title: NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide.
abstract: OBJECTIVE
  The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas.
  
  
  METHODS
  Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence.
  
  
  RESULTS
  Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm.
  
  
  CONCLUSIONS
  Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.
authors.affiliation: Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. wolfgang.wick@med.uni-heidelberg.de
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Corinna
authors.initials: C
authors.lastname: Engel
authors.forename: Mandy
authors.initials: M
authors.lastname: Stoffels
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Florian
authors.initials: F
authors.lastname: Stockhammer
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sabel
authors.forename: Susanne
authors.initials: S
authors.lastname: Koeppen
authors.forename: Ralf
authors.initials: R
authors.lastname: Ketter
authors.forename: Richard
authors.initials: R
authors.lastname: Meyermann
authors.forename: Marion
authors.initials: M
authors.lastname: Rapp
authors.forename: Christof
authors.initials: C
authors.lastname: Meisner
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Kortmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Ernemann
authors.forename: Michael
authors.initials: M
authors.lastname: Bamberg
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011344:Procarbazine / Q000008:administration & dosage / Q000009:adverse effects; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D000077204:Temozolomide; D013997:Time Factors; D017211:Treatment Failure; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide