title: Toxicity burden score: a novel approach to summarize multiple toxic effects.
abstract: BACKGROUND
  Toxicity data from cancer trials are summarized into a single outcome, dose-limiting toxicity (DLT), which does not account for multiple lower grade toxic effects nor differentiates between toxicity types and gradations within DLT.
  
  
  METHODS
  Toxicity data were summarized into a toxicity burden score (TBS) using a weighted sum. The severity weights were estimated via regression using historical data. We demonstrated the method using historical data from a bortezomib trial and illustrated the advantages of defining DLT based on TBS in a simulated dose-finding trial.
  
  
  RESULTS
  The estimated weights were 0.17, 0.40 and 0.85 for grade 1/2, grade 3 and grade 4 platelets, respectively; 0.19, 0.64, 1.03 and 2.53 for grade 1, 2, 3 and 4 neuropathy, respectively and 0.17 for each grade 3 or higher nonhematologic toxic effects unrelated to treatment. In the simulated trial, the probability of selecting doses above the maximum tolerated dose decreased when using the DLT defined based on TBS.
  
  
  CONCLUSIONS
  TBS is a feasible approach to summarize toxicity. It includes information from the grades and types of multiple toxic effects and can be applied in all phases of drug development. Further efforts should focus on validating the method in a large prospective study before applying it in practice.
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York 10032, USA. sml2114@columbia.edu
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.forename: D L
authors.initials: DL
authors.lastname: Hershman
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: J P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Y K
authors.initials: YK
authors.lastname: Cheung
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000633:toxicity*; D001897:Boronic Acids / Q000009:adverse effects / Q000633:toxicity*; D000069286:Bortezomib; D005240:Feasibility Studies; D006305:Health Status Indicators; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011719:Pyrazines / Q000009:adverse effects / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib