Treatment of Brain Tumors

  • Betty M. Tyler
  • Gustavo Pradilla
  • Uri Hadelsberg
  • Hansen Bow
  • Ian Suk
  • Henry Brem
Part of the Advances in Delivery Science and Technology book series (ADST)


Malignant brain tumors are typically characterized by high rates of invasiveness and resistance to many forms of treatment. The main treatment modalities for malignant brain tumors consist of maximum safe surgical resection, chemotherapy, radiosurgery, or combination of these. Locally delivered chemotherapy is particularly suitable for brain tumor therapy following surgical resection since it bypasses the blood–brain barrier, maintains a higher stable drug concentration for longer periods of time, and has a more extensive distribution in the peritumoral areas than systemically administered chemotherapy with subsequent tumoricidal effects. The development of Gliadel, a BCNU-loaded polymer, approved in 1996 and successfully evaluated in clinical trials, has opened the door for a new arsenal of drugs for treatment of malignant primary brain tumors. New chemotherapeutic agents such as platinum-derived drugs, antiangiogenic compounds, and immunomodulatory molecules, among others, have undergone successful preclinical testing and await further clinical evaluation. A new generation of drug delivery microchips, gene-targeted drugs, and nanocarriers will enable simultaneous treatment with multiple agents based on the histological phenotype and genotype profile, which should result in highly individualized and more effective treatments for patients with this devastating disease.


Malignant Glioma Malignant Brain Tumor PLGA Microsphere Sebacic Acid Recurrent Glioma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hulleman E, Helin K (2005) Molecular mechanisms in gliomagenesis. Adv Cancer Res 94:1–27PubMedGoogle Scholar
  2. 2.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068, Epub 2008 Sep 4Google Scholar
  3. 3.
    Gaspar LE, Fisher BJ, Macdonald DR, LeBer DV, Halperin EC, Schold SC Jr, Cairncross JG (1992) Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 24:55–57PubMedGoogle Scholar
  4. 4.
    Palanichamy K, Erkkinen M, Chakravarti A (2006) Predictive and prognostic markers in human glioblastomas. Curr Treat Options Oncol 7:490–504PubMedGoogle Scholar
  5. 5.
    Kornblith PL, Walker M (1988) Chemotherapy for malignant gliomas. J Neurosurg 68:1–17PubMedGoogle Scholar
  6. 6.
    Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 4:278–299PubMedCentralPubMedGoogle Scholar
  7. 7.
    Stupp HME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466PubMedGoogle Scholar
  8. 8.
    McGirt MJ, Than KD, Weingart JD, Chaichana KL, Attenello FJ, Olivin A, Laterra J, Kleinberg LR, Grossman SA, Brem H et al (2009) Gliadel (BCNU) wafers plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 110:583–588PubMedGoogle Scholar
  9. 9.
    Lacroix M, Abi-Said D, Fourney DR et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198PubMedGoogle Scholar
  10. 10.
    Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–766PubMedGoogle Scholar
  11. 11.
    Sanai N, Polley M, McDermott MW et al (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–8PubMedGoogle Scholar
  12. 12.
    Schneider JP, Trantakis C, Rubach M, Schulz T, Dietrich J, Winkler D, Renner C, Schober R, Geiger K, Brosteanu O et al (2005) Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme—a quantitative radiological analysis. Neuroradiology 47(7):489–500. doi: 10.1007/s00234-005-1397-1 PubMedGoogle Scholar
  13. 13.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, ALA-Glioma Study Group (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401PubMedGoogle Scholar
  14. 14.
    Butowski NA, Sneed PK, Chang SM (2006) Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 24:1273–1280PubMedGoogle Scholar
  15. 15.
    Newton HB, Junck L, Bromberg J et al (1990) Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure. Neurology 40:1743–1746PubMedGoogle Scholar
  16. 16.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedGoogle Scholar
  17. 17.
    Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129PubMedGoogle Scholar
  18. 18.
    Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedGoogle Scholar
  19. 19.
    Hansen RJ, Nagasubramanian R, Delaney SM, Samson LD, Dolan ME (2007) Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice. Carcinogenesis 28:1111–1116PubMedGoogle Scholar
  20. 20.
    Hau P, Koch D, Hundsberger T et al (2007) Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology 68:688–690PubMedGoogle Scholar
  21. 21.
    National Comprehensive Cancer Network. NCCN guidelines version 2.2011: central nervous system cancers. Available at: Accessed 16 Aug 2011
  22. 22.
    Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740PubMedGoogle Scholar
  23. 23.
    Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan in recurrent glioblastoma. J Clin Oncol 27:740–745PubMedGoogle Scholar
  24. 24.
    FDA Briefing Document Oncology Drug Advisory Committee Meeting, March 31, 2009.
  25. 25.
    Guckenberger M, Mayer M, Buttmann M, Vince GH, Sweeney RA, Flentie M (2011) Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme. Strahlenther Onkol 187(9):548–554PubMedGoogle Scholar
  26. 26.
    Cohen-Jonathan ME (2011) Optimization of the radiotherapy for the gliomas: hopes and research axis for the next future. Rev Neurol (Paris) 167(10):656–660Google Scholar
  27. 27.
    Guerin C, Laterra J, Hruban RH, Brem H, Drewes LR, Goldstein GW (1990) The glucose transporter and the blood–brain barrier of human brain tumors. Ann Neurol 28:758–765PubMedGoogle Scholar
  28. 28.
    Lee J, Lund-Smith C, Borboa A, Gonzalez AM, Baird A, Eliceiri BP (2009) Glioma-induced remodeling of the neurovascular unit. Brain Res 1288:125–134, Epub 2009 Jul 9PubMedCentralPubMedGoogle Scholar
  29. 29.
    Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129(4):877–896, ReviewPubMedGoogle Scholar
  30. 30.
    Goodman LS, Hardman JG, Limbird LE, Gilman AG (eds) (2001) Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York, NY. pp xxvii, 2148. [2141] fold leaf of platesGoogle Scholar
  31. 31.
    Hannigan E, Green S, Alberts DS, O’toole R, Surwit E (1993) Results of a southwest oncology group phase III trial of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in advanced ovarian cancer. Oncology 50(Suppl 2):2–9PubMedGoogle Scholar
  32. 32.
    Slichenmyer WJ, Rowinsky EK, Dohenower RC, Kaufmann SH (1993) The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85(4):271–291PubMedGoogle Scholar
  33. 33.
    Abbott NJ, Romero IA (1996) Transporting therapeutics across the blood–brain barrier. Mol Med Today 2(3):106–113PubMedGoogle Scholar
  34. 34.
    Grieg NH (1987) Optimizing drug delivery to brain tumors. Cancer Treat Rev 14(1):1–28Google Scholar
  35. 35.
    Rautioa J, Chikhale PJ (2004) Drug delivery systems for brain tumor therapy. Curr Pharm Des 10(12):1341–1353PubMedGoogle Scholar
  36. 36.
    Kushara H, Sugiyama Y (2001) Efflux transport systems for drugs at the blood–brain barrier and blood-cerebrospinal fluid barrier (Part 1). Drug Discov Today 6(3):150–156Google Scholar
  37. 37.
    McDannold N, Vykhodtseva N, Hynynen K (2008) Blood–brain barrier disruption induced by focused ultrasound and circulating performed microbubbles appears to be characterized by the mechanical index. Ultrasound Med Biol 34(5):834–840PubMedCentralPubMedGoogle Scholar
  38. 38.
    Auffinger B, Thaci B, Nigam P, Rincon E, Cheng Y, Lesniak MS (2012) New therapeutic approaches for malignant glioma: in search of the Rosetta stone. F1000 Med Rep 4:18, Epub 2012 Sep 5PubMedCentralPubMedGoogle Scholar
  39. 39.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760, Epub 2006 Oct 18PubMedGoogle Scholar
  40. 40.
    Biswas T, Okunieff P, Schell MC, Smudzin T, Pilcher WH, Bakos RS, Vates GE, Walter KA, Wensel A, Korones DN, Milano MT (2009) Stereotactic radiosurgery for glioblastoma: retrospective analysis. Radiat Oncol 4:11PubMedCentralPubMedGoogle Scholar
  41. 41.
    Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, Friedman HS, Willett CG, Kirkpatrick JP (2012) Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 82(5):2018–2024, Epub 2011 Apr 12PubMedCentralPubMedGoogle Scholar
  42. 42.
    Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di Stefano D, Esposito V, Enrici RM (2013) Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas. J Neurooncol 111(2):187–194PubMedGoogle Scholar
  43. 43.
    Schwer AL, Damek DM, Kavanagh BD, Gaspar LE, Lillehei K, Stuhr K, Chen C (2008) A phase I dose-escalation study of fractionated stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 70(4):993–1001PubMedGoogle Scholar
  44. 44.
    Welsh J, Sanan A, Gabavan AJ, Green SB, Lustig R, Burri S, Kwong E, Stea B (2007) GliaSite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study. Int J Radiat Oncol Biol Phys 68(1):159–165PubMedGoogle Scholar
  45. 45.
    Wernicke AG, Sherr DL, Schwartz TH, Pannullo SC, Stieg PE, Boockvar JA, Molterno JA, Invandize J, Trichter S, Sabbas AM, Parashar B, Nori D (2010) The role of dose escalation with intracavitary brachytherapy in the treatment of localized CNS malignancies: outcomes and toxicities of a prospective study. Brachytherapy 9(1):91–99PubMedGoogle Scholar
  46. 46.
    Rogers LR, Rock JP, Sills AK, Vogelbaum MA, Suh JH, Ellis TL, Stieber VW, Asher AL, Fraser RW, Billingsley JS, Lewis P, Schellingerhout D, Shaw EG, Brain Metastasis Study Group (2006) Results of a phase II trial of the GliaSite radiation therapy system for the treatment of newly diagnosed, resected single brain metastases. J Neurosurg 105(3):375–384PubMedGoogle Scholar
  47. 47.
    Adkison JB, Thomadsen B, Howard SP (2008) Systemic iodine 125 activity after GliaSite brachytherapy: safety considerations. Brachytherapy 7(1):43–46PubMedGoogle Scholar
  48. 48.
    Hodozuka A, Hayashi Y, Annei R, Hiroshima S, Saito M, Orimoto R, Sato M, Tanaka T (2008) Intrathecal infusion of the antineoplastic agents for meningeal dissemination. Gan To Kagaku Ryoho 35(6):900–905PubMedGoogle Scholar
  49. 49.
    Stukel JM, Caplan MR (2009) Targeted drug delivery for treatment and imaging of glioblastoma multiforme. Expert Opin Drug Deliv 6(7):705–718PubMedGoogle Scholar
  50. 50.
    Debinski W, Tatter SB (2009) Convection-enhanced delivery for the treatment of brain tumors. Expert Rev Neurother 9(10):1519–1527PubMedCentralPubMedGoogle Scholar
  51. 51.
    Lopez KA, Tannenbaum AM, Assanah MC, Linskey K, Yun J, Kangarlu A, Gill OD, Canoll P, Bruce JN (2011) Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors. Cancer Res 71(11):3963–3971PubMedCentralPubMedGoogle Scholar
  52. 52.
    Dickinson PJ, Lecouteur RA, Higgins RB, Bringas JR, Roberts B, Larson RF, Yamashita Y, Krauze M, Noble CO, Drummond D, Kirpotin DB, Bankiewicz KS (2008) Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging. J Neurosurg 108:989–998PubMedGoogle Scholar
  53. 53.
    Vogelbaum MA (2005) Convection enhanced delivery for the treatment of malignant gliomas: symposium review. J Neurooncol 73(1):57–69PubMedGoogle Scholar
  54. 54.
    Kunwar S, Chang S, Westphal M, ZVogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M et al (2010) Phase III randomized trial of CED of Il13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 12(8):871–881PubMedCentralPubMedGoogle Scholar
  55. 55.
    Gallia GL, Brem S, Brem H (2005) Local treatment of malignant brain tumors using implantable chemotherapeutic polymers. J Natl Compr Canc Netw 3:721–728PubMedGoogle Scholar
  56. 56.
    Patel SJ, Shapira WR, Laske DW, Jensen RL, Asher AL, Wessels BW, Carpenter SP, Shan JS (2005) Safety and feasibility of convection-enhanced delivery of Cotara for the treatment of malignant glioma: initial experience in 51 patients. Neurosurgery 56(6):1243–1252PubMedGoogle Scholar
  57. 57.
    Shapiro WR, Carpenter SP, Roberts K, Shan JS (2006) 1311-chTNT-1/B mAb: tumour necrosis therapy for malignant astrocytic glioma. Expert Opin Biol Ther 6(5):539–545PubMedGoogle Scholar
  58. 58.
    Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Nass D, Hadani M, Ram Z (2004) Convection enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 47(6):472–479Google Scholar
  59. 59.
    Van Vlerken LE, Amiji MM (2006) Multi-functional polymeric nanoparticles from tumour-targeted drug delivery. Expert Opin Drug Deliv 3(2):205–216PubMedGoogle Scholar
  60. 60.
    Langer R, Folkman J (1976) Polymers for the sustained release of proteins and other macromolecules. Nature 263:797–800PubMedGoogle Scholar
  61. 61.
    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(8964):1008–1012PubMedGoogle Scholar
  62. 62.
    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(1):44–48PubMedGoogle Scholar
  63. 63.
    Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z (2003) A phase III trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro oncol 5(2):79–877PubMedCentralPubMedGoogle Scholar
  64. 64.
    Smith SG, Galanis JC (1995) One-year results of the intrascleral glaucoma implant. J Cataract Refract Surg 21(4):453–456PubMedGoogle Scholar
  65. 65.
    Yue IC, Poff J, Cortés ME, Sinisterra RD, Faris CB, Hildgen P, Langer R, Shastri VP (2004) A novel polymeric chlorhexidine delivery device for the treatment of periodontal disease. Biomaterials 25(17):3743–3750PubMedGoogle Scholar
  66. 66.
    Friend DR (1990) Transdermal delivery of contraceptives. Crit Rev Ther Drug Carrier Syst 7(2):149–186PubMedGoogle Scholar
  67. 67.
    Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K (2012) Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis 15(1):93–99. doi: 10.1038/pcan.2011.50. Epub 2011 Oct 25 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Brady JM, Cutright DE, Miller RA, Barristone GC (1973) Reabsorption rate, route, route of elimination and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat. J Biomed Mater Res 7(2):155–156PubMedGoogle Scholar
  69. 69.
    Frazza EJ, Schmitt EE (1971) A new absorbable suture. J Biomed Mater Res 5(2):43–58PubMedGoogle Scholar
  70. 70.
    Spenlehauer G, Vert M, Benoit JP, Boddaert A (1989) In vitro and in vivo degradation of Poly (D, L lactide/glycolide) type microspheres made by solvent evaporation method. Biomaterials 10(8):557–563PubMedGoogle Scholar
  71. 71.
    Leong KW, Brott BC, Langer R (1985) Bioerodible polyanhydrides as drug-carrier matrices. I: characterization, degradation, and release characteristics. J Biomed Mater Res 19(8):941–955PubMedGoogle Scholar
  72. 72.
    Chasin M, Domb A, Rone E (1990) Polyanhydrides as drug delivery systems. In: Chasin M, Langer R (eds) Biodegradable polymers as drug delivery systems. Macel Dekker, New York, NY, pp 43–70Google Scholar
  73. 73.
    Bindschadeler C, Leong K, Mathiowitz E, Langer R (1988) Polyanhydride microsphere formulation by solvent extraction. J Pharm Sci 77(8):696–698Google Scholar
  74. 74.
    Levy-Nissenbaum E, Khan W, Pawar RP, Tabakman R, Naftali E, Winkler I, Kaufman O, Klapper L, Domb AJ (2012) Pharmacokinetic and efficacy study of cisplatin and paclitaxel formulated in a new injectable poly(sebacic-co-ricinoleic acid) polymer. Eur J Pharm Biopharm 82(1):85–93. doi: 10.1016/j.ejpb.2012.06.004, Epub 2012 Jun 23PubMedGoogle Scholar
  75. 75.
    Leong KW, Kost J, Mathiowitz E, Langer R (1989) Polyanhydrides for controlled release of bioactive agents. Biomaterials 7(5):364–371Google Scholar
  76. 76.
    Brem H, Tamargo RJ, Olivi 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(2):283–290PubMedGoogle Scholar
  77. 77.
    Green SB, Byar DP, Walker MD, Pistenmaa DA, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, Mealey J Jr, Odom GL et al (1983) Comparisons of carmustine, procarbazine and, high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep 67(2):121–132PubMedGoogle Scholar
  78. 78.
    Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr et al (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303(23):1323–1329PubMedGoogle Scholar
  79. 79.
    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(4):640–647PubMedGoogle Scholar
  80. 80.
    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(4):672–684PubMedGoogle Scholar
  81. 81.
    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(2):329–333PubMedGoogle Scholar
  82. 82.
    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(3):441–446PubMedGoogle Scholar
  83. 83.
    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(2):111–123PubMedGoogle Scholar
  84. 84.
    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(5):383–389PubMedGoogle Scholar
  85. 85.
    Olivi A, Grossman SA, Tatter S, Barker F, Judy K, Olsen J, Bruce J, Hilt D, Fisher J, Piantadosi S (2003) New approaches to brain tumor therapy CNS consortium: 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(9):1845–1849PubMedGoogle Scholar
  86. 86.
    Attenello FJ, Mukherjee D, Datoo G, McGirt MJ, Bohan E, Weingart JD, Olivi A, Quiniones-Hinojosa A, Brem H (2008) Use of gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience. Ann Surg Oncol 15(10):2887–2893PubMedGoogle Scholar
  87. 87.
    Chaichana KL, Zaidi H, Pendelton C, McGrit MJ, Grossman R, Weingart JD, Olivi A, Quiniones-Hinojosa A, Brem H (2011) The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival. Neurol Res 33(7):759–764PubMedGoogle Scholar
  88. 88.
    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(5):1185–1193PubMedGoogle Scholar
  89. 89.
    Ewend MG, Brem S, Gilbert M, Goodkin R, Penar PL, Varia M, Cush S, Carey LA (2007) Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res 13(12):3637–3641PubMedGoogle Scholar
  90. 90.
    Benny O, Menon LG, Ariel G, Goren E, Kim SK, Stewman C, Black PM, Carroll RS, Machluf M (2009) Local delivery of poly lactic-co-glycolic acid microspheres containing imatinib mesylate inhibits intracranial xenograft glioma growth. Clin Cancer Res 15(4):1222–1231PubMedGoogle Scholar
  91. 91.
    You J, Shao R, Wei X, Gupta S, Li C (2010) Near-infrared light triggers release of paclitaxel from biodegradable microspheres: photothermal effect and enhanced antitumor activity. Small 6(9):1022–1031PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tahara K, Kato Y, Yamamoto H, Kreuter J, Kawashima Y (2011) Intracellular drug delivery using polysorbate 80-modified poly(D, L-lactide-co-glycolide) nanospheres to glioblastoma cells. J Microencapsul 28(1):29–36PubMedGoogle Scholar
  93. 93.
    Ranganath SH, Fu Y, Arifin DY, Kee I, Zheng L, Lee HS, Chow PK, Wang CH (2010) The use of submicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice. Biomaterials 31(19):5199–5207PubMedGoogle Scholar
  94. 94.
    Esther Gil-Alegre M, González-Alvarez I, Gutiérrez-Paúls L, Torres-Suárez AI (2008) Three weeks release BCNU loaded hydrophilic-PLGA microspheres for interstitial chemotherapy: development and activity against human glioblastoma cells. J Microencapsul 25(8):561–568PubMedGoogle Scholar
  95. 95.
    Kantelhardt SR, Caarls W, de Vries AH, Hagen GM, Jovin TM, Schulz-Schaeffer W, Rohde V, Giese A, Arndt-Jovin DJ (2010) Specific visualization of glioma cells in living low-grade tumor tissue. PLoS One 5(6):e11323PubMedCentralPubMedGoogle Scholar
  96. 96.
    Fillmore HL, Shultz MD, Henderson SC, Cooper P, Broaddus WC, Chen ZJ, Shu CY, Zhang J, Ge J, Dorn HC, Corwin F, Hirsch JI, Wilson J, Fatouros PP (2011) Conjugation of functionalized gadolinium metallofullerenes with IL-13 peptides for targeting and imaging glial tumors. Nanomedicine (Lond) 6(3):449–458Google Scholar
  97. 97.
    Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q, Swaminathan G, Xiang D, Eberhart C, Hanes J (2012) A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med 4(149):149ra119. doi: 10.1126/scitranslmed.3003594 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Arndt-Jovin DJ, Kantelhardt SR, Caarls W, de Vries AH, Giese A, Jovin Ast TM (2009) Tumor-targeted quantum dots can help surgeons find tumor boundaries. IEEE Trans Nanobioscience 8(1):65–71PubMedGoogle Scholar
  99. 99.
    Tobias A, Ahmed A, Moon KS, Lesniak MS (2013) The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry 84(2):213–222PubMedCentralPubMedGoogle Scholar
  100. 100.
    Germano IM, Binello E (2009) Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J Neurooncol 93(1):79–87, Epub 2009 May 9PubMedGoogle Scholar
  101. 101.
    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(11):767–772PubMedGoogle Scholar
  102. 102.
    Santini JTJR, Cima MJ, Langer R (1999) A controlled-release microchip. Nature 397(6717):335–338PubMedGoogle Scholar
  103. 103.
    Masi B, Tyler BM, Bow H, Wicks RT, Xue Y, Brem H, Langer R, Cima M (2012) Intracranial MEMS-based temozolomide delivery in a rat gliosarcoma model. Biomaterials 33(23):5768–5775, Epub 2012 May 14PubMedGoogle Scholar
  104. 104.
    Li Y, Ho Duc HL, Tyler B, Williams T, Tupper M, Langer R, Brem H, Cima MJ (2005) In vivo delivery of BCNU from a MEMS device to a tumor model. J Control Release 106(1–2):138–145PubMedGoogle Scholar
  105. 105.
    Kim GY, Tyler BM, Tupper MM, Karp JM, Langer RS, Brem H, Cima MJ (2007) Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model. J Control Release 123(2):172–178PubMedGoogle Scholar
  106. 106.
    Scott A, Tyler B, Masi B, Upadhyay U, Patta Y, Grossman R, Basaldella L, Langer R, Brem H, Cima M (2011) Intracranial microcapsule drug delivery device for the treatment of an experimental glioma model. Biomaterials 32(10):2532–2539, Epub 2011 Jan 8PubMedGoogle Scholar
  107. 107.
    Hobohm U (2001) Fever and cancer in perspective. Cancer Immunol Immunother 50:391–396PubMedGoogle Scholar
  108. 108.
    Kantoff P, Higano C, Shore N et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422PubMedGoogle Scholar
  109. 109.
    Hodi F, O’Day S, McDermott D et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCentralPubMedGoogle Scholar
  110. 110.
    Vauleon E, Avril T, Collet B et al (2010) Overview of cellular immunotherapy for patients with glioblastoma. Clin Dev Immunol 2010:1–18Google Scholar
  111. 111.
    Aguilar L, Arvizu M, Aguilar-Cordova E et al (2012) The spectrum of vaccine therapies for patients with glioblastoma multiforme. Curr Treat Options Oncol 13(4):437–450PubMedCentralPubMedGoogle Scholar
  112. 112.
    Yu J, Wheeler C, Zeltzer P et al (2001) Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 62:842–847Google Scholar
  113. 113.
    Dillman R, Duma C, PSchiltz P et al (2004) Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27(5):398–404PubMedGoogle Scholar
  114. 114.
    Bloom H, Peckham M, Richardson A et al (1973) Glioblastoma multiforme: a controlled trial to assess the value of specific active immunotherapy in patients treated by radical surgery and radiotherapy. Br J Cancer 27(3):253–267PubMedCentralPubMedGoogle Scholar
  115. 115.
    Sobol R, Fakhrai H, Shawler D et al (1995) Interleukin-2 gene therapy in a patient with glioblastoma. Gene Ther 2(2):164–167PubMedGoogle Scholar
  116. 116.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedGoogle Scholar
  117. 117.
    Levy AP, Tamargo R, Brem H, Nathans D (1989) An endothelial cell growth factor from the mouse neuroblastoma cell line NB41. Growth Factors 2(1):9–19PubMedGoogle Scholar
  118. 118.
    Ferrara N, Henzel W (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161(2):851–858PubMedGoogle Scholar
  119. 119.
    Presta L, Chen H, O’Connor S et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  120. 120.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 305:2335–2342Google Scholar
  121. 121.
    Sandler A, Gray R, Perry M et al (2006) Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 355:2542–2550PubMedGoogle Scholar
  122. 122.
    Brem S, Cotran R, Folkman J (1972) Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48(2):347–356PubMedGoogle Scholar
  123. 123.
    Purow B, Fine H (2004) Progress report on the potential of angiogenesis inhibitors for neuro-oncology. Cancer Invest 22(4):577–587PubMedGoogle Scholar
  124. 124.
    Kunkel P, Ulbricht U, Bohlen P et al (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 62:6624–6628Google Scholar
  125. 125.
    Weingart J, Sipos E, Brem H (1995) The role of minocycline in the treatment of intracranial 9L glioma. J Neurosurg 82:635–640PubMedGoogle Scholar
  126. 126.
    Kirsch M, Strasser J, Allende R et al (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659PubMedGoogle Scholar
  127. 127.
    Pradilla G, Legnani FG, Petrangolini G, Francescato P, Chillemi F, Tyler BM, Gaini SM, Brem H, Olivi A, DiMeco F (2005) Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas. Neurosurgery 57(5):1032–1040, discussion 1032–40PubMedCentralPubMedGoogle Scholar
  128. 128.
    Fine H, Figg W, Jaeckle K et al (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18(4):708–715PubMedGoogle Scholar
  129. 129.
    Fine H, Wen P, Maher E et al (2003) Phase II trial of thalidomide and carmustine for patients with high-grade gliomas. J Clin Oncol 21(12):2299–2304PubMedGoogle Scholar
  130. 130.
    Vredenburgh J, Desjardins A, Herndon J et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729PubMedGoogle Scholar
  131. 131.
    Cohen M, Shen Y, Keegan P et al (2009) FDA drug approval summary: bevacizumab (avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14:1131–1138PubMedGoogle Scholar
  132. 132.
    Wick W, Weller M, van den Bent M et al (2010) Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol 28(12):188–189Google Scholar
  133. 133.
    van den Bent M, Vogelbaum M, Wen P et al (2009) End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's criteria. J Clin Oncol 27(18):2905–2908PubMedGoogle Scholar
  134. 134.
    Bansal K, Engelhard HH (2000) Gene therapy for brain tumors. Curr Oncol Rep 2(5):463–472, ReviewPubMedGoogle Scholar
  135. 135.
    Rainov NG (2000) A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11(17):2389–2401PubMedGoogle Scholar
  136. 136.
    Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, Nabors LB, Markiewicz M, Lakeman AD, Palmer CA, Parker JN, Whitley RJ, Gillespie GY (2009) Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther 17(1):199–207, Epub 2008 Oct 28PubMedGoogle Scholar
  137. 137.
    Patel M, Vogelbaum MA, Barnett GH, Jalali R, Ahluwalia MS (2012) Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions. Expert Opin Investig Drugs 21(9):1247–1266. doi: 10.1517/13543784.2012.703177, Epub 2012 Jun 25PubMedGoogle Scholar
  138. 138.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27(8):1268–1274, Epub 2009 Feb 9PubMedGoogle Scholar
  139. 139.
    Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE 2nd, Bailey L, Peters KB, Friedman HS, Vredenburgh JJ (2012) Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 118(5):1302–1312. doi: 10.1002/cncr.26381. Epub 2011 Jul 26 PubMedGoogle Scholar
  140. 140.
    Møller S, Grunnet K, Hansen S, Schultz H, Holmberg M, Sorensen M, Poulsen HS, Lassen U (2012) A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy. Acta Oncol 51(6):797–804, Epub 2012 May 1PubMedGoogle Scholar
  141. 141.
    Burkhardt JK, Riina H, Shin BJ, Christos P, Kesavabhotla K, Hofstetter CP, Tsiouris AJ, Boockvar JA (2012) Intra-arterial delivery of bevacizumab after blood–brain barrier disruption for the treatment of recurrent glioblastoma: progression-free survival and overall survival. World Neurosurg 77(1):130–134, Epub 2011 Nov 21PubMedCentralPubMedGoogle Scholar
  142. 142.
    Lawson HC, Sampath P, Bohan E, Park MC, Hussain N, Olivi A, Weingart J, Kleinberg L, Brem H (2007) Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience. J Neurooncol 83(1):61–70PubMedGoogle Scholar

Copyright information

© Controlled Release Society 2014

Authors and Affiliations

  • Betty M. Tyler
    • 1
  • Gustavo Pradilla
    • 1
  • Uri Hadelsberg
    • 2
  • Hansen Bow
    • 1
  • Ian Suk
    • 3
  • Henry Brem
    • 1
    • 4
    • 5
  1. 1.Department of Neurosurgery, School of MedicineThe Johns Hopkins UniversityBaltimoreUSA
  2. 2.Technion-Israel Institute of TechnologyHaifaIsrael
  3. 3.Department of Neurosurgery, School of MedicineThe Johns Hopkins UniversityBaltimoreUSA
  4. 4.Department of Oncology, School of MedicineThe Johns Hopkins UniversityBaltimoreUSA
  5. 5.Department of BioMedical Engineering, School of MedicineThe Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations