title: Evolution in the eligibility criteria of randomized controlled trials for systemic cancer therapies.
abstract: BACKGROUND
  Eligibility criteria in randomized controlled trials (RCTs) reduce inter-patient heterogeneity, but may reduce generalizability of results. Here, we explore temporal changes in eligibility criteria of practice-changing RCTs for systemic cancer therapies and in the proportion of patients excluded from these trials after application of eligibility criteria.
  
  
  METHODS
  An electronic search identified practice-changing RCTs published in six major journals between July 2010 and December 2012. Trial protocols were identified through journal websites and communication with authors or study sponsors. Eligibility criteria were extracted from protocols. The number of patients excluded after application of eligibility criteria was extracted from the CONSORT diagrams and text of publications. Changes in eligibility criteria over time were assessed by logistic regression and meta-regression was carried out to evaluate the impact of year of protocol on the proportion of patients who were excluded after screening.
  
  
  RESULTS
  Eighty-six protocols written between 1987 and 2012 were included. Over time, there has been an increasing frequency of exclusion of patients with prior cerebrovascular events (OR 1.34, p=0.003), coagulation/bleeding disorders (OR 1.34, p=0.006), prior gastrointestinal bleeding (OR 1.33, p=0.01), cardiac co-morbidities (OR 1.24, p=0.004) and exclusion based on concurrent medication (OR 1.19, p=0.01). There has been a decrease in upper age limit usage (OR 0.83, p=0.01) and leukopenia (OR 0.83, p=0.009). The proportion of patients excluded from trials has increased from 9% prior to 2000 to 18% after 2010 (p-value for trend <0.001).
  
  
  CONCLUSIONS
  RCTs have become less representative of cancer patients treated in routine practice with increased use of organ-specific and co-morbidity-based exclusion criteria.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Srikanthan
authors.affiliation: NCIC Clinical Trials Group and Department of Oncology, Queen's University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Vera-Badillo
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ethier
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Goldstein
authors.affiliation: Kantonsspital St. Gallen, Department of Medical Oncology, St. Gallen, Switzerland.
authors.forename: A J
authors.initials: AJ
authors.lastname: Templeton
authors.affiliation: Medical Oncology Department and Translational Research Unit, Albacete University Hospital, Edificio de Investigación, Calle Francisco Javier de Moya, 02006 Albacete, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ocana
authors.affiliation: Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška cesta 2, SI - 1000 Ljubljana, Slovenia.
authors.forename: B
authors.initials: B
authors.lastname: Seruga
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address: eitan.amir@uhn.ca.
authors.forename: E
authors.initials: E
authors.lastname: Amir
mesh_terms: D000970:Antineoplastic Agents; D015897:Comorbidity; D000075202:Contraindications; D004347:Drug Interactions; D004608:Eligibility Determination / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000453:epidemiology; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards
chemical_list: D000970:Antineoplastic Agents
keywords: Eligibility criteria; Randomized controlled trials; Systemic therapy; Trial evaluation