Abstract
Current systemic treatment options for patientswith relapsed gliomas are limited. Thetopoisomerase I inhibitor topotecan has demonstrated broadantitumor activity in both preclinicalstudies as well as a number of phase I and II trials in humans.Studies in primates have shown goodcerebrospinal fluid levels of topotecan following systemicadministration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5mg/m2 intravenously daily for 5 consecutive days repeatedevery three weeks. For patients who had received priornitrosourea-containing chemotherapy, thestarting dose was 1.25 mg/m2. Thirty-three patients wereentered on this study. All patients wereeligible and evaluable for both response and toxicity. Sevenpatients experienced grade 4 leukopeniawith 2 of these patients dying of infection-relatedcomplications. Six of these seven patients werenot taking anticonvulsants during treatment. Nine patientsdeveloped grade 3-4 thrombocytopenia,seven of whom were not taking anticonvulsants. Nonhematologicside effects were infrequent andmanageable. One patient experienced a partial response to thistreatment for an overall response rateof 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9weeks and median survival 19.9 weeks. Topotecan at this dose andschedule showed no substantial activity in relapsed gliomas.
Similar content being viewed by others
References
Walker MD, Alexander E, Hunt WE, MacCarty CS, Mahaley MS, Mealey J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA: Evaluation BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 49: 333–343, 1978
Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, Hatlevoll R, Lindgren M, Brun A, Lingren S, Notter G, Andersen AP, Elgen K: Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 47: 649–652, 1981
Shaw EG, Daumas-Duport C, Scheithauer BW, Gilbertson DT, O'Fallon JR, Earle JD, Laws ER, Okazaki H: Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg 70: 853–861, 1989
Karim ABMF, Maat B, Hatlevoll R, Menten J, Rutten EHJM, Thomas DGT, Mascarenhas F, Horiot JC, Parvinen LM, van-Reijn M, Jager JJ, Fabrini MG, vanAlphen AM, Hamers HP, Gaspar L, Noordman E, Pierart M, vanGlabbeke M: A randomized trial on dose-response in radiation therapy of lowgrade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) study 22844. Int J Radiat Oncol Biol Phys 36: 549–556, 1996
Walker MD, Green SB, Byar DP, Alexander E, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS, Mealey J, Owens G, Ransohoff J, Roberstson JT, Shapiro WR, Smith KR, Wilson CB, Strike TA: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. New Engl J Med 303: 1323–1329, 1980
Yung WKA: Chemotherapy for malignant brain tumors. Curr Opin Oncol 2: 673–678, 1990
Eck SL, Alavi JB, Alavi A, Davis A, Hackney D, Judy K, Mollman J, Phillips PC, Wheeldon EB, Wilson JM: Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial. Human Gene Therapy 7: 1465–1482, 1996
Walter KA, Tamargo RJ, Olivi A, Burger PC, Brem H: Intratumoral chemotherapy. Neurosurg 37: 1129–1145, 1995
Potmesil M: Camptothecins: from bench research to hospital wards. Cancer Res 54: 1431–1439, 1994
Slichemyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH: The current status of camptothecin analogues as antitumor agents. J Nat Cancer Inst 85: 271–291, 1993
Lynch T: Topotecan today. J Clin Oncol 14: 3053–3055, 1996
Blaney SM, Cole DE, Balis FM, Godwin K, Poplack DG: Plasma and cerebrospinal pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53: 725–727, 1993
Jennison C, Tumbull BW: Confidence interval for a binomial parameter following a multistage test with application MILSTD 105D and medical trials. Technometrics 25: 49–58, 1983
Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Freidinan HS, Danks MK, Houghton JA: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36: 393–403, 1995
Hare CB, Elion GB, Houghton PJ, Houghton JA, Keir S, Marcelli SL, Bigner DD, Friedman HS: Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 39: 187–191, 1997
Friedman HS, Houghton PJ: Treatment of central nervous system xenografts with camptothecins. Ann NY Acad Sci 803: 210–212, 1996
Pottnesil M, Vardeman D, Kozielski AJ, Mendoza J, Stehlin JS, Giovanella BC: Growth inhibition of human cancer metastases by camptothecins in newly developed xenograft models. Cancer Res 55: 5637–5641, 1995
Rajkurnar SV, Burch PA, Nair S, Dinapoli RP, Scheithauer B, O'Fallon JR, Etzell PS, Leitch JM, Morton RF, Marks RS: Phase II study of 2-chlorodcoxyadenosine in patients with recurrent glioma. Am J Clin Oncol (in press)
Cascino TL, Veeder MH, Buckner X, O'Fallon JR, Wiesenfeld M, Levitt R, Goldberg RM, Kuross SA, Morton RF, Scheithauer BW: Phase II study of 5-fluorouracil and leucovorin in recurrent primary brain tumor. J Neuro-Oncol 30: 243–246, 1996
Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach J, Chang CH, Rotman M, Asbell SO, Krisch RE, Nelson DF: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Nat Cancer Inst 85: 704–710, 1993
Macdonald D, Cairricross G, Stewart D, Forsyth P, Sawka C, Wainman N, Eisenhauer E for the National Cancer Institute of Canada Clinical Trials Group (NCIC CW): Phase II study of topotecan in patients with recurrent malignant glioma. Ann Oncol 7: 205–207, 1996
Blaney SM, Phillips PC, Packer RJ, Heideman RL, Berg SL, Adamson PC, Allen X, Sallan SE, Jakacki RI, Lange IB, Reaman GH, Horowitz ME, Poplack DG, Balis FM: Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78: 527–531, 1996
Kyritsis A, Newlands ES, Brock CS, Gleason M, Jaeckle K, Levin V, Mower M, Evans H, Dane G, DeWitte M, Yung W: Phase II trial of topotecan as a continuous intravenous infusion in patients with high-grade glioma. Proc Am Soc Clin Oncol 16: 394a, 1997
Friedman HS, Kerby T, Fields, Zilsch JE, Graden D, McLendon RE, Houghton PJ, Arbuck S, Cokgor I, Friedman AH: Topotecan treatment of adults with primary malignant glioma. Cancer 85, 1160–1165, 1999
Grossman SA, Hochberg F, Fisher J, Chen TL, Kim L, Gregory R, Gochow LB, Piantadosi S: Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. Cancer Chemother Pharmacol 42: 118–126, 1998
Friedman HS, Petros WP, Friedman AJ, Schaaf LF, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provensale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17: 1516–1525, 1999
Reid J, Buckner J, Schaaf L, Novotny P, Wright K, Kimmel D, Miller L: Pharmacokinetics of irinotecan (CPT-11) in recurrent glioma patients: results of an NCCTG phase II trial. Proceedings ASCO 18: 141, 1999
Stewart CF, Baker SD, Heideman RL, Jones D, Crom WR, Pratt CB: Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. J Clin Oncol 12: 1946–1954, 1994
Zamboni WC, Gajjar AJ, Heideman RL, Beijnen JH, Rosing H, Houghton PJ, Stewart CF: Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 4: 783–789, 1998
Straathof CSM, van den Bent MJ, Loos WJ, Vecht CJ, Schellens JHM: The accumulation of topotecan in 9L, glioma and in brain parenchyma with and without dexamethasone administration. J Neuro-Oncol 42: 117–122, 1999
Hochberg F, Grossman SA, Mikkelsen T, Calabresi P, Fisher J, Piantadosi S: Efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. Proceedings ASCO 17: 1494, 1998
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Burch, P.A., Bernath, A.M., Cascino, T.L. et al. A North Central Cancer Treatment Group Phase II Trial of Topotecan in Relapsed Gliomas. Invest New Drugs 18, 275–280 (2000). https://doi.org/10.1023/A:1006438109266
Issue Date:
DOI: https://doi.org/10.1023/A:1006438109266