Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas

Henry BremDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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M. Stephen Mahaley Jr.Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Nicholas A. VickDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Keith L. BlackDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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S. Clifford Schold Jr.Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Peter C. BurgerDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Allan H. FriedmanDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Ivan S. CiricDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Theodore W. EllerDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Jeffrey W. CozzensDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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James N. KenealyDepartment of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Neurological Surgery, University of Alabama, Birmingham, Alabama; Department of Neurology and Division of Neurosurgery, Northwestern University, Evanston Hospital, Evanston, Illinois; Department of Neurosurgery, University of California, Los Angeles, California; Departments of Neurology and Pathology and Division of Neurosurgery, Duke University, Durham, North Carolina; and Clinical Research Department, Nova Pharmaceutical Corporation, Baltimore, Maryland

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Page Range:
441–446
Volume/Issue:
Volume 74: Issue 3
DOI link:
https://doi.org/10.3171/jns.1991.74.3.0441
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✓ Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I–II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks.

Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy.

Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.

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Contributor Notes

Address reprint requests to: Henry Brem, M.D., Department of Neurosurgery, Johns Hopkins Hospital, Meyer 7–113, 600 North Wolfe Street, Baltimore, Maryland 21205.
  • 1.

    Ammirati M, , Galicich JH, & Arbit E, et al: Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 21:607–614, 1987 Ammirati M, Galicich JH, Arbit E, et al: Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 21:607–614, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Barba D, , Saris SC, & Holder C, et al: Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70:175–182, 1989 Barba D, Saris SC, Holder C, et al: Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70:175–182, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Bindschnedler C, , Leong KW, & Mathiowitz E, et al: Polyanhydride microsphere formulation by solvent extraction. J Pharra Sci 77:696–698, 1988 Bindschnedler C, Leong KW, Mathiowitz E, et al: Polyanhydride microsphere formulation by solvent extraction. J Pharra Sci 77:696–698, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Brem H: Controlled-release polymer systems for drug delivery to the brain. Polymer Preprints 31:229, 1990 (Abstract) Brem H: Controlled-release polymer systems for drug delivery to the brain. Polymer Preprints 31:229, 1990 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 5.

    Brem H: Polymers to treat brain tumors. Biomaterials (In press, 1990) Brem H: Polymers to treat brain tumors. Biomaterials (In press, 1990)

    • Search Google Scholar
    • Export Citation
  • 6.

    Brem H, , Kader A, & Epstein JI, et al: Controlled delivery of 1,3,-bis(2-chloroethyl)-1-nitrosourea from ethylenevinyl acetate copolymer. Select Cancer Ther 5:55–65, 1989 Brem H, Kader A, Epstein JI, et al: Controlled delivery of 1,3,-bis(2-chloroethyl)-1-nitrosourea from ethylenevinyl acetate copolymer. Select Cancer Ther 5:55–65, 1989

    • Search Google Scholar
    • Export Citation
  • 7.

    Brem H, , Tamargo RJ, & Olivi A: Delivery of drugs to the brain by use of a sustained release polymer system, in Salem H (ed): New Technologies and Concepts for Reducing Drug Toxication. Caldwell, NJ: Telford Press, 1990 (In press) Brem H, Tamargo RJ, Olivi A: Delivery of drugs to the brain by use of a sustained release polymer system, in Salem H (ed): New Technologies and Concepts for Reducing Drug Toxication. Caldwell, NJ: Telford Press, 1990 (In press)

    • Search Google Scholar
    • Export Citation
  • 8.

    Butti G, , Knerich R, & Tanghetti B, et al: Perioperative carmustine chemotherapy for malignant brain tumors. Cancer Treat Rep 68:1505–1506, 1984 Butti G, Knerich R, Tanghetti B, et al: Perioperative carmustine chemotherapy for malignant brain tumors. Cancer Treat Rep 68:1505–1506, 1984

    • Search Google Scholar
    • Export Citation
  • 9.

    Chasin M, , Domb A, & Ron E, et al: Polyanhydrides as drug delivery systems, in Langer R, & Chasin M (eds): Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990, pp 43–70 Chasin M, Domb A, Ron E, et al: Polyanhydrides as drug delivery systems, in Langer R, Chasin M (eds): Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990, pp 43–70

    • Search Google Scholar
    • Export Citation
  • 10.

    Chasin M, , Lewis D, & Langer R: Polyanhydrides for controlled drug delivery. Biopharm Manufact 1:33–46, 1988 Chasin M, Lewis D, Langer R: Polyanhydrides for controlled drug delivery. Biopharm Manufact 1:33–46, 1988

    • Search Google Scholar
    • Export Citation
  • 11.

    Domb A, & Langer R: I. Preparation of high molecular weight polyanhydride. J Polymer Sci 25:3373–3386, 1987 Domb A, Langer R: I. Preparation of high molecular weight polyanhydride. J Polymer Sci 25:3373–3386, 1987

    • Search Google Scholar
    • Export Citation
  • 12.

    Domb A, & Langer R: Polyanhydrides for controlled drug delivery. Makromol Chem Macromol Symp 19:189–200, 1988 Domb A, Langer R: Polyanhydrides for controlled drug delivery. Makromol Chem Macromol Symp 19:189–200, 1988

    • Search Google Scholar
    • Export Citation
  • 13.

    Domb A, , Ron E, & Langer R: Polyanhydride II: one step polymerization using phosgene or diphosgene as coupling agents. Macromolecules 12:1925–1929, 1988 Domb A, Ron E, Langer R: Polyanhydride II: one step polymerization using phosgene or diphosgene as coupling agents. Macromolecules 12:1925–1929, 1988

    • Search Google Scholar
    • Export Citation
  • 14.

    Grossman SA, , Rienhard CS, & Brem H, et al: The intracerebral delivery of BCNU with surgically implanted bioerodible polymers: a quantitative autoradiographic study. Proc Am Soc Clin Oncol 7:84, 1988 (Abstract) Grossman SA, Rienhard CS, Brem H, et al: The intracerebral delivery of BCNU with surgically implanted bioerodible polymers: a quantitative autoradiographic study. Proc Am Soc Clin Oncol 7:84, 1988 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 15.

    Harbaugh RE, , Saunders RL, & Reeder RF: Use of implantable pumps for central nervous system drug infusions to treat neurological disease. Neurosurgery 23:693–698, 1988 Harbaugh RE, Saunders RL, Reeder RF: Use of implantable pumps for central nervous system drug infusions to treat neurological disease. Neurosurgery 23:693–698, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Harsh GR IV, , Levin VA, & Gutin PH, et al: Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery 21:615–621, 1987 Harsh GR IV, Levin VA, Gutin PH, et al: Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery 21:615–621, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Hochberg FH, & Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911, 1980 Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911, 1980

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Hochberg FH, , Pruitt AA, & Beck DO, et al: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma. J Neurosurg 63:876–880, 1985 Hochberg FH, Pruitt AA, Beck DO, et al: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma. J Neurosurg 63:876–880, 1985

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Karnofsky DA, , Abelmann WH, & Craver LF, et al: Nitrogen mustards in Hodgkins disease. Lancet 1:889–901, 1947 Karnofsky DA, Abelmann WH, Craver LF, et al: Nitrogen mustards in Hodgkins disease. Lancet 1:889–901, 1947

    • Search Google Scholar
    • Export Citation
  • 20.

    Kornblith PL, & Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68:1–17, 1988 Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68:1–17, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Kumar PP, , Good RR, & Jones EO, et al: Contrast-enhancing computed tomography ring in glioblastoma after intraoperative endocurietherapy. Cancer 61:1759–1765, 1988 Kumar PP, Good RR, Jones EO, et al: Contrast-enhancing computed tomography ring in glioblastoma after intraoperative endocurietherapy. Cancer 61:1759–1765, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Leong KW, , Brott BC, & Langer R: Bioerodible polyanhydrides as drug-carrier matrices. I. Characterization, degradation and release characteristics. J Biomed Mat Res 19:941–955, 1985 Leong KW, Brott BC, Langer R: Bioerodible polyanhydrides as drug-carrier matrices. I. Characterization, degradation and release characteristics. J Biomed Mat Res 19:941–955, 1985

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Leong KW, , D'Amore P, & Marietta M, et al: Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity. J Biomed Mat Res 20:51–64, 1986 Leong KW, D'Amore P, Marietta M, et al: Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity. J Biomed Mat Res 20:51–64, 1986

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Leong KW, , Simonte V, & Langer R: Synthesis of polyanhydrides: melt-polycondensation, dehydrochlorination, and dehydrative coupling. Macromolecules 20:705–712, 1987 Leong KW, Simonte V, Langer R: Synthesis of polyanhydrides: melt-polycondensation, dehydrochlorination, and dehydrative coupling. Macromolecules 20:705–712, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Loo TL, , Dion RL, & Sixon RL, et al: The antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea. J Pharm Sci 55:492–497, 1966 Loo TL, Dion RL, Sixon RL, et al: The antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea. J Pharm Sci 55:492–497, 1966

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Mathiowitz E, & Langer R: Polyanhydride microspheres as drug carriers. J Controlled Release 5:13–22, 1987 Mathiowitz E, Langer R: Polyanhydride microspheres as drug carriers. J Controlled Release 5:13–22, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Mathiowitz E, , Saltzman M, & Domb A, et al: Polyanhydride microspheres as drug carriers. II. Microencapsulation by solvent removal. J Appl Polymer Sci 35:755–774, 1988 Mathiowitz E, Saltzman M, Domb A, et al: Polyanhydride microspheres as drug carriers. II. Microencapsulation by solvent removal. J Appl Polymer Sci 35:755–774, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Mcbiddle EK, , Selby PJ, & Perren TJ, et al: High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma. Br J Cancer 58:779–782, 1988 Mcbiddle EK, Selby PJ, Perren TJ, et al: High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma. Br J Cancer 58:779–782, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Neuwelt EA, , Howieson J, & Frenkel EP, et al: Therapeutic efficacy of multiagent chemotherapy with drug delivery enhanced by blood-brain barrier modification in glioblastoma. Neurosurgery 19:573–582, 1986 Neuwelt EA, Howieson J, Frenkel EP, et al: Therapeutic efficacy of multiagent chemotherapy with drug delivery enhanced by blood-brain barrier modification in glioblastoma. Neurosurgery 19:573–582, 1986

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Penta JS, , Rosencweiz M, & Guarino AM, et al: Mouse and large-animal toxicology studies of twelve antitumor agents: relevance to starting dose for Phase I clinical trials. Cancer Chemother Pharmacol 3:97–101, 1979 Penta JS, Rosencweiz M, Guarino AM, et al: Mouse and large-animal toxicology studies of twelve antitumor agents: relevance to starting dose for Phase I clinical trials. Cancer Chemother Pharmacol 3:97–101, 1979

    • Search Google Scholar
    • Export Citation
  • 31.

    Tamargo RJ, , Epstein JI, & Reinhard CS, et al: Brain biocompatibility of a biodegradable controlled release polymer in rats. J Biomed Mat Res 23:253–266, 1989 Tamargo RJ, Epstein JI, Reinhard CS, et al: Brain biocompatibility of a biodegradable controlled release polymer in rats. J Biomed Mat Res 23:253–266, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Willis BK, , Heilbrun MP, & Sapozink MD, et al: Stereotactic interstitial brachytherapy of malignant astrocytomas with remarks on postimplantation computed tomographic appearance. Neurosurgery 23:348–354, 1988 Willis BK, Heilbrun MP, Sapozink MD, et al: Stereotactic interstitial brachytherapy of malignant astrocytomas with remarks on postimplantation computed tomographic appearance. Neurosurgery 23:348–354, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Wolpert SM, , Swan ES, & Heros D, et al: Selective delivery of chemotherapeutic agents with a new catheter system. Radiology 166:547–549, 1988 Wolpert SM, Swan ES, Heros D, et al: Selective delivery of chemotherapeutic agents with a new catheter system. Radiology 166:547–549, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Yang MB, , Tamargo RJ, & Brem H: Controlled delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer. Cancer Res 49:5103–5107, 1989 Yang MB, Tamargo RJ, Brem H: Controlled delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer. Cancer Res 49:5103–5107, 1989

    • Search Google Scholar
    • Export Citation
  • 35.

    Zar JH: Biostatistical Analysis. Englewood Cliffs, NJ: Prentice Hall, 1984 Zar JH: Biostatistical Analysis. Englewood Cliffs, NJ: Prentice Hall, 1984

    • Search Google Scholar
    • Export Citation

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