concentration of SCMC was 10-fold higher in liver than in brain 1 h after administration of SCMC, these findings suggest that the SCMC found after IF was formed in the brain in situ. The concentration of glutamic acid was similar in IF and SCMC treated animals. Methylene blue, which is used clinically to treat and to prevent IF encephalopathy, did not decrease the formation of SCMC in brain. By inhibiting monoamine oxidase activity it did, however, markedly increase the concentration of serotonin in brain which could modulate the effects of SCMC on AMPA/kainate receptors. Thus, SCMC is present in brain following the administration of IF and could contribute to the IF-associated encephalopathy by activation of AMPA/kainate receptors.

Concomitant administration of high-dose methotrexate (HDMTX) and ifosfamide in osteosarcoma patients: A clinico-pharmacological study

9063 Background: HDMTX is active against osteosarcoma but is given sequentially with other anticancer agents because of the high risk of acute nephrotoxicity. We studied the feasibility of a concomitant administration of HDMTX and ifosfamide. Methods: HDMTX was given as a single agent (8–12 g/m2) on day 1 and was given on day 8 with ifosfamide. Ifosfamide was given at 2.5 g/m2/day on days 7 and 8. Thereafter, the two agents were given concomitantly every other week, in the adjuvant setting in good responders to neoadjuvant chemotherapy. Methotrexatemia was measured at H4, H24, H48 and H72 and urinary pH was verified on each miction. Creatininemia was measured on days 1, 3 and 8 after each HDMTX infusion. Results: Between 1999 and 2003, 19 patients were included (7 females, 12 males). Median age: 17 years (range: 15–19). Primary tumors were located on extremities in 15 patients. Nineteen cycles of HDMTX alone (day one) and 285 cycles of the combination of HDMTX + ifosfamide were evaluable for toxicity and for the pharmacokinetics (PK) of MTX. For each patient, the PK of HDMTX given alone was compared to its PK when given with ifosfamide. The Cmax, AUC, and renal clearance of methotrexate were not modified by concomitant administration of ifosfamide. Toxicity included manageable nausea and emesis, and severe hypokaliemia requiring potassium supplementation. In 5 cycles (1.8%) of HDMTX + ifosfamide, reversible creatininemia elevation (< 1.5 ULN) was observed. Grade 3 neutropenia occurred in 65% of patients. No grade 4 toxicity occurred. No re-hospitalisation was required. Conclusions: HDMTX can be administered with ifosfamide the same day in osteosarcoma patients. This result may allow to develop new therapeutic strategies with higher dose-intensity of active anticancer agents in the neoadjuvant setting. No significant financial relationships to disclose.

Alternating sequential chemotherapy with high-dose ifosfamide and doxorubicin/cyclophosphamide for adult non-small round cell soft tissue sarcomas

Doxorubicin and ifosfamide are the two most active agents used to treat soft tissue sarcomas. However, because of their overlapping side effects, concurrent administration to achieve optimal doses of each agent is difficult. We therefore conducted a Phase II trial to investigate the efficacy and feasibility of a novel alternating sequential chemotherapy regimen consisting of high dose ifosfamide and doxorubicin/cyclophosphamide in advanced adult non-small round cell soft tissue sarcomas. Adult patients with non-small round cell soft tissue sarcomas were enrolled. The treatment consisted of four sequential courses of chemotherapy that was planned for every 3weeks. Cycles 1 and 3 consisted of ifosfamide (14g/m2), and cycles 2 and 4 consisted of doxorubicin (60mg/m2) and cyclophosphamide (1200mg/m2). Forty-two patients (median age 47years) were enrolled. Of the 36 assessable patients, 1 complete response and 16 partial responses were observed, for a response rate of 47.2%. Responses were observed in 57% of patients who had received no previous chemotherapy and 13% of those who had previously undergone chemotherapy. Grade 3-4 neutropenia was observed during 70% of all cycles. Sequential administration of high-dose ifosfamide and doxorubicin/cyclophosphamide has promising activity with manageable side effects in patients with advanced adult nonsmall round cell soft tissue sarcomas.

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r2=0.554, P=0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean±s.d., 2736±597) than those patients in whom IFO was administered by continuous infusion (1453±730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data.

Harvest of Autologous Peripheral Blood Stem Cells Using Ifosfamide/Etoposide Regimen Combined with Granulocyte Colony-Stimulating Factor.

Aim: To make clear the feasibility of Ifosfamide/Etoposide (IE) regimen combined with granulocyte colony-stimulating factor (G-CSF) for the collection of autologous peripheral blood stem cells (APBSC), we evaluated the number of the collected CD34 positive cells, and the regimen-related toxicities.Patients' characteristics and Methods: 19 Patients (male 12, female 7) were received APBSC harvest in our hospitals during Aug. 2000 to Dec. 2003 with age of 54.3 years on average (30–66). Diagnoses were included HD (n=2), NHL (n=13), MM (n=3), and malignant synovioma (n=1). IE regimen was included with Ifomide 2000 mg/m2 (day 1), and Etoposide 200 mg/m2 (day 1–3) (4cases) or 500 mg/m2 (day 1,2) (15 cases). For the prevention of hemorrhagic cystitis patients were administered with Mesna, and NaHCO3 during and after 1 day of the administration of Ifosfamide. G-CSF was administered at the dose of 10 ug/kg (lenograstim) or 300 ug/m2 (filgrastim) when blood absolute neutrophil count came down to 1000/mm3. When the suppression of bone marrow was recovered and blood WBC count came up to 5000/m3, CD34-positive cells were counted in blood, and APBSC was harvested when blood CD34-positive cells were determined above 0.1 %. APBSC was harvested with CS-3000 plus (Fenwall).Result: The median duration from the start of the administration of G-CSF to the finish of APBSC harvest was 6.5 days (4–11). The median number of CD34-positive cells of the harvested was 4.32 x 106/kg (1.10–13.50). All cases were harvested. The toxicities during from the conditioning to the harvest were included with grade 1 headache (2 cases), grade 2 nausea (6 cases), grade 1 bleeding (1 case), grade 1 constipation (1 case), grade 1 fever (1 case), and grade 1 thrombocytopenia (1 case).Conclusion: IE regimen combined with G-CSF was feasible to harvest APBSC on the yield of the collection of the transplantable stem cells, and on the regimen-related toxicities.

Mesna ameliorates intestinal mucosa damage after ifosfamide administration in the rabbit at a dose-Related manner

Background Cancer chemotherapy may lead to mucositis, a serious dose-limiting side effect. The alkylating agent ifosfamide is used in the treatment of various forms of cancer in combination with the uroprotective thiol mesna (2-mercaptoethane-sulfonate). The aims of this study were to assess the dose response intestinal mucosa damage of ifosfamide and to investigate the potential protective effect of mesna on rabbit intestinal epithelium. Materials and methods Fifty New Zealand White rabbits were randomly assigned to 10 groups of five animals each and received intravenously every week for 10 weeks either normal saline, ifosfamide, mesna, or ifosfamide plus mesna at three escalating dose levels (ifosfamide: 30, 45, or 60 mg/kg; mesna: 12, 18, or 24 mg/kg divided into two equal doses administered 4 h apart). Intestinal mucosa damage was assessed on the basis of crypt cell apoptosis and proliferation as well as intestinal morphometry. Apoptosis was detected by agarose gel electrophoresis and quantified by the DNA fragmentation assay and a standard terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method by which the percentage of fragmented DNA and the apoptotic index were determined, respectively. The mitotic index and the crypt-villus (c/v) unit height were also measured in histological sections. Results Ifosfamide caused a dose-related increase of crypt cell apoptosis and shortening of c/v unit, while it had a steady antimitotic effect. Mesna as a sole agent had no apoptotic or trophic effect on intestinal mucosa and hence no effect on intestinal morphometry. However, mesna, when administered concurrently with ifosfamide, ameliorated apoptosis, hypoproliferation, and mucosal atrophy at a dose-related manner. Conclusions Ifosfamide causes intestinal mucosa damage, which may be ameliorated in a dose-related manner by coadministration of mesna.

Dose related effects of ifosfamide on enterocyte apoptosis in different sites of the rabbit intestine.

We investigated the potential dose related apoptotic effect of subchronic administration of the alkylating chemotherapeutic agent ifosfamide in different sites of the small and large rabbit intestine. Twenty New Zealand White rabbits received intravenously every week, for 10 weeks, 0 (group S, controls, n = 5), 30 (group A, n = 5), 45 (group B, n = 5) or 60 mg/kg ifosfamide (group C, n = 5). One day after the end of the treatment period, segments of jejunum, ileum, cecum, proximal and distal colon were excised. Intestinal mucosa apoptosis was detected by agarose gel electrophoresis and quantified by DNA fragmentation and standard terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labelling (TUNEL) assays by which the percentage of fragmented DNA and the ratio of apoptotic cells per crypt (apoptotic index) were determined, respectively. At low dose (group A), ifosfamide had minor apoptotic effect on enterocytes, which was enhanced mainly in the small intestine when the dose was increased (group B); at the highest dose tested (group C), this effect was extended to the large intestine. In all groups of animals, the observed crypt cell apoptosis was maximal in the ileum, while minimal in the proximal colon. Our results show a dose and intestinal site-dependent induction of enterocyte apoptosis after subchronic ifosfamide administration in the rabbit.

Dose related effects of ifosfamide on enterocyte apoptosis in different sites of the rabbit intestine

Objective : We investigated the potential dose related apoptotic effect of subchronic administration of the alkylating chemotherapeutic agent ifosfamide in different sites of the small and large rabbit intestine. Materials and methods : Twenty New Zealand White rabbits received intravenously every week, for 10 weeks, 0 (group S, controls, n =5), 30 (group A, n =5), 45 (group B, n =5) or 60 mg/kg ifosfamide (group C, n =5). One day after the end of the treatment period, segments of jejunum, ileum, cecum, proximal and distal colon were excised. Intestinal mucosa apoptosis was detected by agarose gel electrophoresis and quantified by DNA fragmentation and standard terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labelling (TUNEL) assays by which the percentage of fragmented DNA and the ratio of apoptotic cells per crypt (apoptotic index) were determined, respectively. Results : At low dose (group A), ifosfamide had minor apoptotic effect on enterocytes, which was enhanced mainly in the small intestine when the dose was increased (group B); at the highest dose tested (group C), this effect was extended to the large intestine. In all groups of animals, the observed crypt cell apoptosis was maximal in the ileum, while minimal in the proximal colon. Conclusions : Our results show a dose and intestinal site-dependent induction of enterocyte apoptosis after subchronic ifosfamide administration in the rabbit.

Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats.

To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for initial uroprotection.

Recurrent Atrial Ectopic Tachycardia Following Chemotherapy with Ifosfamide

In most pediatric tumors, particularly sarcomas, cyclophosphamide or ifosfamide represent essential first-line chemotherapeutic agents [1]. Whereas cyclophosphamide is known to be associated with a well-defined cardiomyopathy [2], only a few cardiac complications following ifosfamide chemotherapy have been observed to date. Here we report a patient treated for Ewing sarcoma with multiple pulmonary and osseous metastases who repeatedly developed a supraventricular tachyarrhythmia following administration of ifosfamide as part of a polychemotherapy regimen.

Side Effects of Ifosfamide

Ifosfamide is relatively well tolerated but it can be associated occasionally with life-threatening complications such as arrhythmias and heart failure, severe encephalopathy and hemorrhagic cystitis. Mesna administration can control the urothelial toxicity of ifosfamide, but it is without effect on the other complications. Other preventive measures, such as amifostine or methylene blue administration, have not yet been adequately evaluated in a sufficient number of patients. Clinicians prescribing ifosfamide, especially in high doses, should be watchful for early signs of toxicity in order to discontinue ifosfamide administration soon enough to avoid development of major toxicity.

Current role and future perspectives for ifosfamide in the treatment of malignant non-Hodgkin’s lymphoma—resultsfrom an expert meeting

In this supplemental issue of Annals of Oncology, leading experts from Australia, Europe and the USA present results from their trials using ifosfamide-containing chemotherapy regimens for the treatment of malignant non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). The relative merits of the established regimens, achievable treatment results and future perspectives for ifosfamide regimens were discussed during a workshop, held in October 2002 at Cap Ferrat, France. The expert faculty discussed practical issues related to the use of ifosfamide and mesna including suggestions for inpatient and outpatient ifosfamide regimens in combination with rituximab and guidelines for the management of possible side-effects. The practical guidelines for outpatient ifosfamide-based regimens, by fractionating the administration of ifosfamide, infusomates or oral mesna, were discussed as well. Many patients with aggressive NHL can be cured with anthracycline-containing chemotherapy regimens. The benefit of adding rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy for non-pretreated elderly patients with aggressive NHL was demonstrated in a recently published randomized trial performed by Groupe d’Etude des Lymphomes de l’Adulte (GELA) [1]. Despite this, more than half of the patients are primarily refractory or relapse and require salvage therapy. A certain subset of patients with chemosensitive disease can be cured with high-dose therapy and stem cell transplantation. Before high-dose therapy, patients usually receive combination chemotherapy regimens to establish tumor chemosensitivity and to reduce tumor bulk. It is critical that a cytoreductive regimen has a high response rate with minimal organ-related toxicities, while at the same time providing adequate collection of peripheral blood stem cells (PBSC).

Effects of single dose administration of ifosfamide on testes and semen characteristics in the rabbit

The effects on testes and semen characteristics were studied in the rabbit after a single dose administration of the chemotherapeutic agent ifosfamide. Sexually mature male rabbits received a single intravenous injection of either 0, 60, 90, 120, or 240 mg/kg body weight ifosfamide. Two phases of experimentation were conducted, lasting 1 and 18 weeks, respectively, at the end of which half of the animals from each treatment group were euthanized. Reproductive organs weighing, as well as testicular qualitative and quantitative histological examinations were performed 1 and 18 weeks post-treatment, while semen quality and libido were evaluated on a weekly basis. A decrease in the paired testes weight (90, 120, and 240 mg/kg groups) and the accessory sex glands weight (240 mg/kg group) were noted 1 week post-treatment. Although no histopathologic lesions or significant changes in the quantitative histologic examination were observed, semen quality examination revealed transient oligospermia (60, 90, 120, and 240 mg/kg groups), teratozoospermia (120 and 240 mg/kg groups), and asthenozoospermia (240 mg/kg group), which returned to normal by the 6th (60 and 90 mg/kg groups), 7th (120 mg/kg group), or 8th week after treatment (240 mg/kg group). Libido remained normal. The results suggest that ifosfamide, at a single dose, causes transient and dose-dependent depression of spermatocytogenesis (240 mg/kg), spermiogenesis (60, 90, and 120 mg/kg), and sperm maturation in the epididymis (240 mg/kg).

Tumor Necrosis Factor-α and Interleukin-1β Mediate the Production of Nitric Oxide Involved in the Pathogenesis of Ifosfamide Induced Hemorrhagic Cystitis in Mice

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. 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. 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. 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.

Ifosfamide encephalopathy presenting with asterixis

CNS toxic effects of the antineoplastic agent ifosfamide (IFX) are frequent and include a variety of neurological symptoms that can limit drug use. We report a case of a 51-year-old man who developed severe, disabling negative myoclonus of the upper and lower extremities after the infusion of ifosfamide for plasmacytoma. He was awake, revealed no changes of mental status and at rest there were no further motor symptoms. Cranial magnetic resonance imaging and extensive laboratory studies failed to reveal structural lesions of the brain and metabolic abnormalities. An electroencephalogram showed continuous, generalized irregular slowing with admixed periodic triphasic waves indicating symptomatic encephalopathy. The administration of ifosfamide was discontinued and within 12 h the asterixis resolved completely. In the patient described, the presence of asterixis during infusion of ifosfamide, normal laboratory findings and imaging studies and the resolution of symptoms following the discontinuation of the drug suggest that negative myoclonus is associated with the use of IFX.

Phase I study of twelve-day prolonged infusion of high-dose ifosfamide and doxorubicin as first-line chemotherapy in adult patients with advanced soft tissue sarcomas

PurposeTo determine whether a prolonged 12-day continuous infusion allows the administration of high-dose ifosfamide (IFO) with an acceptable toxicity profile when combined with full-dose doxorubicin (Adriamycin®; ADM) as first-line chemotherapy in patients with advanced soft tissue sarcomas. Patients and methodsEscalating doses of continuous infusion IFO (8–15 g/m2) given on days 1 to 12 in combination with ADM 75 mg/m2 given on day 8 and prophylactic granulocyte colony-stimulating factor support were administered every 4 weeks to 35 chemonaïve patients with advanced soft tissue sarcomas. ResultsThe maximum tolerated dose was IFO 15 g/m2. Hematological toxicity was the main dose-limiting toxicity and was dose dependent. Furthermore, thrombocytopenia was cumulative. Grade 4 (WHO) neutropenia and thrombocytopenia were recorded in 48% and 14% of courses, respectively. Eight patients experienced febrile neutropenia. A partial response was observed in 16 out of 30 assessable patients [53%, 95% confidence interval (CI) 25–63]; median time to progression was 25 weeks (range 4–91). ConclusionsThis study proved that a prolonged 12-day continuous infusion allows an increase in the total IFO dose that can be safely combined with ADM. A multicentric phase II study by the Italian Sarcoma Group to assess its antitumor activity is currently ongoing in patients with advanced soft tissue sarcomas.

Novel treatment for the management of ifosfamide neurotoxicity: Rationale for the use of methylene blue

Objective. To provide an overview of the proposed pathophysiology of ifosfamide encephalopathy and the role of methylene blue for the treatment and prevention of this toxicity. Data Source. A Medline search using the terms ‘‘ifosfamide encephalopathy’’ and ‘‘methylene blue’’ was conducted for the period of 1990-2001. The reference lists from retrieved articles were reviewed Data Extraction. The author reviewed the retrieved material and included animal and pharmacokinetic data related to ifosfamide and the pathophysiology of ifosfamide neurotoxicity. Additionally, preclinical data and case reports describing the clinical use and rationale for methylene blue were included. Data Synthesis. Encephalopathy is a unique toxicity described with ifosfamide, but not with cyclophosphamide. Ifosfamide undergoes a secondary ‘‘deactivation’’ metabolic pathway to yield dechloroethylated metabolites and chloroacetalde-hyde. Chloroacetaldehyde is a metabolite that contributes to both the nephrotoxicity and neurotoxicity described with ifosfamide. Chloroacetaldehyde (or a dechloroethylated metabolite) may exert neurotoxic effects by one or more of the following mechanisms: (a) direct neurotoxic damage, (b) depletion of central nervous system (CNS) glutathione level, or (c) inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism. The biochemical derangements described with this acute toxicity appear to mimic a neonatal mitochondrial disorder, for which methylene blue has been used. Methylene blue has been shown to restore and maintain mitochondrial respiration and therefore can be used to correct or prevent acute neurotoxic effects. Methylene blue has been used to treat moderate to severe cases of ifosfamide neurotoxicity and has also been used prophylactically to prevent encephalopathy in high-risk conditions with the use of oral and bolus iv ifosfamide regimens. Methylene blue may be useful in the treatment of grade III or IV neurotoxicity or in those patients with recurrent neurological symptoms associated with ifosfamide administration. The use of prophylactic or concurrent administration of methylene blue with ifosfamide requires further clinical evaluation.

Evaluation of ifosfamide for treatment of various canine neoplasms.

lfosfamide (3-[2-chloroethyl]-2[(2 chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) is an alkylating agent with a broad spectrum of antitumor activity. The efficacy and toxicity of ifosfamide were evaluated in 72 dogs with spontaneously occurring tumors. Forty dogs (56%) had lymphoma, 31 (43%) had sarcomas, and 1 had a metastatic carcinoma. Five dogs received ifosfamide at dosages <350 mg/m2 IV. Neither toxicity nor response were observed, and the remaining dogs received ifosfamide at 350 mg/m2 (n = 18) and 375 mg/m2 body surface area IV (n = 49). Saline diuresis and the thiol compound mesna were used to prevent urothelial toxicity. Fifty-two dogs had measurable tumors and could be evaluated for response. Complete responses were seen in 1 dog with metastatic leiomyosarcoma of the urinary bladder and in 1 dog with metastatic cutaneous hemangiosarcoma. One dog with lymphoma had a partial response for 112 days. Six dogs with splenic hemangiosarcoma received ifosfamide postsplenectomy and their median survival time was 147 days. The acute dose limiting toxicity was neutropenia 7 days after administration of ifosfamide. The median and mean neutrophil counts 7 days after ifosfamide at 350 mg/m2 were 2,035 cells/microL and 4,773 cells/microL, respectively (n = 12). The median and mean neutrophil counts 7 days after ifosfamide at 375 mg/m2 were 2,500 cells/microL and 3,594 cells/microL, respectively (n = 37). No dog developed clinical or microscopic evidence of hemorrhagic cystitis. Ifosfamide appears safe to use in tumor-bearing dogs, and the evaluation of combination chemotherapy protocols that include ifosfamide should be considered.