title: Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: a review of the literature.
abstract: OBJECTIVE
  There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA).
  
  
  METHODS
  We retrieved all phase I trials testing monotherapy with an MTA published over the last decade. In each trial, all items used to define DLTs were recorded.
  
  
  RESULTS
  Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE classification. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. Specifications about minimum duration of toxicity, degree of reversibility, the need to delay treatment and to reduce dose-intensity because of toxicity were infrequently incorporated in the definition of DLT. The definition of DLT varied with administration schedule. Discrepancies between the initial and the final definition of DLT were reported in 25% of trials.
  
  
  CONCLUSIONS
  While our results do not support a standardisation of the definition of DLT, the inclusion of following specifications in its definition when relevant would reduce the heterogeneity observed across trials: (1) DLT assessment period, (2) absolute severity according to NCI CTCAE classification as well as severity relative to baseline status, (3) minimum duration of toxicity, (4) reversibility of toxicity within a certain period of time, and (5) necessity to delay treatment or to reduce dose-intensity.
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France. Christophe.LeTourneau@curie.net
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.forename: Albiruni R A
authors.initials: AR
authors.lastname: Razak
authors.forename: Hui K
authors.initials: HK
authors.lastname: Gan
authors.forename: Simona
authors.initials: S
authors.lastname: Pop
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: Patricia
authors.initials: P
authors.lastname: Tresca
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D020714:Maximum Tolerated Dose; D008495:Medical Oncology / Q000592:standards*; D009369:Neoplasms / Q000188:drug therapy*; D018675:Toxicity Tests / Q000379:methods / Q000592:standards*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents