title: Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival.
abstract: OBJECTIVE
  The importance of enhanced drug delivery in patients with central nervous system (CNS) malignancies has not yet been demonstrated conclusively. Intra-arterial chemotherapy in combination with osmotic bloodbrain barrier disruption (BBBD) increases drug delivery to tumor by 2- to 5-fold and to surrounding brain tissue by 10- to 100-fold as compared with intravenous administration of chemotherapy. Primary CNS lymphoma (PCNSL) is an excellent model for studying dose intensity because PCNSL is a highly infiltrative, chemosensitive, primary CNS malignancy in which the integrity of the blood-brain barrier is highly variable.
  
  
  METHODS
  Survival time was assessed in 74 non-acquired immunodeficiency syndrome patients with PCNSL who underwent a total of 1047 BBBD procedures. Total dose intensity is estimated by using the number of intraarterial infusions or a cumulative degree of BBBD score.
  
  
  RESULTS
  Using proportional hazards multivariable analyses to adjust for baseline characteristics, survival was significantly associated with the total intensity of BBBD (P < 0.05). Additional statistical analyses demonstrate that survival bias does not fully explain these associations. Even when only patients who attained a complete response are considered, increased dose intensity resulted in increased survival.
  
  
  CONCLUSIONS
  In patients with PCNSL, a chemotherapy-responsive tumor type, survival time is highly associated with total drug dose delivered, even in analyses designed to control for potential survival biases. These results probably constitute the strongest evidence to date of the importance of total dose intensity in treating CNS malignancies.
authors.affiliation: Division of Medical Informatics and Outcomes Research, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Kraemer
authors.forename: D
authors.initials: D
authors.lastname: Fortin
authors.forename: N D
authors.initials: ND
authors.lastname: Doolittle
authors.forename: E A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D008223:Lymphoma / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents