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PubMed1992

Clinical trials with ifosfamide: the Indiana University experience.

At Indiana University, we began clinical trials with ifosfamide in 1981. Although our initial efforts were in a variety of tumor types, including pancreatic cancer, we have most recently focused our attention on two tumors that have historically exhibited a higher degree of chemosensitivity--testicular cancer and small cell lung cancer (SCLC). In phase II trials, ifosfamide has proven to have single-agent activity in both diseases. Coupling this data with preclinical observations of synergy with cisplatin and etoposide, we began trials of ifosfamide plus cisplatin with either vinblastine (VeIP) or etoposide (VIP) in patients with recurrent germ cell tumors; we also investigated the use of VIP in SCLC. In third-line or greater therapy for recurrent germ cell tumors, a 36% disease-free status was attained, with 16% of patients continuously free of disease for 5 or more years. Currently, ifosfamide is being evaluated as part of initial therapy in patients with advanced disease. In SCLC, VIP has also been investigated as part of initial therapy in patients with extensive disease. The complete response rate of 38% achieved in 37 evaluable patients has spurred the Hoosier Oncology Group to compare the VIP regimen to cisplatin/etoposide in patients with extensive-disease SCLC. Ifosfamide has the broad range of clinical activity, but its ultimate role as part of initial therapy remains to be discerned.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Novel approaches with ifosfamide in small cell lung cancer.

During the past 5 years, ifosfamide has been used increasingly in combination chemotherapy for small cell lung cancer (SCLC). The high activity and favorable toxicity spectrum (with the uroprotector mesna) will encourage further use. A policy of no dosage reduction is feasible in patients receiving combination chemotherapy with ifosfamide given as a 24-hour intravenous (IV) infusion, which is much more convenient than the more commonly used 4- to 5-day fractionated regimen. This policy has resulted in actual 2-year survivals of 22% to 33% among SCLC patients not intensively staged. The stability of ifosfamide and its high bioavailability have allowed its use in chronic, 7-day ambulatory IV infusions, with decreased toxicity and hospitalization. Recently, oral and subcutaneous administration also have been tried, again allowing outpatient treatment. The first studies with hemopoietic growth factor support, eg, granulocyte colony-stimulating factor, conducted with combination chemotherapy with ifosfamide-containing regimens in SCLC, demonstrated significant reduction in neutropenia, infections, and antibiotic use. It is clear that the dosage of ifosfamide can be intensified in the future. The broad versatility of the drug will allow interesting new studies, including those to be conducted with outpatients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Gynecologic Oncology Group studies with ifosfamide.

The Gynecologic Oncology Group has conducted a series of phase II studies with ifosfamide and mesna since 1985. Previously untreated patients received ifosfamide 1.5 g/m2 intravenously daily for 5 days. Mesna was given intravenously every 4 hours three times daily at 20% of the daily ifosfamide dose. Because of the toxic effects observed in previously treated patients with ovarian cancer, the ifosfamide dose was reduced to 1.2 g/m2/d in patients with prior chemotherapy or radiotherapy. In epithelial ovarian cancer, responses were observed in eight (20%) of 41 evaluable patients, with three (7%) complete responses. In patients with squamous carcinoma of the cervix, an 11.1% response rate (three of 27 patients) was observed in those who had received prior platinum therapy. In 51 previously untreated patients, the response rate was 15.7%. In nonsquamous cervical carcinomas, there were three partial responses among 25 patients (12%). An 8.6% response rate was observed among 23 patients with previously treated endometrial adenocarcinomas. In uterine sarcomas, response rates were 30.7% in mixed müllerian tumors, 17.2% in leiomyosarcomas, and 27.3% in endometrial stromal sarcomas. Patients with ovarian sarcomas responded in 27.8% of cases. Studies with ifosfamide combinations are currently under way by the Gynecologic Oncology Group.

Adenocarcinoma↗
PubMed2004

High-dose ifosfamide with hematopoietic growth factor support in advanced bone and soft tissue sarcomas.

AIM: Ifosfamide and doxorubicin are the most effective agents in the treatment of sarcomas, although their contributions to survival are usually limited. High-dose ifosfamide can be used as a salvage treatment in patients with recurrent or advanced sarcoma. We evaluated efficacy and toxicity of high-dose ifosfamide in the patients with recurrent or advanced sarcoma in this study. METHODS: 39 patients with recurrent or advanced sarcoma were enrolled onto the study between 1996 and 2002. All patients had histological proven high grade sarcoma with measurable or evaluable disease. Ifosfamide was administered at the dose of 2 g/m(2) as continuous intravenous infusion for 24 h on day 1-9, in conjunction with the continuous infusion of mesna. Granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor was given every cycle. The efficacy and toxicity of high dose ifosfamide (HDI) were evaluated clinically before subsequent cycle. The objective response was evaluated every two cycles. Histopathologic response was also evaluated in patients who underwent surgical resection. RESULTS: Male/female ratio was 24/15, with a median age of 20 (11-48) years. 9 patients had locally inoperable advanced disease and 30 patients had metastatic disease. 10 patients were chemo-naive. The total number of HDI-chemotherapy cycles was 103 (median 2 cycles (range, 1 to 7)). 2 patients refused the further treatment after the first cycle and 1 patient died due to neutropenic sepsis in the first cycle of treatment. 36 patients were available for the evaluation of treatment efficacy. Overall response rates were 53.8% and 90% in pre-treated patients and in chemo-naive patients, respectively. Median follow-up time was 43 months. 13 patients underwent total surgical tumor resection. Pathologic complete response was observed in 5 of 13 these patients who underwent surgery. Median progression-free survival (PFS) was 7 months (95%CI: 3.8-10.2). The median progression-free survival (PFS) were 3 and 12 months in patients who did not have tumor resection, and in those having complete tumor resection (p = 0.002). Median overall survival (OS) was 10 months (95%CI: 0.0-20) in all patients. Median OS times were 8 months in patients without tumor resection and 26.5 months in patients with those underwent surgical treatment (p = 0.0369). 2 patients who underwent surgery are still alive and disease-free. Major toxicity was myelosuppression. CONCLUSION: HDI seems to be feasible and effective in selected patients with advanced or recurrent sarcomas. Survival advantage of HDI is better when the total tumor resection can be done.

Adolescent↗
PubMed2005

Doxorubicin and ifosfamide-mesna in advanced and recurrent uterine sarcomas.

PURPOSE OF INVESTIGATION: To report the experience of a single institution in the south of Israel with doxorubicin and ifosfamide-mesna in patients with advanced/recurrent uterine sarcomas. METHODS: The hospital records of five patients with advanced/recurrent uterine sarcomas who had combination chemotherapy with doxorubicin and ifosfamide-mesna were retrospectively reviewed. Doxorubicin 30 mg/m2 was given on days 1 and 2 and ifosfamide 2000 mg/m2 (+ mesna, W/W 60%) was given on days 1, 2 and 3 of every 21 days. Dose intensity, relative dose intensity and average relative dose intensity (ARDI) of chemotherapy were calculated. Response was determined using clinical evaluation and radiological reports. Toxicity was graded using the National Cancer Institute (NCI) criteria. RESULTS: The median ARDI of the combination of doxorubicin and ifosfamide received by the patients was 0.68 (range, 0.53-0.74). One (20%) patient had disease complete response lasting three months and four (80%) patients had progressive disease. Toxicity was mainly hematological with grade 3 or 4 leukopenia--four (80%) patients, neutropenia--four (80%), thrombocytopenia--one (20%) and anemia--one (20%). Non-hematological toxicity was negligible. At follow-up, four (80%) patients had died of disease and one (20%) was alive with disease. CONCLUSION: Although the combination of doxorubicin and ifosfamide has certain activity in advanced/recurrent uterine sarcomas, the toxicity is of much concern and the results of treatment in terms of response duration and survival are poor.

Adult↗
PubMed1989

The role of ifosfamide in cervical cancer.

A series of phase II studies using ifosfamide as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer were coordinated at the West Midlands Cancer Research Campaign Clinical Trials Unit, Birmingham, UK. The aim of these studies was to identify single agents and combination regimens that might be of value for palliation and have potential for neoadjuvant and adjuvant therapy in primary treatment. Ninety-eight patients were studied. Seventy-nine patients with disease not amenable to radical local therapy were treated with single-agent ifosfamide or the BIP combination. In 30 patients treated with single-agent ifosfamide, ten objective responses (33%) were seen, with one complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with ten complete responses (20%). Eleven (79%) of 14 patients with primary inoperable disease had at least a 50% reduction in tumor bulk before radical local radiotherapy. Toxicity resulted in alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function, and disturbance of consciousness. There was no evidence that neoadjuvant chemotherapy enhanced the acute toxic effects of pelvic radiotherapy. These data indicate that ifosfamide is highly active in cervical cancer and that in combination with bleomycin and cisplatin, it can be used for effective palliation and cytoreduction in around 70% of patients. Ifosfamide-containing regimens have potential for use as neoadjuvant and adjuvant therapy in patients at high risk of recurrence with conventional treatment. These hypotheses are currently being tested in prospective randomized trials.

Adult↗
PubMed1989

Ifosfamide in the treatment of non-small cell lung cancer.

Thirteen single-agent and 23 combination chemotherapeutic regimen trials using ifosfamide involving 1,326 evaluable patients with non-small cell lung cancer were reviewed. From these studies, several conclusions can be drawn: (1) ifosfamide as a single agent shows response rates greater than 20%; (2) in combination with cisplatin, with or without a third drug, ifosfamide induces response rates of 38%; however, survival is not increased significantly; (3) other combinations with ifosfamide have a response rate greater than 35%; and (4) ifosfamide warrants continued evaluation and testing in combination with other effective agents.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Ifosfamide in testicular cancer: the Indiana University experience.

The systemic treatment of patients with metastatic germ cell tumors has improved dramatically during the past 15 years. Nonetheless, a cohort of patients are candidates for salvage chemotherapy. Having ruled out the possibility of pseudoprogression (eg, false elevated serum markers, teratoma, bleomycin lung disease), salvage therapy is indicated. Numerous trials in Europe and at Indiana University have confirmed single-agent activity of ifosfamide in patients with refractory germ cell tumors. As a consequence, a trial evaluating VeIP (vinblastine, ifosfamide, cisplatin) and VIP (etoposide, ifosfamide, cisplatin) was undertaken in 57 patients previously not cured with cisplatin, vinblastine, and etoposide regimens. Twenty patients achieved disease-free status with chemotherapy alone (n = 12) or chemotherapy plus surgical resection of residual carcinoma or teratoma (n = 8). Fifteen of these 20 patients remained free of recurrent disease from 18 to 53 months, including seven patients in continuous remission for over 2 years. Ifosfamide combination chemotherapy has curative potential in this heavily pretreated population. Further work to determine the role of ifosfamide in initial therapy is under way.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Administration, Oral↗
PubMed1983

[Ifosfamide in the treatment of small cell carcinoma of the lung].

A total of 36 cases with small cell carcinoma of the lung were treated with Ifosfamide. Fourteen cases (38.9%) out of 36 cases showed good or marked clinical response, and 120 mg/kg of Ifosfamide was necessary as a minimum dose to obtain effective response. As side effects of Ifosfamide, gastrointestinal disturbance (66.7%), depilation (66.7%), leukopenia (38.9%) and hematuria (36.1%) were observed. Mean survival time (M.S.T.) was prolonged by using Ifosfamide, comparing with the groups treated by with other anticancer drugs. Ifosfamide, therefore, should be used for the treatment of small cell carcinoma of the lung.

Adult↗
PubMed1981

The bioavailability of oral and intravenous ifosfamide in the treatment of bronchogenic carcinoma.

This study tested the feasibility of using oral ifosfamide to treat bronchogenic carcinoma and compared the pharmacokinetics of intravenous and oral doses of the drug. Patients with advanced bronchogenic carcinoma were evaluated for toxicities associated with oral ifosfamide therapy. Pharmacokinetics for various oral and intravenous doses of ifosfamide were determined by a gas-liquid chromatographic assay of plasma and urine samples. Toxicities associated with oral ifosfamide therapy were minimal. Calculated pharmacokinetics parameters are listed, with the half-lives varying from 0.5 to 4.6 h. Oral ifosfamide therapy was determined to be feasible, and further studies are justified to assess the pharmacokinetics of the optimum dosage and scheduling regimens.

Administration, Oral↗
PubMed1995

Dose intensification--a phase I study of ifosfamide with vinorelbine (Navelbine): rationale and study design in advanced non-small cell lung cancer.

A phase I trial of a combination of vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and ifosfamide given on a novel schedule on 3 consecutive days with granulocyte colony-stimulating factor was conducted to establish the maximum tolerated dose of vinorelbine and the dose-limiting toxicities of this regimen. Doses of vinorelbine were escalated in cohorts of patients. Of the 29 patients enrolled at the time of data analysis, 26 were evaluable for toxicity. At the first dose level (ifosfamide 2.0 g/m2 days 1, 2, and 3; vinorelbine 15 mg/m2 days 1, 2, and 3), two of three patients had dose-limiting toxicities. The dose of ifosfamide was decreased by 20%, and dose escalation of vinorelbine was restarted. At the vinorelbine dose level of 35 mg/m2/d for 3 days, three of four patients had dose-limiting toxicities. The recommended phase II doses were established as 1.6 g/m2/d ifosfamide for 3 days and 30 mg/m2/d vinorelbine for 3 days. This study established that granulocyte colony-stimulating factor was needed for approximately 8 days. We are currently examining the feasibility of two dose levels of vinorelbine (25 mg/m2 and 30 mg/m2/d for 3 days) in combination with ifosfamide (1.6 g/m2/d) given every 2 weeks.

Adult↗
PubMed1995

Rationale for examining the combination of paclitaxel and ifosfamide in the treatment of advanced ovarian cancer.

Both paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide have been demonstrated to be active agents in patients with clinically defined platinum-refractory ovarian cancer. While there might be interest in combining these two drugs as salvage therapy for this disease, the recent inclusion of paclitaxel as initial therapy for advanced ovarian cancer, along with a platinum agent (cisplatin or carboplatin), makes it unlikely that paclitaxel and ifosfamide will be used clinically in this malignancy. However, if alkylating agents are not to be used as part of the initial chemotherapy strategy for women with advanced ovarian cancer, it will be important to evaluate the activity of ifosfamide as salvage therapy in individuals treated only with, and demonstrated to be refractory to, a platinum agent and paclitaxel. If significant activity for ifosfamide is observed in this clinical setting, evaluation of the potential utility of a three-drug combination regimen comprising ifosfamide, paclitaxel, and cisplatin or carboplatin may be quite relevant.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Phase I study of high-dose ifosfamide, carboplatin and etoposide with autologous hematopoietic stem cell support.

More effective high-dose combination regimens are needed which have broad cytotoxic activity, steep dose-response relations and non-overlapping non-hematologic toxicities (to allow administration of full doses of each agent). This study was designed to define the dose-limiting toxicities and maximum tolerated doses of ifosfamide, carboplatin and etoposide (ICE) with hematopoietic stem cell support. Ifosfamide and carboplatin were initially fixed at 75% and 80% of the single agent maximum tolerated doses, respectively, and etoposide added to the combination. After the dose-limiting toxicity of etoposide was reached, its dose was fixed and ifosfamide and carboplatin were individually dose escalated as tolerated. All agents were given by 96h continuous infusion (days -7 to -3). Autologous marrow, with or without peripheral blood progenitor cells, was reinfused on day 0. Forty eight adults with advanced malignancies were enrolled in cohorts of three to five patients. At the maximum tolerated doses of ifosfamide 16 g/m2, carboplatin 1.8 g/m2 and etoposide 1.2 g/m2, renal toxicity precluded further dose escalation. Two patients died of organ (renal, CNS) toxicity (4%). Renal toxicity was particularly prominent in patients with prior cisplatin exposure. An early chemotherapy-stopping rule was developed, supported by pharmacologic analysis, which resulted in immediate discontinuation of ifosfamide and carboplatin if the serum creatinine, monitored twice daily during chemotherapy, exceeded 1.5 mg/dl and was > 0.5 mg/dl above baseline. High-dose ICE is well tolerated if serum creatinines are carefully monitored during chemotherapy administration. The early chemotherapy-stopping rule may enhance safety of the regimen but requires validation by addition correlation with pharmacokinetic data for each of the chemotherapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The role of ifosfamide in germ cell tumors and small cell lung cancer.

Ifosfamide has been found to have antineoplastic activity in a variety of solid tumors. In germ cell tumors, the substitution of ifosfamide for bleomycin in the standard combination bleomycin/etoposide/cisplatin (BEP) did not improve efficacy and caused significantly more toxicity than BEP. This regimen (VIP), however, has shown promise when used with high-dose carboplatin/etoposide as salvage therapy in patients with germ cell tumors not responding to first-line BEP. It is unclear whether the addition of ifosfamide to the carboplatin/etoposide regimen results in an improved therapeutic outcome in patients with multiple recurrent germ cell tumors. In such patients, as well as in those with poor-risk germ cell cancer, high-dose chemotherapy given with hematopoietic growth factors and bone marrow rescue may have a role. In small cell lung cancer, single-agent ifosfamide has produced response rates of 48% to 76%. Currently, the role of ifosfamide is being defined in untreated and recurrent small cell lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience.

We have used ifosfamide to treat patients with sarcomas in four completed single-agent protocols and one pilot study since 1985. All the studies have used either N-acetyl-L-cysteine (NAC) or mesna as a uroprotective agent, except in one arm of one study where hydration alone was employed. Mesna has proven superior to NAC in providing protection against ifosfamide-induced hematuria. Mesna given as a loading dose followed by continuous 24-h infusion has been effective and most practical in this regard. Ifosfamide has demonstrated clinically useful antitumor activity in our hands against most sarcoma subtypes. Our studies suggest a dose-response relationship for ifosfamide. At a total dose of 6 g/m2 per course, the overall response rate was 10%; at 10 g/m2 per course, it rose to 21%. Future clinical trials will determine ifosfamide's role in combination chemotherapy and more clearly define the best schedule or schedules for the uroprotective administration of mesna.

Acetylcysteine↗
PubMed1996

Ifosfamide in the treatment of soft tissue sarcomas.

Ifosfamide is one of the three most active agents in the treatment of soft tissue sarcomas. Ifosfamide-induced urothelial toxicity has been adequately controlled with the use of hydration and the uroprotective agent mesna. This is a review of pilot and phase I and II studies of ifosfamide as a single agent and randomized trials of combination chemotherapy regimens incorporating ifosfamide in the treatment of soft tissue sarcomas. Issues of schedule and dose of ifosfamide will be addressed as well.

Antineoplastic Agents, Alkylating↗
PubMed1996

High-dose ifosfamide in the treatment of advanced soft tissue sarcomas.

Ifosfamide, an oxazaphosphorine analogue, is now commonly used in first-line anthracycline-containing regimens for advanced soft tissue sarcomas, based on its demonstrated single-agent activity in previously treated patients. At the Institut Gustave-Roussy, we performed a phase II study of high-dose ifosfamide without hematopoietic support in patients with adult advanced soft tissue sarcomas previously treated with a doxorubicin-based regimen. Our goal was to confirm a dose-response relationship for ifosfamide in soft tissue sarcoma. Ifosfamide was given at a dose of 4 g/m2/d over 3 days by continuous infusion with an equivalent dose of mesna; an additional 4 g/m2 of mesna was given on day 4. Among 36 evaluable patients, we observed no complete responses and 12 partial responses, for an overall response rate of 33%. No patients with leiomyosarcoma responded to treatment, and some histologic subtypes clearly showed better chemosensitivity than others. The major dose-limiting toxicities were hematologic. Our results confirm a dose-response effect for high-dose ifosfamide in soft tissue sarcomas, with a threshold of approximately 10 g/m2.

Adult↗