title: Variation over time and interdependence between disease progression and death among patients with glioblastoma on RTOG 0525.
abstract: BACKGROUND
  We assessed the longitudinal hazard characteristics for death and progression in patients with glioblastoma, evaluated the impact of prognostic factors and treatment on the hazard within different time intervals to determine if effects are time varying, and quantified the influence of progression on survival.
  
  
  METHODS
  Among patients randomized to Radiation Therapy Oncology Group trial 0525, which compared dose-dense with standard-dose temozolomide, we estimated the hazards of death and treatment failure (death or progression) over time and their interdependence.
  
  
  RESULTS
  The peak hazard of death was reached at around 16 months with a slow decline after that; the hazard of progression/death reached a peak at around 6 months and decreased dramatically thereafter. The survival advantages for patients with MGMT gene promoter methylation and recursive partitioning analysis class III were substantial in the first 2 years, but lessened thereafter. The progression-free survival benefit of dose-dense over standard-dose temozolomide occurred in the first 6 months (hazard ratio: 0.70; 95% CI: 0.58-0.86; P < .001), although it diminished thereafter. After adjusting for recursive partitioning analysis class and MGMT methylation status, the hazard ratio of death for patients who had progressed over nonprogressors was 6.59 (95% CI: 5.15-8.43; P < .001).
  
  
  CONCLUSIONS
  After the peak hazard of death, a consistently high hazard remains, but it is lower than in the peak period. The progression hazard peak is earlier, and then hazard consistently declines. The rate of dying after disease progression is about 6.59 times the rate for nonprogressors, suggesting that progression-free survival may be a relevant clinical endpoint.
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: Meihua
authors: M
authors: Wang
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: James J
authors: JJ
authors: Dignam
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: Minhee
authors: M
authors: Won
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: Walter
authors: W
authors: Curran
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: Minesh
authors: M
authors: Mehta
authors: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (M.W., J.J.D., M.W.); Department of Public Health Sciences, University of Chicago, Chicago, Illinois (J.J.D.); Winship Cancer Institute of Emory University, Atlanta, Georgia (W.C.); Department of Radiation Oncology, Northwestern University, Chicago, Illinois (M.M.); Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas (M.R.G.).
authors: Mark R
authors: MR
authors: Gilbert
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; 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; D018450:Disease Progression; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D006801:Humans; D016016:Proportional Hazards Models; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: glioblastoma; hazard of death; hazard of failure (progression or death)