Abstract
Intratumoral (IT) chemotherapy has theoretical advantages in the treatment of brain tumors. The blood–brain barrier is not a factor in drug delivery, and large concentrations of drug can be instilled in the tumor with little systemic toxicity. Bleomycin has activity against gliomas and is a cell cycle selective agent whose efficacy should be enhanced by continuous infusion. We performed a phase I trial to test the feasibility of IT chemotherapy using a refillable, sustained release device, and to determine the maximum tolerable dose of IT bleomycin. The study was an open-ended dose escalation study. A modified Ommaya reservoir (containing a semipermeable membrane) was implanted with the delivery tube in the center of the tumor. Groups of three patients with recurrent glioblastoma multiforme were entered at progressively higher dose levels of bleomycin. The study closed when all patients at a given starting dose level developed toxicity. Nine patients received doses ranging from 5 to 34 U/wk; the median total cumulative dose was 195 U. No dose limiting systemic toxicity was detected. Neurologic toxicity occurred only at doses above 16 U/wk. We conclude that continuously infused IT bleomycin is well tolerated; the MTD (and recommended dose for a phase II efficacy trial) of IT bleomycin is 16 U/wk.
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References
Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68: 1–17, 1988
Tomita T: Interstitial chemotherapy for brain tumors: a review. J Neuro-Oncol 10: 57–74, 1991
Vats TS, Morantz RA, Wood GW, Tizler BA: Study of effectiveness of bleomycin in rat brain tumor model intravenously and intracerebrally. Int J Radiat Oncol Phys 5: 1527–1529, 1979
Nakazawa S, Ohwaki K, Shimura T, Itoh Y, Yajima K: Anew treatment of malignant brain tumors. 1. Local injection of bleomycin. No Shinkei Geka 9: 1487–1493, 1981
Nakazawa S, Itoh Y, Shimura T, Matsumoto M, Yajima K: A new treatment of brain neoplasms. 2. Local injection of adriamycin. No Shinkei Geka 11: 821–827, 1983
Shimura T, Nakazawa S, Itoh Y, Matsumoto M: Effect of local injections of adriamycin on survival in malignant brain tumors: histopathological evaluation. Gan To Kagaku Ryoho 10: 1179–1187, 1983
Kimler BF, Liu C, Evans RG, Morantz RA: Intracerebral chemotherapy in the 9L rat tumor model. J Neuro-Oncol 14: 191–200, 1992
Kroin JS, Penn RD: Intracerebral chemotherapy: chronic microinfusion of cisplatin. Neurosurgery 10: 349–354, 1982
Tator CH, Wassenaar W, Day A, So WS: Therapy of an experimental glioma with systemic or intraneoplastic methotrexate or radiation. J Neurosurg 46: 175–184, 1977
Brem H, Gabikian P: Biodegradable polymer implants to treat brain tumors. J Control Release 74: 63–67, 2001
Smith TJ, Pearson PA, Blandford DL, Brown JD, Goins KA, Hollins JL, Schmeisser ET, Glavinos P, Baldwin LB, Ashton P: Intravitreal sustained-release ganciclovir. Arch Ophthalmol 110: 255–258, 1992
Anand R, Nightingale SD, Fish RH, Smith TJ, Ashton P: Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir. Arch Ophthalmol 111: 223–227, 1993
Martin DF, Parks DJ, Mellow SD, Ferris FL, Walton RC, Ramaley NA, Chew EY, Ashton P, Davis MD, Nussenblatt RB: Treatment of cytomegalovirus retinitis with an intraocular sustained release ganciclovir implant: a randomized controlled clinical trial. Arch Ophthalmol 112: 1531–1539, 1994
Morantz RA, Kimler BF, Vats TS, Henderson SD: Bleomycin and brain tumors: a review. J Neuro-Oncol 1: 249–255, 1983
Kanno T, Kudo T, Nakazawa T: Anti-brain tumor activity of bleomycin. Clin Neurol 10: 409–414, 1970
Bosch DA, Hindmarsch T, Larsson, Backlund EO: Intraneoplastic administration of Bleomycin in intracerebral gliomas: a pilot study. Acta Neurochir 30(Suppl): 441–444, 1980
Takahashi H, Nakazawa S, Shimura T: Evaluation of postoperative intratumoral injection of bleomycin for craniopharyngioma in children. J Neurosurg 62: 120–127, 1985
Zulch KJ (ed): Histological Typing of Tumours of the Central Nervous System: International Classification of Tumours. World Health Organization: Geneva, 1979
Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM (ed) Evaluation of Chemotherapeutic Agents, 1949, pp. 191–205. Columbia University Press, New York
Schneiderman MA: Mouse to man. Statistical problems in bringing a drug to clinical trial. In: Proceedings of the fifth Berkeley symposium on mathematical statistical probability, University of California 4: 855–866, 1967
Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10: 239–253, 1992
Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastomas. Neurology 30: 907–911, 1980
Hoshino T, Barker M, Wilson CB, Boldrey EB, Fewer D: Cell kinetics of human gliomas. J Neurosurg 37: 15–26, 1972
Hoshino T, Nagashima T, Cho KG, Murovic JA, Hodes JE, Wilson CB, Edwards MS, Pitts LH: S phase fraction of human brain tumors in situ measured by uptake of bromodeoxyuridine. Int J Cancer 38: 369–374, 1986
Engelhard HH: The role of interstitial BCNU chemotherapy in treatment of malignant gliomas. Surg Neurol 53: 458–464, 2000
Blum RH, Carter SK, Agre K: A clinical review of bleomycin-a new antineoplastic agent. Cancer 31: 903–914, 1973
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Patchell, R.A., Regine, W.F., Ashton, P. et al. A Phase I Trial of Continuously Infused Intratumoral Bleomycin for the Treatment of Recurrent Glioblastoma Multiforme. J Neurooncol 60, 37–42 (2002). https://doi.org/10.1023/A:1020291229317
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DOI: https://doi.org/10.1023/A:1020291229317