title: Impact of delays in initiating postoperative chemoradiation while determining the MGMT promoter-methylation statuses of patients with primary glioblastoma.
abstract: BACKGROUND
  The benefits of new innovations in glioblastoma therapies should not be curtailed as a result of delays in commencement of radiation therapy, caused by clinical circumstances as well as diagnostic procedures. This study evaluates whether delays in chemo-radiotherapy after surgery, while determining O6-methylguanine-DNA-methyltransferase (MGMT) promoter status, affect the survival rates of patients with glioblastoma (GBM).
  
  
  METHODS
  Our sample comprised 50 GBM patients in a retrospective analysis of three prospective studies that focused on combined radiotherapy and required MGMT promoter-status testing as inclusion criteria. Results were compared with a reference group of 127 favourable GBM cases (Karnofsky performance-status scale ≥ 70), in which the patients underwent standard postoperative chemo-radiotherapy with temozolomide. Survival time was calculated using the Kaplan-Meier method, and a multivariate analysis of the delays between surgical and radiotherapy procedures was performed using the Cox regression model.
  
  
  RESULTS
  The study group's median overall survival time was 16.2 months (with a range of 2 to 56 months), versus the reference group's survival time of 18.2 months (with a range of 1 to 92 months) (p = 0.64). The delay between surgery and radiotherapy was increased by 8 days in the study patients (p < 0.001), with a median delay of 35 days (range: 18-49 days) corresponding to the typical 27-day delay (range: 5-98 days) for those in the reference group. Univariate and multivariate analyses did not show any negative association between survival time and delaying radiation therapy to determine MGMT-promoter status; commencement of radiation therapy sooner than 24 days after surgery was the threshold for significantly decreased overall survival (p = 0.01) and progression-free (p = 0.03) survival.
  
  
  CONCLUSIONS
  Delaying postoperative chemoradiation for GBM patients--carried out in order to determine MGMT-promoter status-did not have a negative impact on survival time. Indeed, the data of the present study shows that initiating radiation therapy sooner than 24 days after surgery has a negative impact on progression and survival.
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.|Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Adeberg
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Tilman.bostel@med.uni-heidelberg.de.|Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany. Tilman.bostel@med.uni-heidelberg.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Bostel
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Semi.harrabi@med.uni-heidelberg.de.|Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany. Semi.harrabi@med.uni-heidelberg.de.
authors.forename: Semi
authors.initials: S
authors.lastname: Harrabi
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Denise.bernhardt@med.uni-heidelberg.de.
authors.forename: Denise
authors.initials: D
authors.lastname: Bernhardt
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Thomas.welzel@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Welzel
authors.affiliation: Department of Neurooncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Wolfgang.wick@med.uni-heidelberg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Juergen.debus@med.uni-heidelberg.de.|Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany. Juergen.debus@med.uni-heidelberg.de.|Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. Juergen.debus@med.uni-heidelberg.de.
authors.forename: Juergen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Stephanie.combs@tum.de.|Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany. Stephanie.combs@tum.de.|Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany. Stephanie.combs@tum.de.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
mesh_terms: D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy / Q000379:methods*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016019:Survival Analysis; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide