Skip to main content

Advertisement

SpringerLink
Log in

Chemotherapeutic dose intensification for treatment of malignant brain tumors: Recent developments and future directions

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Despite a large amount of research on malignant brain tumors over the past 70 years, the prognosis for most tumor types is poor. One current focus of research is increasing dose intensity of chemotherapeutic agents. Various ways to increase dose intensity include high-dose chemotherapy followed by stem cell rescue (eg, bone marrow transplant), blood-brain barrier disruption or use of RMP7 to increase transvascular drug delivery, local delivery of chemotherapeutic agents (convection enhancement or clysis, antibody conjugates, and biodegradable polymers), chemoprotective agents, and tumor sensitizers. Improved identification of patients likely to respond to a given regimen may also increase the effectiveness of chemotherapy. We also discuss approaches to improve the design of nonrandomized trials by identifying and controlling potential confounding variables. This will improve the quality of individual studies and perhaps the comparability across studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. DeAngelis LM: Medical progress: brain tumors. N Engl J Med 2001, 344:114–123. Reviews the best therapy (among surgery, radiation, and chemotherapy) for various types of malignant brain tumors.

    Article  PubMed  CAS  Google Scholar 

  2. Doolittle ND, Muldoon LL, Brummett RE, et al.: Delayed sodium thiosulfate as an otoprotectant agent against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 2001, 7:493–500. Provides an example of chemoprotection (using sodium thiosulfate) against ototoxicity following cisplatin chemotherapy for malignant brain tumors.

    PubMed  CAS  Google Scholar 

  3. McAllister LD, Doolittle ND, Guastadisegni PE, et al.: Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 2000, 46:51–61.

    Article  PubMed  CAS  Google Scholar 

  4. Kroll RA, Neuwelt EA: Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998, 42:1083–1100.

    Article  PubMed  CAS  Google Scholar 

  5. Keshelava N, Seeger RC, Groshen S, Reynolds CP: Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 1998, 58:5396–5405.

    PubMed  CAS  Google Scholar 

  6. Fortin D, Neuwelt EA: Therapeutic manipulation of the blood brain-barrier. Neurology Medlink, Arbor. 2002.

  7. Hryniuk WM, Pater JL: Implications of dose intensity for cancer chemotherapy. Semin Oncol 1987, 14:43–44.

    Google Scholar 

  8. Doolittle ND, Anderson CP, Bleyer WA, et al., for the Blood-Brain Barrier Disruption Consortium: Importance of dose intensity in neuro-oncology clinical trials: summary of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium. Neuro-Oncology 2001, 3:46–54.

    Article  PubMed  CAS  Google Scholar 

  9. Schabel FMJr, Griswold DPJr, Corbett TH, Laster WRJr: Increasing the therapeutic response rates to anticancer drugs by applying the basic principles of pharmacology. Cancer 1984, 54:1160–1167.

    Article  PubMed  CAS  Google Scholar 

  10. Seeger RC, Reynolds CP: Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplant. Pediatr Clin North Am 1991, 38:393–424.

    PubMed  CAS  Google Scholar 

  11. Ioannidis JP, Schmid CH, Lau J: Meta-analysis in hematology and oncology. Hematol Oncol Clin North Am 2000, 14:973–991.

    Article  PubMed  CAS  Google Scholar 

  12. Stadtmauer EA, O’Neill A, Goldstein L, et al.: Conventionaldose chemotherapy compared with high dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000, 342:1069–1076.

    Article  PubMed  CAS  Google Scholar 

  13. Cheung NK, Heller G: Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 1991, 9:1050–1058.

    PubMed  CAS  Google Scholar 

  14. Finlay JL, August C, Packer R, et al.: High-dose multi-agent chemotherapy followed by bone marrow ‘rescue’ for malignant astrocytomas of childhood and adolescence. J Neuro-Oncol 1990, 9:239–248.

    Article  CAS  Google Scholar 

  15. Kalifa C, Hartmann O, Demeocq F, et al.: High-dose busulfan and thiotepa with autologous bone marrow transplantation in childhood malignant brain tumors: a phase II study. Bone Marrow Transplant 1992, 9:227–233.

    PubMed  CAS  Google Scholar 

  16. Mahoney DH Jr, Strother D, Camitta B, et al.: High-dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: a pilot Pediatric Oncology Group study. J Clin Oncol 1996, 14:382–388.

    PubMed  CAS  Google Scholar 

  17. Tada T, Takizawa T, Nakazato F, et al.: Treatment of intracranial nongerminous germ-cell tumors by high dose chemotherapy and autologous stem-cell rescue. J Neuro-Oncol 1999, 44:71–76.

    Article  CAS  Google Scholar 

  18. Graham ML, Herndon JE II, Casey JR, et al.: High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol 1997, 15:1814–1823.

    PubMed  CAS  Google Scholar 

  19. Mason WP, Grovas A, Halpern S, et al.: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 1998, 16:210–221.

    PubMed  CAS  Google Scholar 

  20. Cairncross G, Swinnen L, Bayer R, et al.: Myeloablative chemotherapy for recurrent aggressive oligodendroglioma. Neuro-Oncology 2000, 2:114–119. A multi-institutional trial of dose-intense chemotherapy in recurrent aggressive oligodendroglioma, but with substantial mortality. However, efficacy increased and toxicity decreased in newly diagnosed patients.

    Article  PubMed  CAS  Google Scholar 

  21. Abrey LE, Paleologos N, Rosenfeld S, et al.: Intensive PCV chemotherapy followed by high dose thiotepa with autologous stem cell rescue (ASCR) for patients with newly diagnosed anaplastic oligodendroglioma. Neuro-Oncology 2001, 3:354. A multi-institutional trial of dose-intense chemotherapy in recurrent aggressive oligodendroglioma, but with substantial mortality. However, efficacy increased and toxicity decreased in newly diagnosed patients.

    Google Scholar 

  22. Finlay JL, Goldman S, Wong MC, et al.: Pilot study of highdose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children’s Cancer Group. J Clin Oncol 1996, 14:2495–2503.

    PubMed  CAS  Google Scholar 

  23. Doolittle ND, Miner ME, Hall WA, et al.: Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000, 88:637–647. Demonstrates efficacy and safety of blood-brain barrier disruption protocols for the treatment of malignant brain tumors when implemented across multiple centers.

    Article  PubMed  CAS  Google Scholar 

  24. Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA: Association of total dose intensity of chemotherapy in primary CNS lymphoma (human non-AIDS) and survival. Neurosurgery 2001, 48:1033–1041. Illustrates the use of time-dependent covariate analyses for demonstration of a positive association between number of treatments (disruptions) and longer survival times.

    Article  PubMed  CAS  Google Scholar 

  25. Bobo RH, Laske DW, Akbasak A, et al.: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 1994, 91:2076–2080.

    Article  PubMed  CAS  Google Scholar 

  26. Lieberman DM, Laske DW, Morrison PF, Bankiewicz KS, Oldfield EH: Convection-enhanced distribution of large molecules in gray matte during interstitial drug infusion. J Neurosurgery 1995, 82:1021–1029.

    CAS  Google Scholar 

  27. Groothuis DR, Wards S, Itskovich AC: Comparison of Dsucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion. J Neurosurgery 1999, 90:321–331. Compares different routes of delivery to the central nervous system with particular emphasis on convection-enhanced delivery.

    CAS  Google Scholar 

  28. Kaiser MG, Parsa AT, Fine RL, et al.: Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. Neurosurgery 2000, 47:1391–1398.

    Article  PubMed  CAS  Google Scholar 

  29. Bruce JN, Falavigna A, Johnson JP, et al.: Intracerebral clysis in a rat glioma model. Neurosurgery 2000, 46:683–691.

    Article  PubMed  CAS  Google Scholar 

  30. Cunningham J, Oiwa Y, Nagy D, et al.: Distribution of AAV-TK following intracranial convection-enhanced delivery into rats. Cell Tranplant 2000, 9:585–594.

    CAS  Google Scholar 

  31. Groothuis DR: The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro-Oncology 2000, 2:45–59.

    Article  PubMed  CAS  Google Scholar 

  32. Mardor Y, Roth Y, Lidar Z, et al.: Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. Cancer Res 2001, 61:4971–4973.

    PubMed  CAS  Google Scholar 

  33. Muldoon LL, Nilaver G, Kroll RA, et al.: Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol 1995, 147:1840–1851.

    PubMed  CAS  Google Scholar 

  34. Kroll RA, Pagel MA, Muldoon LL, Roman-Goldstein S, Neuwelt EA: Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurgery 1996, 38:746–752.

    Article  PubMed  CAS  Google Scholar 

  35. Bartus RT, Snodgrass P, Marsh J, et al.: Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival. J Pharmacol Exper Therapeut 2000, 293:903–911. Describes a bradykinin analogue that preferentially opens the blood tumor barrier.

    CAS  Google Scholar 

  36. Brem H, Ewend MG, Piantadosi S, et al.: 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 Neuro-Oncol 1995, 26:111–123.

    Article  CAS  Google Scholar 

  37. Brem H, Gabikian P: Biodegradable polymer implants to treat brain tumors. J Controlled Release 2001, 74:63–67. Reviews biodegradable polymers that release chemotherapy from the walls of the surgical tumor cavity.

    Article  CAS  Google Scholar 

  38. Remsen LG, Trail PA, Hellström I, Hellström KE, Neuwelt EA: Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model. Neurosurgery 2000, 46:704–709.

    Article  PubMed  CAS  Google Scholar 

  39. Boviatsis EJ, Chase M, Wei MX, et al.: Gene transfer into experimental brain tumors mediated by adenovirus, herpes simplex virus, and retrovirus vectors. Human Gene Ther 1994, 5:183–191.

    CAS  Google Scholar 

  40. Breakefield XO, DeLuca NA: Herpes simplex virus for gene delivery to neurons. New Biologist 1991, 3:203–218.

    PubMed  CAS  Google Scholar 

  41. Davidson BL, Doran SE, Shewach DS, et al.: Expression of Escherichia coli —Galactosidase and rat HPRT in the CNS of Macaca mulatta following adenoviral mediated gene transfer. Exper Neurol 1994, 125:258–267.

    Article  CAS  Google Scholar 

  42. Nilaver G, Muldoon LL, Kroll RA, et al.: Delivery of herpes virus and adenovirus to nude rat intracerebral tumors following osmotic blood-brain barrier disruption. Proc Natl Acad Sci U S A 1995, 92:9829–9833.

    Article  PubMed  CAS  Google Scholar 

  43. Boviatsis EJ, Park JS, Sena-Esteves M, et al.: Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res 1994, 54:5745–5741.

    PubMed  CAS  Google Scholar 

  44. Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SLC: Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A 1994, 91:3054–3057.

    Article  PubMed  CAS  Google Scholar 

  45. Markert JM, Malick A, Coen DM, Martuza RL: Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir. Neurosurgery 1993, 32:597–603.

    Article  PubMed  CAS  Google Scholar 

  46. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM: Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991, 252:854–856.

    Article  PubMed  CAS  Google Scholar 

  47. Laske DW, Ilercil O, Abbasak A, Youle RJ, Oldfield EH: Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J Neurosurg 1994, 80:520–526.

    PubMed  CAS  Google Scholar 

  48. Bartlett JS, Samulski RJ, McCown TJ: Selective and rapid uptake of adeno-associated virus type 2 in brain. Human Gene Ther 1998, 9:1181–1186.

    CAS  Google Scholar 

  49. Davidson BL, Allen ED, Kozarsky KF, Wilson JM, Roessler BJ: A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nature Genet 1993, 3:219–223.

    Article  PubMed  CAS  Google Scholar 

  50. Eck SL, Alavi JB, Alavi A, et al.: Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial. Human Gene Ther 1996, 7:1465–1482.

    CAS  Google Scholar 

  51. Ram Z, Culver KW, Oshiro EM, et al.: Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nature Med 1997, 3:1354–1361.

    Article  PubMed  CAS  Google Scholar 

  52. Silbergeld DL, Chicoine MR: Isolation and characterization of human malignant glioma cells from histologically normal brain. J Neurosurg 1997, 86:525–531.

    Article  PubMed  CAS  Google Scholar 

  53. Waxman DJ, Chen L, Hecht JE, Jounaidi Y: Cytochrome P450-based cancer gene therapy: recent advances and future prospects. Drug Metab Rev 1999, 31:503–522.

    Article  PubMed  CAS  Google Scholar 

  54. Jounaidi Y, Waxman DJ: Frequent, moderate-dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase-based cancer gene therapy. Cancer Res 2001, 61:4437–4444. Gene therapy delivered to tumor can activate cyclophosphamide.

    PubMed  CAS  Google Scholar 

  55. Mullen CA, Kilstrup M, Blaese RM: Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci U S A 1992, 89:33–37.

    Article  PubMed  CAS  Google Scholar 

  56. Ichikawa T, Tamiya T, Adachi Y, et al.: In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Cancer Gene Ther 2000, 7:74–82.

    Article  PubMed  CAS  Google Scholar 

  57. Erbs P, Regulier E, Kintz J, et al.: In vivo cancer gene therapy by adenovirus-mediated transfer of a bifunctional yeast cytosine deaminase/uracil phosphoribosyltransferase fusion gene. Cancer Res 2000, 60:3813–3822.

    PubMed  CAS  Google Scholar 

  58. Hamstra DA, Rice DJ, Fahmy S, Ross BD, Rehemtulla A: Enzyme/prodrug therapy for head and neck cancer using a catalytically superior cytosine deaminase. Human Gene Ther 1999, 10:1993–2003.

    Article  CAS  Google Scholar 

  59. Stegman LD, Rehemtulla A, Hamstra DA, et al.: Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy. Gene Ther 2000, 7:1005–1010.

    Article  PubMed  CAS  Google Scholar 

  60. Kievit E, Nyati MK, Ng E, et al.: Yeast cytosine deaminase improves radiosensitization and bystander effect by 5-fluorocytosine of human colorectal cancer xenografts. Cancer Res 2000, 60:6649–6655.

    PubMed  CAS  Google Scholar 

  61. Stackhouse MA, Pederson LC, Grizzle WE, et al.: Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models. Gene Ther 2000, 7:1019–1026.

    Article  PubMed  CAS  Google Scholar 

  62. Lambin P, Nuyts S, Landuyt W, et al.: The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase. Int J Radiat Biol 2000, 76:285–293.

    Article  PubMed  CAS  Google Scholar 

  63. Hanna NN, Mauceri HJ, Wayne JD, et al.: Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts. Cancer Res 1997, 57:4205–4209.

    PubMed  CAS  Google Scholar 

  64. Pederson LC, Buchsbaum DJ, Vickers SM, et al.: Molecular chemotherapy combined with radiation therapy enhances killing of cholangiocarcinoma cells in vitro and in vivo. Cancer Res 1997, 57:4325–4332.

    PubMed  CAS  Google Scholar 

  65. Koukourakis MI, Giatromanolaki A, Schiza S, Kakolyris S, Georgoulias V: Concurrent twice-a-week docetaxel and radiotherapy: a dose escalation trial with immunological toxicity evaluation. Int J Radiat Oncol Biol Physics 1999, 43:107–114.

    CAS  Google Scholar 

  66. Barth RF, Yang W, Bartus RT, Moeschberger ML, Goodman JH: Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analog Cereport (Receptor-Mediated Permeabilizer-7). Neurosurgery 1999, 44:351–359.

    Article  PubMed  CAS  Google Scholar 

  67. Rosenthal DI, Nurenberg P, Becerra CR, et al.: A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res 1999, 5:739–745. Gadolinium texaphyrin sensitizes tumors to radiation and can be imaged by magnetic resonance.

    PubMed  CAS  Google Scholar 

  68. Neuwelt EA, Brummett RE, Doolittle ND, et al.: First evidence of otoprotection against carboplatin-induced hearing loss with a two compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 1998, 286:77–84.

    PubMed  CAS  Google Scholar 

  69. Doolittle ND, Tyson RM, Lacy C, et al.: Potential role of delayed high-dose sodium thiosulfate as protectant against carboplatin-based thrombocytopenia in patients with malignant brain tumors. Neuro-Oncology 2001, 3:357. A preliminary evaluation of potential for protection of bone marrow from toxicity to carboplatin-based chemotherapy.

    Article  Google Scholar 

  70. Doolittle ND, Abrey LE, Ferrari N, et al.: Targeted delivery in primary and metastatic brain tumors: enhanced delivery versus neurotoxicity. Clin Cancer Res 2002, in press. Discusses increased dose intensity in the treatment of malignant brain tumors.

  71. Xu Y, Hansen WK, Rosenquist TA, et al.: Protection of mammalian cells against chemotherapeutic agents thiotepa, 1,3-N,N’-bis(2-chloroethyl)-N-nitrosourea, and mafosfamide using the DNA base excision repair genes Fpg and alpha-hOgg1: implications for protective gene therapy applications. J Pharmacol Exper Therapeut 2001, 296:825–831.

    CAS  Google Scholar 

  72. Esteller M, Garcia-Foncillas J, Andion E, et al.: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000, 343:1350–1354.

    Article  PubMed  CAS  Google Scholar 

  73. Friedman HS, Kokkinakis DM, Pluda J, et al.: Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J Clin Oncol 1998, 16:3570–3575.

    PubMed  CAS  Google Scholar 

  74. Lai GM, Moscow JA, Alvarez MG, Fojo AT, Bates SE: Contribution of glutathione and glutathiuone-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. Int J Cancer 1991, 49:688–695.

    Article  PubMed  CAS  Google Scholar 

  75. Anderson CP, Tsai JM, Meek WE, et al.: Depletion of glutathione by buthione sulfoximine is cytotoxic for human neuroblastoma cells lines via apoptosis. Exper Cell Res 1999, 246:183–192. Lowering tumor glutathione sensitized the tumor to alkylating chemotherapy.

    Article  CAS  Google Scholar 

  76. Curran WJ, Scott CB, Horton J, et al.: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993, 85:704–710.

    Article  PubMed  Google Scholar 

  77. Hess KR: Extent of resection as a prognostic variable in the treatment of gliomas. J Neuro-Oncology 1999, 227–231. A systematic review of studies of aggressive surgical resection for high-grade astrocytomas that concludes that the evidence is limited due to lack of clinical trial data and potential biases and uncontrolled confounding variables.

  78. Keles GE, Lamborn KR, Berger MS: Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurgery 2001, 95:735–745. Systematic review of the association of extent of resection of low-grade gliomas on clinical outcomes. Due to lack of randomization, control of confounders is essential in analysis of nonrandomized trials.

    CAS  Google Scholar 

  79. Laws ERJr: Resection for low-grade gliomas [editorial]. J Neurosurgery 2001, 95:731–732. Supports notion that due to lack of randomization, control of confounders is essential in analysis of nonrandomized trials.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neurology and Neurosurgery, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, 97201, Portland, OR, USA

    Dale F. Kraemer MD, David Fortin MD & Edward A. Neuwelt MD

Authors
  1. Dale F. Kraemer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Fortin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward A. Neuwelt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kraemer, D.F., Fortin, D. & Neuwelt, E.A. Chemotherapeutic dose intensification for treatment of malignant brain tumors: Recent developments and future directions. Curr Neurol Neurosci Rep 2, 216–224 (2002). https://doi.org/10.1007/s11910-002-0080-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-002-0080-8

Keywords

Search

Navigation