title: Time trends in glioblastoma multiforme survival: the role of temozolomide.
abstract: BACKGROUND
  In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population-based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement.
  
  
  METHODS
  We used national Veterans Health Administration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997-2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997-2000, 2001-2004, and 2005-2008) using Kaplan-Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates.
  
  
  RESULTS
  Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005-2008 versus 1997-2000, the HR was 0.72 (95% CI, 0.64-0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86-1.19; p-trend = 0.84).
  
  
  CONCLUSIONS
  The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings.
authors.affiliation: Corresponding Author: Robert Dubrow, MD, PhD, Department of Chronic Disease Epidemiology, Yale School of Public Health, P.O. Box 208034, New Haven, CT 06520-8034. robert.dubrow@yale.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Dubrow
authors.forename: Amy S
authors.initials: AS
authors.lastname: Darefsky
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Jacobs
authors.forename: Lesley S
authors.initials: LS
authors.lastname: Park
authors.forename: Michal G
authors.initials: MG
authors.lastname: Rose
authors.forename: Maxwell S H
authors.initials: MS
authors.lastname: Laurans
authors.forename: Joseph T
authors.initials: JT
authors.lastname: King
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011879:Radiotherapy Dosage; D015996:Survival Rate; D000077204:Temozolomide; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
keywords: brain neoplasms; glioblastoma; survival; temozolomide; time trends
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