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Journal of Neuro-Oncology

, Volume 83, Issue 1, pp 61–70 | Cite as

Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience

  • H. Christopher Lawson
  • Prakash Sampath
  • Eileen Bohan
  • Michael C. Park
  • Namath Hussain
  • Alessandro Olivi
  • Jon Weingart
  • Lawrence Kleinberg
  • Henry Brem
Clinical–Patient Studies

Abstract

Malignant gliomas are very difficult neoplasms for clinicians to treat. The reason for this is multifaceted. Many treatments that are effective for systemic cancer are unable to cross the blood-brain barrier and/or have unacceptable systemic toxicities. Consequently, in recent years an effort has been placed on trying to develop innovative local treatments that bypass the blood-brain barrier and allow for direct treatment in the central nervous system (CNS)—interstitial treatment. In this paper, we present our extensive experience in using interstitial chemotherapy as a strategy to treat malignant brain tumors at a single institution (The Johns Hopkins Hospital). We provide a comprehensive summary of our preclinical work on interstitial chemotherapy at the Hunterian Neurosurgery Laboratory, reviewing data on rat, rabbit, and monkey studies. Additionally, we present our clinical experience with randomized placebo-controlled studies for the treatment of malignant gliomas. We compare survival statistics for those patients who received placebo versus Gliadel® as initial therapy (11.6 months vs. 13.9 months, respectively) and at the time of tumor recurrence (23 weeks vs. and 31 weeks, respectively). We also discuss the positive impact of local therapy in avoiding the toxicities associated with systemic treatments. Furthermore, we provide an overview of newer chemotherapeutic agents and other strategies used in interstitial treatment. Finally, we offer insight into some of the lessons we have learned from our unique perspective.

Keywords

Carmustine·Gliadel® Glioblastoma multiforme Interstitial chemotherapy Malignant glioma 

Notes

Acknowledgements

Disclosure: Dr. Henry Brem and the Johns Hopkins University are entitled to a share of royalty by MGI Pharma, Inc. on potential sales of some products that are in development and described in this work. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Prakash Sampath is a member of the Speakers Bureau for MGI Pharma, Inc., formerly Guildford Pharmaceuticals, Inc.

References

  1. 1.
    Black PM (1991) Brain tumors. Part 1. N Engl J Med 324:1471–1476CrossRefGoogle Scholar
  2. 2.
    Kornblith PL, Walker M (1988) Chemotherapy for malignant gliomas. J Neurosurg 68:1–17PubMedGoogle Scholar
  3. 3.
    Hochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911PubMedGoogle Scholar
  4. 4.
    Sampath P, Long DM, Brem H (2000) The Hunterian Neurosurgical Laboratory: the first 100 years of neurosurgical research. Neurosurgery 46:184–194PubMedCrossRefGoogle Scholar
  5. 5.
    Guerin C, Laterra J, Drewes LR, Brem H, Goldstein GW (1992) Vascular expression of glucose transporter in experimental brain neoplasms. Am J Pathol 140:417–425PubMedGoogle Scholar
  6. 6.
    Guerin C, Wolff JE, Laterra J, Drewes LR, Brem H, Goldstein GW (1992) Vascular differentiation and glucose transporter expression in rat gliomas: effects of steroids. Ann Neurol 31:481–487PubMedCrossRefGoogle Scholar
  7. 7.
    Sampath P, Hanes J, DiMeco F, Tyler BM, Brat D, Pardoll DM, Brem H (1999) Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors. Cancer Res 59:2107–2114PubMedGoogle Scholar
  8. 8.
    Thompson RC, Pardoll DM, Jaffee EM, Ewend MG, Thomas MC, Tyler BM, Brem H (1996) Systemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors. J Immunother Emphasis Tumor Immunol 19:405–413PubMedGoogle Scholar
  9. 9.
    Weingart JD, Thompson RC, Tyler B, Colvin OM, Brem H (1995) Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model. Int J Cancer 62:605–609PubMedCrossRefGoogle Scholar
  10. 10.
    Weingart JD, Sipos EP, Brem H (1995) The role of minocycline in the treatment of intracranial 9L glioma. J Neurosurg 82:635–640PubMedGoogle Scholar
  11. 11.
    Sampath P, Brem H (1998) Implantable slow-release chemotherapeutic polymers for the treatment of malignant brain tumors. Cancer Control 5:130–137PubMedGoogle Scholar
  12. 12.
    Walter KA, Tamargo RJ, Olivi A, Burger PC, Brem H (1995) Intratumoral chemotherapy. Neurosurgery 37:1128–1145PubMedCrossRefGoogle Scholar
  13. 13.
    Langer R, Folkman J (1996) Polymers for the sustained release of proteins and other macromolecules. Nature 263:797–800CrossRefGoogle Scholar
  14. 14.
    Tamargo RJ, Myseros JS, Epstein JI, Yang MB, Chasin M, Brem H (1993) Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain. Cancer Res 53:329–333PubMedGoogle Scholar
  15. 15.
    Brem H (1990) Polymers to treat brain tumours. Biomaterials 11:699–701PubMedCrossRefGoogle Scholar
  16. 16.
    Leong KW, Brott BC, Langer R (1985) Bioerodible polyanhydrides as drug-carrier matrices. I: characterization, degradation, and release characteristics. J Biomed Mater Res 19:941–955PubMedCrossRefGoogle Scholar
  17. 17.
    Tamargo RJ, Epstein JI, Reinhard CS, Chasin M, Brem H (1989) Brain biocompatibility of a biodegradable, controlled-release polymer in rats. J Biomed Mater Res 23:253–266PubMedCrossRefGoogle Scholar
  18. 18.
    Brem H, Kader A, Epstein JI, Tamargo RJ, Domb A, Langer R, Leong KW (1989) Biocompatibility of a biodegradable, controlled-release polymer in the rabbit brain. Sel Cancer Ther 5:55–65PubMedGoogle Scholar
  19. 19.
    Yang MB, Tamargo RJ, Brem H (1989) Controlled delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer. Cancer Res 49:5103–5107PubMedGoogle Scholar
  20. 20.
    Grossman SA, Reinhard C, Colvin OM, Chasin M, Brundrett R, Tamargo RJ, Brem H (1992) The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg 76:640–647PubMedGoogle Scholar
  21. 21.
    Brem H, Tamargo RJ, Olivi A, Pinn M, Weingart JD, Wharam M, Epstein JI (1994) Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain. J Neurosurg 80:283–290PubMedGoogle Scholar
  22. 22.
    Fung LK, Ewend MG, Sills A, Sipos EP, Thompson R, Watts M, Colvin OM, Brem H, Saltzman WM (1998) Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58:672–684PubMedGoogle Scholar
  23. 23.
    Bohan E, Brem H (1997) Treatment of brain tumors by local delivery of chemotherapy via biodegradable polymers. Hospital Pharmacist Report (Supplement):12–16Google Scholar
  24. 24.
    Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M (1995) The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol 26:111–123PubMedCrossRefGoogle Scholar
  25. 25.
    Brem H, Langer R (1996) Polymer-based drug delivery to the brain. Sci Med 3:2–11Google Scholar
  26. 26.
    Brem H, Mahaley MS Jr, Vick NA, Black KL, Schold SC Jr, Burger PC, Friedman AH, Ciric IS, Eller TW, Cozzens JW et al (1991) Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74:441–446PubMedGoogle Scholar
  27. 27.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345:1008–1012Google Scholar
  28. 28.
    Sipos EP, Tyler B, Piantadosi S, Burger PC, Brem H (1997) Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors. Cancer Chemother Pharmacol 39:383–389PubMedCrossRefGoogle Scholar
  29. 29.
    Olivi A, Grossman SA, Tatter S, Barker F, Judy K, Olsen J, Bruce J, Hilt D, Fisher J, Piantadosi S (2003) Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a new approaches to brain tumor therapy CNS consortium trial. J Clin Oncol 21:1845–1849PubMedCrossRefGoogle Scholar
  30. 30.
    Valtonen S, Timonen U, Toivanen P, Kalimo H, Kivipelto L, Heiskanen O, Unsgaard G, Kuurne T (1997) Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41:44–48PubMedCrossRefGoogle Scholar
  31. 31.
    Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol 5:79–88PubMedCrossRefGoogle Scholar
  32. 32.
    Kleinberg LR, Weingart J, Burger P, Carson K, Grossman SA, Li K, Olivi A, Wharam MD, Brem H (2004) Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management. Cancer Invest 22:1–9PubMedCrossRefGoogle Scholar
  33. 33.
    Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, Grossman SA, Cairncross JG (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1886–1893Google Scholar
  34. 34.
    Renaudin J, Fewer D, Wilson CB, Boldrey EB, Calogero J, Enot KJ (1973) Dose dependency of decadron in patients with partially excised brain tumors. J Neurosurg 39:302–305PubMedGoogle Scholar
  35. 35.
    Ewend MG, Williams JA, Tabassi K, Tyler BM, Babel KM, Anderson RC, Pinn ML, Brat DJ, Brem H (1996) Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Res 56:5217–5223PubMedGoogle Scholar
  36. 36.
    Ewend MG, Sampath P, Williams JA, Tyler BM, Brem H (1998) Local delivery of chemotherapy prolongs survival in experimental brain metastases from breast carcinoma. Neurosurgery 43:1185–1193PubMedCrossRefGoogle Scholar
  37. 37.
    Ewend MG, Brem S, Gilbert M, Goodkin R, Penar P (2004) Treating single brain metastasis with resection, placement of BCNU-polymer wafers, and radiation therapy (abstract). Presented at: 72nd Annual Meeting of the American Association of Neurological Surgeons, Toronto, Canada, April 24–26, 2001. Available at: http://www.aans.org/Library/Article.aspx?ArticleId=13719. Accessed October 15
  38. 38.
    Golden GA, Meldorf M, Group at PS (2004) Patients with metastatic brain cancer, undergoing resection and Gliadel® implantation experienced low local recurrence rates in the PROLONG® Registry (abstract). Presented at the Annual Meeting of the Society of Neuro-Oncology, Abstract TA-25, Toronto, Canada; November 18–21Google Scholar
  39. 39.
    Brem S, Staller A, Wotoczek-Obadia Mea, Robb J, Vrionis FD, Pearlman JL, Rojiani A, Snodgrass S (2004) Interstitial chemotherapy for local control of CNS metastases. Presented at the annual meeting of the Soc Neuro-Oncology, Abstract TA-06, Toronto, Canada; November 18–21Google Scholar
  40. 40.
    Pegg AE, Boosalis M, Samson L, Moschel RC, Byers TL, Swenn K, Dolan ME (1993) Mechanism of inactivation of human O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. Biochemistry 32:11998–12006PubMedCrossRefGoogle Scholar
  41. 41.
    Felker GM, Friedman HS, Dolan ME, Moschel RC, Schold C (1993) Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol 32:471–476PubMedCrossRefGoogle Scholar
  42. 42.
    Rhines LD, Sampath P, Dolan ME, Tyler BM, Brem H, Weingart J (2000) O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma. Cancer Res 60:6307–6310PubMedGoogle Scholar
  43. 43.
    Walter KA, Cahan MA, Gur A, Tyler B, Hilton J, Colvin OM, Burger PC, Domb A, Brem H (1994) Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma. Cancer Res 54:2207–2212PubMedGoogle Scholar
  44. 44.
    Cahan MA, Walter KA, Colvin OM, Brem H (1994) Cytotoxicity of taxol in vitro against human and rat malignant brain tumors. Cancer Chemother Pharmacol 33:441–444PubMedGoogle Scholar
  45. 45.
    Olivi A, Ewend MG, Utsuki T, Tyler B, Domb AJ, Brat DJ, Brem H (1996) Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat. Cancer Chemother Pharmacol 39:90–96PubMedCrossRefGoogle Scholar
  46. 46.
    Storm PB, Moriarity JL, Tyler B, Burger PC, Brem H, Weingart J (2002) Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy. J Neurooncol 56:209–217PubMedCrossRefGoogle Scholar
  47. 47.
    Sampath P, Amundson E, Wall ME, Tyler BM, Wani MC, Alderson LM, Colvin M, Brem H, Weingart JD (2003) Camptothecin analogs in malignant gliomas: comparative analysis and characterization. J Neurosurg 98:570–577PubMedCrossRefGoogle Scholar
  48. 48.
    Judy KD, Olivi A, Buahin KG, Domb A, Epstein JI, Colvin OM, Brem H (1995) Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas. J Neurosurg 82:481–486PubMedCrossRefGoogle Scholar
  49. 49.
    Sipos EP, Witham TF, Ratan R, Burger PC, Baraban J, Li KW, Piantadosi S, Brem H (2001) l-buthionine sulfoximine potentiates the antitumor effect of 4-hydroperoxycyclophosphamide when administered locally in a rat glioma model. Neurosurgery 48:392–400PubMedCrossRefGoogle Scholar
  50. 50.
    DiMeco F, Li KW, Tyler BM, Wolf AS, Brem H, Olivi A (2002) Local delivery of mitoxantrone for the treatment of malignant brain tumors in rats. J Neurosurg 97:1173–1178PubMedGoogle Scholar
  51. 51.
    Frazier JL, Wang PP, Case D, Tyler BM, Pradilla G, Weingart JD, Brem H (2003) Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma. J Neurooncol 64:203–209PubMedCrossRefGoogle Scholar
  52. 52.
    Rhines LD, Sampath P, DiMeco F, Lawson HC, Tyler BM, Hanes J, Olivi A, Brem H (2003) Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma. Neurosurgery 52:872–879PubMedCrossRefGoogle Scholar
  53. 53.
    Richards Grayson AC, Choi IS, Tyler BM, Wang PP, Brem H, Cima MJ, Langer R (2003) Multi-pulse drug delivery from a resorbable polymeric microchip device. Nat Mater 2:767–772PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • H. Christopher Lawson
    • 1
  • Prakash Sampath
    • 3
    • 5
  • Eileen Bohan
    • 1
  • Michael C. Park
    • 3
  • Namath Hussain
    • 4
  • Alessandro Olivi
    • 1
    • 2
  • Jon Weingart
    • 1
    • 2
  • Lawrence Kleinberg
    • 1
    • 2
  • Henry Brem
    • 1
    • 2
  1. 1.Department of Neurological SurgeryJohns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of Radiation OncologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of Clinical Neurosciences Program in NeurosurgeryBrown Medical School, Rhode Island HospitalProvidenceUSA
  4. 4.Department of NeurosurgeryUniversity of ArizonaTucsonUSA
  5. 5.Roger Williams HospitalProvidenceUSA

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