Summary
Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors.
Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M2/qod × 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8–62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors.
Similar content being viewed by others
References
Allen JC, Helson L: High dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55: 749–756, 1981
Friedman HS, Schold SC, Mahaley S, Colvin OM, Oakes J, Vick NA, Burger PC, Bigner SH, Borowitz M, Halperin EC, Djang W, Falletta JM, DeLong R, Garvin JC, DeVivo DC, Norris D, Golembe B, Winter J, Bodziner RA, Sipahi H, Bigner DD: Phase II treatment of medulloblastoma and pineoblastoma with melphalan: Clinical therapy based on experimental models of human medulloblastoma. J Clin Oncol 7: 904–911, 1989
Friedman HS, Mahaley S, Schold SC, Vick NA, Falletta JM, Bullard DE, D'Souza BJ, Khandekar JD, Lew S, Oakes WJ, Bigner DD: Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma. Neurosurg 18: 335–340, 1986
Longee DC, Friedman HS, Albright RE, Burger PC: Treatment of patients with recurrent gliomas with cyclophosphamide and vincristine. J Neurosurg 72: 583–588, 1990
Friedman H, Colvin O, Ludeman Set al.: Experimental chemotherapy of human medulloblastoma with classical alkylators. Cancer Res 46: 2827–2833, 1986
Alien JC, Bosl G, Walker R: Chemotherapy trials in recurrent primary intracranial germ cell tumors. J Neuro-oncol 3: 147–152, 1985
Pratt CB, Douglass EC, Etcubanas EL, Goren MP, Green AA, Hayes FA, Horowitz ME, Meyer WH, Thompson El, Wilimas JA: Ifosfamide in pediatric malignant solid tumors. Cancer Chemother Pharmacol 24: s24-s27, 1989
Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst 80: 556–566, 1988
Treuner J, Koscielniak E, Keim M: Comparison of the rates of response to ifosf amide and cyclophosphamide in primary unresectable rhabdomyosarcoms. Cancer Chemother Pharmacol 24: s48-s50, 1989
Pratt CB, Douglass EC, Kovnar EH, Heideman R, Kun L, Avery L, Kellie SJ: A phase I study of ifosfamide given on alternate days to treat children with brain tumors. Cancer 71: 3666–3669, 1993
Miser J, Krailo M, Smithson W, Belasco J, Ortega J, Hammond GD: Treatment of children with recurrent brain tumors with ifosfamide, etoposide, and mesna. Proc ASCO 8: 84, 1989
Gieron MA, Barak LS, Estrada J: Sever e necphalopathy associated with ifosfamide administration in two children with metastatic tumors. J Neuro-oncol 6: 29–39, 1988
Davies SM, Pearson ADJ, Craft AW: Toxicity of high-dose ifosfamide in children. Cancer Chemother Pharmacol 24: s8-s10, 1989
Pratt CB, Green AA, Horowitz ME, Meyer WH, Etcubanas E, Douglass E, Hayes FA, Thompson E, Wilimas J, Igarashi M, Kovnar E: Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna. J Clin Oncol 4: 1253–1261, 1986
Goren MP, Wright RK, Pratt CB, Horowitz ME, Dodge RK, Viar MJ, Kovnar EH: Potentiation of ifosfamide neurotoxicity, hematotoxicity and tubular nephrotoxicity by prior cisdamminedichloroplatinum (II) therapy. Cancer Res 47: 1457–1460, 1987
Gehan EA: The determination of the number of patients required in a preliminary and follow-up trial of a new chemotherapeutic agent. J Chron Dis 13: 346–353, 1961
Investigators Handbook. A manual for participants in clinical trials of investigational agents sponsored by the Division of Cancer Treatment, National Cancer Institute, Washington, D.C.: Department of Health and Human Serives., 1993. pp. 153–157
Chastagner P, Sommelet-Olive D, Kalifa C, Brunat-Mentigny M, Zucker JM, Demeocq F, Baranzelli MC, Tron P, Bergeron C, Pein F: Phase II study of ifosfamide in childhood brain tumors: a report by the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 21: 49–53, 1993
Elliott TE, Buckner JC, Cascino TL, Levitt R, O'Fallon JR, Scheithauer BW: Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma. J Neurooncol 10: 27–30, 1991
Cerny T, Castiglione M, Brunner K, Kupfer A, Martinelli G, Lind M: Ifosfamide by continuous infusion to prevent encephalopathy. Lancet 335: 175, 1990
Pratt CB, Meyer WH, Jenkins JJ, Avery L, McKay CP, Wyatt RJ, Hancock ML: Ifosfamide, Fanconi's syndrome, and rickets. J Clin Oncol 9: 1495–1499, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Heideman, R.L., Douglass, E.C., Langston, J.A. et al. A phase II study of every other day high-dose ifosfamide in pediatric brain tumors. J Neuro-Oncol 25, 77–84 (1995). https://doi.org/10.1007/BF01054726
Issue Date:
DOI: https://doi.org/10.1007/BF01054726