title: Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.
abstract: The prognosis for children with malignant glioma is poor. This study was designed to determine whether lomustine and temozolomide following radiotherapy and concurrent temozolomide improves event-free survival (EFS) compared with historical controls with anaplastic astrocytoma (AA) or glioblastoma (GBM) and whether survival is influenced by the expression of O6-methylguanine-DNA-methyltransferase (MGMT).
  
  
  
  Following maximal surgical resection, newly diagnosed children with nonmetastatic high-grade glioma underwent involved field radiotherapy with concurrent temozolomide. Adjuvant chemotherapy consisted of up to 6 cycles of lomustine 90 mg/m(2) on day 1 and temozolomide 160 mg/m(2)/day ×5 every 6 weeks.
  
  
  
  Among the 108 eligible patients with AA or GBM, 1-year EFS was 0.49 (95% CI, 0.39-0.58), similar to the original CCG-945-based design model. However, EFS and OS were significantly improved in ACNS0423 compared with the 86 AA or GBM participants treated with adjuvant temozolomide alone in the recent ACNS0126 study (1-sided log-rank P = .019 and .019, respectively). For example, 3-year EFS was 0.22 (95% CI, 0.14-0.30) in ACNS0423 compared with 0.11 (95% CI, 0.05-0.18) in ACNS0126. Stratifying the comparison by resection extent, the addition of lomustine resulted in significantly better EFS and OS in participants without gross-total resection (P = .019 and .00085 respectively). The difference in EFS and OS was most pronounced for participants with GBM (P = .059 and 0.051, respectively), and those with MGMT overexpression (P = .00036 and .00038, respectively).
  
  
  
  The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Cohen
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Allen
authors.initials: A
authors.lastname: Buxton
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Marc K
authors.initials: MK
authors.lastname: Rosenblum
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Sandrah P
authors.initials: SP
authors.lastname: Eckel
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Tianni
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.).
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lavey
authors.affiliation: Departments of Pediatrics (R.I.J.), Pathology (R.L.H.) and Neurosurgery (I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, PA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Children's Oncology Group, Operations Office, Monrovia, California (A.B., M.D.K.); Department of Preventive Medicine, University of Southern California, Los Angeles, California (M.D.K, S.P.E.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.C.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (M.K.R.); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia (D.J.B.); Department of Mathematics and Statistics, California State University, Long Beach, California (T.Z.); Maurer Family Cancer Care Center, Bowling Green, Ohio (R.S.L.) ian.pollack@chp.edu.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D008130:Lomustine; D003606:Dacarbazine; D000077204:Temozolomide
keywords: astrocytoma; glioblastoma; lomustine; pediatric high-grade glioma; temozolomide