Polymeric drug delivery for the treatment of glioblastoma.
Glioblastoma (GBM) remains an almost universally fatal diagnosis. The current therapeutic mainstay consists of maximal safe surgical resection followed by radiation therapy (RT) with concomitant temozolomide (TMZ), followed by monthly TMZ (the "Stupp regimen"). Several chemotherapeutic agents have been shown to have modest efficacy in the treatment of high-grade glioma (HGG), but blood-brain barrier impermeability remains a major delivery obstacle. Polymeric drug-delivery systems, developed to allow controlled local release of biologically active substances for a variety of conditions, can achieve high local concentrations of active agents while limiting systemic toxicities. Polymerically delivered carmustine (BCNU) wafers, placed on the surface of the tumor-resection cavity, can potentially provide immediate chemotherapy to residual tumor cells during the standard delay between surgery and chemoradiotherapy. BCNU wafer implantation as monochemotherapy (with RT) in newly diagnosed HGG has been investigated in 2 phase III studies that reported significant increases in median overall survival. A number of studies have investigated the tumoricidal synergies of combination chemotherapy with BCNU wafers in newly diagnosed or recurrent HGG, and a primary research focus has been the integration of BCNU wafers into multimodality therapy with the standard Stupp regimen. Overall, the results of these studies have been encouraging in terms of safety and efficacy. However, the data must be qualified by the nature of the studies conducted. Currently, there are no phase III studies of BCNU wafers with the standard Stupp regimen. We review the rationale, biochemistry, pharmacokinetics, and research history (including toxicity profile) of this modality.
Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (S.D.W., A.L.A.); Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina (S.D.W.); Department of Neurosurgery, Levine Cancer Institute, and Neuroscience Institute, Carolinas Medical Center, Charlotte, North Carolina (S.D.W., T.G.A., A.L.A.); Southeast Radiation Oncology, Charlotte, North Carolina (R.S.P., S.H.B.); Department of Radiation Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina (R.S.P., S.H.B.).
Scott D
SD
Wait
Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (S.D.W., A.L.A.); Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina (S.D.W.); Department of Neurosurgery, Levine Cancer Institute, and Neuroscience Institute, Carolinas Medical Center, Charlotte, North Carolina (S.D.W., T.G.A., A.L.A.); Southeast Radiation Oncology, Charlotte, North Carolina (R.S.P., S.H.B.); Department of Radiation Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina (R.S.P., S.H.B.).
Roshan S
RS
Prabhu
Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (S.D.W., A.L.A.); Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina (S.D.W.); Department of Neurosurgery, Levine Cancer Institute, and Neuroscience Institute, Carolinas Medical Center, Charlotte, North Carolina (S.D.W., T.G.A., A.L.A.); Southeast Radiation Oncology, Charlotte, North Carolina (R.S.P., S.H.B.); Department of Radiation Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina (R.S.P., S.H.B.).
Stuart H
SH
Burri
Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (S.D.W., A.L.A.); Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina (S.D.W.); Department of Neurosurgery, Levine Cancer Institute, and Neuroscience Institute, Carolinas Medical Center, Charlotte, North Carolina (S.D.W., T.G.A., A.L.A.); Southeast Radiation Oncology, Charlotte, North Carolina (R.S.P., S.H.B.); Department of Radiation Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina (R.S.P., S.H.B.).
Tyler G
TG
Atkins
Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (S.D.W., A.L.A.); Levine Children's Hospital, Carolinas Medical Center, Charlotte, North Carolina (S.D.W.); Department of Neurosurgery, Levine Cancer Institute, and Neuroscience Institute, Carolinas Medical Center, Charlotte, North Carolina (S.D.W., T.G.A., A.L.A.); Southeast Radiation Oncology, Charlotte, North Carolina (R.S.P., S.H.B.); Department of Radiation Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina (R.S.P., S.H.B.).
Anthony L
AL
Asher
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004343:Drug Implants; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D015918:Infusion Pumps, Implantable; D011108:Polymers; D016019:Survival Analysis; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D004343:Drug Implants; D011108:Polymers; D002330:Carmustine
BCNU; carmustine; chemotherapy; glioblastoma; high-grade glioma; polymeric delivery