mesna and Nervous-System-Diseases

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.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Combined Modality Therapy; Creatinine; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Diseases; Sarcoma; Survival Rate

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cranial Irradiation; Drug Administration Schedule; Etoposide; Germany; Humans; Ifosfamide; Lomustine; Medulloblastoma; Mesna; Nervous System Diseases; Neutropenia; Postoperative Period; Prospective Studies; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome; Vincristine

Twenty-four evaluable patients with recurrent or advanced squamous carcinoma of the cervix were treated with ifosfamide (IFX) and mesna every 3 weeks. The initial dose of IFX was 1.5 g/m2 q.d. Days 1-5. Mesna was given by continuous infusion (1.5 g/m2/day Days 1-6). Seventy-four courses of treatment were given to 24 patients. All patients were evaluable for toxicity and response. The median survival was 26 weeks from initiation of chemotherapy. There were 4 complete responders (CR); there was 1 partial responder. The response rate was 20.8% (CI, 4-38%). One CR patient remains in clinical remission 30 months after initiation of therapy. The other 3 responders recurred after a disease-free interval of 8, 12, and 18 weeks. WBC below 3000/mm3 occurred in 19 patients and was life threatening (below 1000/mm3) in 5 patients. One patient had life-threatening hemorrhagic cystitis. Eleven patients developed CNS symptoms during treatment including somnolence, coma, and acute delirium.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Recurrence, Local; Nervous System Diseases; Uterine Cervical Neoplasms

The Gastrointestinal Tumor Study Group (GITSG) investigated the efficacy of ifosfamide with mesna uroprotection in 30 patients with advanced inoperable pancreatic carcinoma that was confirmed histologically. All patients were required to have at least one bidimensional measurable lesion that could be followed by palpation or radiologic examination. Genitourinary toxicity presenting as hematuria occurred in five patients, but was not severe enough to curtail treatment in any of these patients. The major toxicity was neurologic, with 12 patients (41%) reporting at least one episode; four of which were graded as severe and two as fatal. Three partial tumor responses to treatment were reported (10%) and the median survival time was just 11 weeks. In our experience, ifosfamide with mesna uroprotection does not appear to be active in pancreatic carcinoma.

Topics: Adult; Aged; Carcinoma; Drug Evaluation; Female; Hematuria; Humans; Ifosfamide; Male; Mesna; Nervous System Diseases; Pancreatic Neoplasms

Ifosfamide was given to 61 patients with malignant solid tumors diagnosed before the age of 21 years. In this phase II study, all patients received 1.6 g/m2/day X 5 iv over 15 minutes followed by mesna at a dose of 400 mg/m2 iv at 15 minutes and 4 and 6 hours after ifosfamide. Responses were observed in five of 15 patients with osteosarcoma, two of ten with neuroblastoma, two of six with Wilms' tumor, two of five with rhabdomyosarcoma, four of eight with other soft tissue sarcomas, one of one with retinoblastoma, one of two with germ cell tumors, one of one with B-cell lymphoma, and one of one with a primitive neuroectodermal tumor. Fifty-nine of 61 patients had received prior alkylating agent therapy which included cyclophosphamide, cisplatin, mechlorethamine, melphalan, or dacarbazine. Fourteen of 19 responses developed in patients whose tumors were resistant to treatment with cyclophosphamide. A patient with malignant Schwannoma who had received no prior chemotherapy developed a complete response which lasted 12 months. A patient with brain metastases of osteosarcoma has had complete response for greater than 2 years. Complete response was also observed in a patient with B-cell lymphoma. Toxicity consisted of mild to moderate nausea and vomiting, transient reversible myelosuppression, occasional elevation of serum BUN or creatinine, and transient neurotoxicity characterized by somnolence, confusion, weakness, tremor, hallucinations, or seizures. We conclude that ifosfamide is an important alkylating agent without apparent complete cross-resistance with cyclophosphamide, and as such should be further investigated for determination of its activity in patients with pediatric neoplasms and considered for incorporation into phase II-III trials for certain tumors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Evaluation; Female; Hematologic Diseases; Humans; Ifosfamide; Infant; Lymphoma; Male; Mesna; Neoplasms; Nervous System Diseases; Neurilemmoma; Osteosarcoma; Urologic Diseases