title: Dactinomycin and vincristine toxicity in the treatment of childhood cancer: a retrospective study from the Children's Oncology Group.
abstract: BACKGROUND
  Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking.
  
  
  METHODS
  Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (VCR) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines.
  
  
  RESULTS
  For the same dose/body size, AMD toxicity rates were higher in patients <1 year than older patients and VCR toxicity rates increased with age. The statistical model provided estimates for AMD and VCR toxicity risk under current dosing schedules and indicated that patients of smaller body size were at lower risk of VCR toxicity than larger patients of the same age. The rate of AMD toxicity was highest early in treatment and was lower in patients who tolerated initial AMD without toxicity.
  
  
  CONCLUSIONS
  The observed decrease in AMD toxicity rate with cumulative dose may indicate sensitivity in a subgroup of patients while the observed increase in VCR toxicity risk with age may indicate changing sensitivity to VCR. Current dosing practices result in a fairly uniform toxicity profile within age group. However, PK/PD studies should be done to provide further provide further information on best dosing guidelines.
authors.affiliation: Children's Oncology Group and Keck School of Medicine, University of Southern California, Los Angeles, California, USA. langholz@usc.edu
authors.forename: Bryan
authors.initials: B
authors.lastname: Langholz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Jamie
authors.initials: J
authors.lastname: Renbarger
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.forename: Anne
authors.initials: A
authors.lastname: Zajicek
authors.forename: Carola A S
authors.initials: CA
authors.lastname: Arndt
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy*; D016013:Likelihood Functions; D008297:Male; D020258:Neurotoxicity Syndromes / Q000209:etiology; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D012307:Risk Factors; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects; D009396:Wilms Tumor / Q000188:drug therapy*
chemical_list: D003609:Dactinomycin; D014750:Vincristine