title: High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.
abstract: OBJECTIVE
  To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT).
  
  
  METHODS
  We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d.
  
  
  RESULTS
  Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT.
  
  
  CONCLUSIONS
  HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco 94143-0324, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Smith
authors.forename: L E
authors.initials: LE
authors.lastname: Damon
authors.forename: H S
authors.initials: HS
authors.lastname: Rugo
authors.forename: C A
authors.initials: CA
authors.lastname: Ries
authors.forename: C A
authors.initials: CA
authors.lastname: Linker
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D009422:Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051437:Renal Insufficiency / Q000150:complications* / Q000503:physiopathology; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine