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PubMed1985

Sequential studies of rat urinary bladder epithelial lesions induced by ifosfamide (Z4942).

Urinary bladder damage caused by ifosfamide in male F344 rats was studied by light microscopy and scanning electron microscopy. Ifosfamide was injected intraperitoneally at doses of 30, 60 and 120 mg. per kg. body weight, and rats were killed at several intervals following treatment. The changes in the epithelium observed by light microscopy and scanning electron microscopy following ifosfamide injection were compared to those observed following cyclophosphamide injection. Necrosis and exfoliation of the urinary bladder epithelium occurred after day 1 of ifosfamide treatment and were followed by regenerative hyperplasia. This hyperplasia was reversible. A dose response was evident in the number and size of lesions induced and the time of regeneration and repair. Scanning electron microscopy disclosed short, uniform microvilli on the luminal surface of cells during the early phases of hyperplasia. These microvilli persisted for only 1 day, from days 1 to 7, and days 1 to 12 respectively, following injection of 30, 60 and 120 mg. per kg. of ifosfamide. The hyperplastic lesions also contained cells with pleomorphic microvilli and ropy or leafy microridges on their surfaces. These findings after ifosfamide administration were similar to those reported to be induced in the urinary bladder by cyclophosphamide.

Animals↗
PubMed2000

Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites.

Nephrotoxicity is a limiting factor in the use of ifosfamide in children. Despite the co-administration of uroprotective agents such as sodium 2-mercaptoethanesulfonate (mesna), ifosfamide chemotherapy is associated with nephropathy characterized by glomerular toxicity and Fanconi syndrome in many children treated with this drug. This is in distinction to cyclophosphamide, an analogue which differs solely by the position of a chloroethyl group, and which is not associated with nephrotoxicity. We hypothesized that ifosfamide is metabolized by cytochrome P450 (CYP) enzymes located in the renal tubular cell to the toxic metabolite chloroacetaldehyde; and, that the higher production of chloroacetaldehyde from ifosfamide than from cyclophosphamide explains the clinical differences in nephrotoxicity. We found that in both pig renal cortical microsomes and whole human kidney microsomes incubated with 1 mM ifosfamide for 3 hr, 2 and 3 dechloroethylifosfamide (DCEI) were produced. Our study provides evidence that porcine and human kidney microsomes are capable of biotransforming ifosfamide to DCEI metabolites that are produced in equimolar amounts with chloroacetaldehyde, indicating that chloroacetaldehyde is locally produced by renal cells as a possible mechanism for nephrotoxicity.

Animals↗
PubMed1996

Risk factors for ifosfamide nephrotoxicity in children.

BACKGROUND: Risk factors for long-term nephrotoxicity after ifosfamide for childhood cancers are not fully known. We have studied patient-related and treatment-related risk factors for chronic ifosfamide nephrotoxicity. METHODS: A group of 23 children who had received ifosfamide at age 2.1-16.2 years (median 6.9) for various cancers were assessed for nephrotoxicity, at 1-28 (2) months after the end of treatment, by renal function testing, laboratory values, and a grading score (none, mild, moderate, severe). No patient had received cisplatin or undergone nephrectomy. 13 children were reassessed at 10-26 (23) months; eight had died and two were not evaluable. The median total ifosfamide dose was 100.8 (9.0-160.4) g/m2 over a median of 15 courses every 3 weeks as a 48-72 h continuous intravenous infusion (in 22 cases), with mesna and hydration. FINDINGS: Glomerular filtration rate was below normal in ten (45%) of 22 evaluable children; their rate was 61-85 mL/min per 1.73 m2. Proximal tubular toxicity led to hypophosphataemic rickets and/or renal tubular acidosis in six children, and distal tubular toxicity caused nephrogenic diabetes insipidus in one. Of the risk factors analysed by multiple regression, only total ifosfamide dose was associated with proximal tubular toxicity. Only two of ten evaluable patients who received under 100 g/m2 developed moderate nephrotoxicity, whereas six of ten who received over this dose had moderate or severe nephrotoxicity. INTERPRETATION: High total ifosfamide dose was the only risk factor we identified. Although inter-patient variability was high, cumulative doses of 100 g/m2 or higher should be avoided in children with cancer.

Adolescent↗
PubMed1996

Partitioning of ifosfamide and its metabolites between red blood cells and plasma.

A recently developed GC-MS analytical method for the quantitative determination of oxazaphosphorines and their metabolites in blood plasma, using stable trifluoroacetyl derivatives and electron capture negative chemical ionization detection, was applied to measure the partitioning of the antitumor drug ifosfamide and its metabolites between plasma and red blood cells for four cancer patients. The separation of a constant volume of red blood cells was performed using a special instrument, MESED, through centrifugation of blood samples. The measured compounds were ifosfamide, 2- and 3-dechloroethylifosfamide, 4-ketoifosfamide, carboxyifosfamide, ifosfamide mustard, 2-chloroethylamine and 1,3-oxazolidin-2-one. Concentration-time profiles for the metabolites in the two blood fractions and partitioning factors between erythrocytes and plasma were obtained. For ifosfamide itself, and metabolites with an intact ring system, a partitioning factor between 1 and 2 was observed for the concentration ratio between red blood cells and plasma in the patients studied. However, for the compounds with an open structure, carboxyifosfamide and ifosfamide mustard, partitioning factors higher than 3 were obtained. The active antitumor metabolite ifosfamide mustard showed a strong preference for the red blood cells in the measured patient samples. This means that erythrocytes may play an important role in the transport and the subsequent release of the active alkylating agent to the tumor cells.

Erythrocytes↗
PubMed1996

Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines.

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer.

The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m(2) intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m(2)/day to 2750 mg/m(2)/day as a continuous infusion from day 1-3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m(2) on day 1 and ifosfamide 2750 mg/m(2)/day on days 1-3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m(2) on day 1 and ifosfamide 2500 mg/m(2)/day continuous infusion on days 1-3.

Adenocarcinoma↗
PubMed1995

Evaluation of ifosfamide plus mesna as first-line chemotherapy in women with metastatic breast cancer.

Ifosfamide is an oxazaphosphorine analogue of cyclophosphamide with proven activity in breast cancer but substantial urotoxicity. The introduction of mesna as a uroprotective agent provided a stimulus for reexamination of ifosfamide for therapy of women with metastatic breast cancer. Twenty women with measurable (18 patients) or evaluable (2 patients) disease were entered into a phase II clinical trial of ifosfamide plus mesna as first-line chemotherapy. Ifosfamide was administered i.v. at a dose of 1,800 mg/m2 in 1 L D5W over 2 h on five consecutive days. Mesna was administered i.v. at a dose of 400 mg/m2 over 15 min immediately before and 1 h after ifosfamide, and then every 4 h for three more doses. The last three doses could be given either i.v. or orally. The planned cycle length was 28 days. Three patients (15%), all with measurable disease, achieved a partial response (95% confidence interval: 3 to 38%). Median time to progression was 137 days and median survival was 407 days. Toxicities included cumulative myelosuppression and substantial nausea and emesis. Four patients were removed from treatment because of toxicity alone and a fifth refused further therapy. We conclude that ifosfamide, plus mesna, as given in this protocol has definite but limited antitumor activity and poor tolerability.

Aged↗
PubMed2003

Neurological toxicity of ifosfamide.

Ifosfamide is an alkylating agent with well-demonstrated efficacy against a large number of malignant diseases. With cyclophosphamide it shares a toxicity profile characterized by myelosuppression and urotoxicity, but ifosfamide has additionally disclosed adverse neurological effects. Ifosfamide-related central nervous system toxicity is characterized by metabolic encephalopathy of varying severity. Symptoms have been reported in 5-30% of all patients treated with ifosfamide. The mechanism of ifosfamide-related central nervous system toxicity has not been fully elucidated, although the symptoms have most often been noted when the drug is given at high doses or administered orally. The neurotoxicity is generally self-limiting and reversible between 48 and 72 h after discontinuation of ifosfamide, although fatal sequelae have been reported. Therapeutic options are now available.

Acetaldehyde↗
PubMedDate not supplied

Phase II study of high-dose ifosfamide as a single agent and in combination with cisplatin in the treatment of advanced and/or recurrent squamous cell carcinoma of head and neck.

152 patients with histologically proven squamous cell carcinoma of the head and neck (advanced and/or recurrent) were treated with a single drug therapy of ifosfamide 1.5 g/m2 by intravenous drip for half an hour in 125 ml of dextrose saline for 5 days and mesna 20% of the total ifosfamide dose in 3 doses for 5 days, or in combination with cisplatin 10 mg/m2 by intravenous infusion for 5 days following the ifosfamide drip. The courses of treatment were repeated at the interval of every 4 weeks, and a total of 3 cycles was given. Out of 152 patients 64 received ifosfamide alone, and 88 received ifosfamide with cisplatin. 6 complete and 25 partial remissions (total response 53%) were observed in 58 evaluable patients of the ifosfamide group, and 10 complete and 40 partial remissions (total response 65.7%) were observed in 76 evaluable patients of the combination group. Nausea, vomiting, alopecia and leucopenia were experienced by all patients.

Adolescent↗
PubMedDate not supplied

Ifosfamide and etoposide in previously treated patients with advanced breast cancer.

AIMS AND BACKGROUND: Ifosfamide is an active alkylating agent in the treatment of breast cancer, as a first-line therapy and in advanced disease. Since the combination of etoposide with an alkylating agent produces a synergistic and tolerable activity in various malignancies, in the present study, ifosfamide and etoposide were administered to patients with advanced breast cancer to evaluate the response characteristics and the toxicity profile. STUDY DESIGN: The combination of ifosfamide, mesna and etoposide was prospectively administered to 41 previously treated patients with stage IV breast carcinoma. The treatment schedule consisted of ifosfamide, 1500 mg/m2, infused over 24 hrs with 1500 mg/m2 mesna on days 1 to 5 and 120 mg/m2 etoposide, infused over 1 hr on days 1 to 3, to be repeated every 4th week. RESULTS: After a median follow-up of 10 months, an objective response rate of 23% (overall 2.5% complete remission and 20.5% partial remission) and a median response duration of 5.3 months were obtained in 39 assessable patients. The non-responder group consisted of 28.3% stable disease and 48.7% progressive disease. The prior status of chemotherapy was the only significant prognostic factor with an impact on the response rate. The overall toxicity was generally mild, with grade 3 myelotoxicity encountered in 25.7% of patients. CONCLUSIONS: The tolerable side effect profile of the ifosfamide and etoposide combination might be advantageous as regards the quality of life. To improve the rate and/or the duration of response and to clarify the precise role of the ifosfamide-etoposide combination in previously treated advanced breast cancer, further trials are warranted.

Adult↗
PubMedDate not supplied

Increasing dose of continuous infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4'-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients. METHODS: Treatment consisted of epidoxorubicin, 60 mg/m2 days one and two, and ifosfamide, 1.5 g/m2 every 12 hrs as a 72-hr infusion, at the first level. Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program. G-CSF 300 microg/die was administered from days +7 to +14. Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of > or =5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients had to complete at least 2 consecutive cycles, and MTD was defined as the level in which 20% of patients developed a DLT; 10-15 patients were entered in each level. RESULTS: First level: overall, 13 patients entered, 3 were not assessable for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients. Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84 hrs. Eight patients of 29 assessable for response achieved an objective response: 1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%). CONCLUSIONS: If we accept 4-day G4 leukopenia as a reliable cutoff for safety, ifosfamide intensification cannot be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines.

Adult↗
PubMed1995

Ifosfamide-induced Fanconi syndrome.

OBJECTIVE: To report a case of possible ifosfamide-induced Fanconi syndrome in and adult with cancer. CASE SUMMARY: A 20-year old man was treated for an osteosarcoma with a chemotherapy regimen that included ifosfamide, methotrexate, and doxorubicin. Three months after completing therapy he developed polyuria, polydypsia, and bilateral ankle pain. Laboratory findings showed decreased serum concentrations of phosphorus, uric acid, calcium potassium, and bicarbonate; elevated blood urea nitrogen and creatinine; and increased urinary excretion of phosphorus, potassium, calcium, citrate, and protein. The patient was diagnosed with Fanconi syndrome and osteomalacia. Treatment with oral supplements of potassium, sodium, citric acid, calcium, and calcitriol corrected the electrolyte abnormalities. DISCUSSION: The adverse effect most frequently associated with ifosfamide is hemorrhagic cystitis. The incidence of hemorrhagic cystitis is decreased with the concomitant administration of the uroprotective agent mesna. The development of Fanconi syndrome after ifosfamide therapy has been described previously, although it occurs more frequently in children than adults. the mechanism by which ifosfamide causes renal tubular damage is not well understood, but it appears to involve metabolites of the drug. CONCLUSIONS: The development of renal tubular defects and renal failure should be considered in patients receiving ifosfamide. Although this complication appears more frequently in children, adults also can be affected. Renal function should be monitored closely to detect the appearance of this adverse effect. Renal tubular dysfunction can, as this case illustrates, develop months after completing chemotherapy.

Adult↗
PubMed1991

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Adult↗
PubMed1993

An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.

PURPOSE AND METHODS: Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin. RESULTS: Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis. CONCLUSION: In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.

Adolescent↗
PubMed2002

Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Eligible women were randomized to receive either cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable. RESULTS: There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P =.013) and a lower risk of death (P =.009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities. CONCLUSION: The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer.

Adult↗
PubMed1998

Ifosfamide: new idications-new dose strength. Limited evidence of effectiveness.

In three new approved indications (non Hodgkin's lymphoma, Hodgkin's lymphoma and acute lymphoblastic leukaemia) and in three previously existing indications (ovarian cancer, soft tissue sarcomas and osteogenic sarcomas), non comparative trials show that ifosfamide can induce tumour regression in patients who relapse after a first course of chemotherapy (sometimes containing cyclophosphamide). But clinical assessment has not yet formally demonstrated that this leads to a significant increase in survival time and/or quality of life, mainly because of toxicity. In cervical cancer, a new indication, a comparative trial shows higher tumour response rates with the ifosfamide + cisplatin combination than with cisplatin alone. However, the greater toxicity of the combination and the lack of any increase in survival must both be taken into account. In breast cancer and lung cancer comparative trials show no difference in efficacy between cyclophosphamide and ifosfamide, while toxicity may be worse with ifosfamide. Ifosfamide has no specific value in these approved indications. The same applied to ENT cancer, against which ifosfamide seems to have little activity.

Adult↗
PubMed1999

[High-dose ifosfamide in patients with stage IV non-small cell lung cancer: phase II trial from the Groupe français de pneumo-cancérologie (GFPC)].

PURPOSE: To assess the toxicity and efficacy of high dose ifosfamide in stage IV NSCLC. METHODS: In a previous trial, we have determined maximum tolerated dose for 3-days ifosfamide treatment by 3-weeks schedule as 9 g/m2 according to hematologic tolerance. We therefore set up a phase II to study the toxicity and efficacy of this schedule in chemotherapy naive metastatic NSCLC. Ifosfamide (+ mesna 1 g/m2) was administered by a two hour infusion (3 g/m2) for three days every three weeks. Patients received three mesna bolus infusions (1 g/m2) at 4, 8 and 12 hours after the end of ifosfamide infusion. Antitumoral efficacy was performed after 2 cycles and treatment could be pursued for responding patients until disease progression. From september 1995 to January 1997, 31 patients have been included in this study. Median age was 60.7 years +/- 1.33 (41-70) for 27 males and 4 females. Patients (pts) presented metastases in lung for 10 pts, bone for 10 pts, liver for 6 pts, adrenal for 4 pts and multiorgan metastatic localisation for 1 patient. Seven patients were unassessable: 1 lost for follow-up, 1 sudden death, 5 treatment interruptions before evaluation time and 3 toxic deaths (9.6%). TOXICITY: neutropenia grade 4 (10 pts and 1 death), cardiotoxicity grade 4 (1 pt) and 2 deaths following neurotoxicity grade 4. We achieve 4 partial responses (13%, 95CI: 3.6-29.8), 10 progressive diseases (32.3%, 95CI: 16.7-51.4) and 10 stabilizations (32.3%, 95CI: 16.7-51.4). Median response duration was 91 days +/- 55 d. Median survival was 9.3 months, e.g. 280 days (8-863). Overall survival at one year is 48%. CONCLUSION: This modality of high dose ifosfamide is as effective as standard monotherapy schedules in stage IV NSCLC. Unexpected toxicities particularly hematological ones could be due to a short duration of fractionated treatment. Results in term of survival leads us to further evaluate ifosfamide monotherapy treatment on a 5-day schedule basis.

Adult↗
PubMed2001

Phase 1 trial of ifosfamide and adriamycin in metastatic breast cancer.

OBJECTIVE: A Phase 1 trial was conducted in patients with estrogen negative receptors (ER) or hormone refractory metastatic breast cancer to determine the maximum tolerated dose (MTD) of ifosfamide with a fixed dose of doxorubicin. A secondary objective was to determine the efficacy of the combination in metastatic breast cancer. METHODS: Fifteen patients were entered in the study in cohorts of three patients at each dose level of ifosfamide. The dose of doxorubicin was fixed at 45 mg/m2. Five different dose levels of ifosfamide were tested ranging from dose level 1 of 1.5 gms/m2 day 1-3 to level V at 2.5 gms/m2 day 1-3. RESULTS: Dose escalation of ifosfamide was stopped at 2.5 gms/m2. The MTD of ifosfamide was 2.25 gms/m2 day 1-3 in combination with doxorubicin. All patients in the study were assessable for toxicity. Neutropenia and thrombocytopenia were the major dose limiting toxicities. Other toxicities included anemia, confusion and hematuria. Objective responses were documented in 11 of 15 patients (73.3%). Median time to treatment failure (TTF) was 13 months. Median overall survival (OS) was 18 months. CONCLUSION: The combination of ifosfamide and doxorubicin was a practical well tolerated regimen. There was substantial evidence of clinical activity in this phase I trial. This combination should be further evaluated, as an attractive alternative to taxanes for patients in developing countries where cost effectiveness is important.

Adult↗