title: Statistical controversies in clinical research: should schedules of tumor size assessments be changed?
abstract: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules.
  
  
  
  A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule.
  
  
  
  For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks.
  
  
  
  Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing.
authors: Biostatistics Unit, Institut Claudius Regaud, IUCT-O, Toulouse.
authors: T
authors: T
authors: Filleron
authors: Methodology and Biostatistics Unit, Oscar Lambret Cancer Center, Lille.|SIRIC OncoLille, Lille.|Biostatistics Unit, Lille University Hospital, Lille.
authors: W
authors: W
authors: Kouokam
authors: Biostatistics Unit, Institut Claudius Regaud, IUCT-O, Toulouse.
authors: J
authors: J
authors: Gilhodes
authors: SIRIC OncoLille, Lille.|Biostatistics Unit, Lille University Hospital, Lille.
authors: A
authors: A
authors: Duhamel
authors: Methodology and Biostatistics Unit, Oscar Lambret Cancer Center, Lille.|SIRIC OncoLille, Lille.|Medical Oncology Department, Oscar Lambret Cancer Center, Lille.
authors: N
authors: N
authors: Penel
authors: Medical Oncology, Centre François Baclesse, Centre de Lutte Contre le Cancer, Caen.
authors: F
authors: F
authors: Joly
authors: Methodology and Biostatistics Unit, Oscar Lambret Cancer Center, Lille.|SIRIC OncoLille, Lille.
authors: E
authors: E
authors: Tresch-Bruneel
authors: Methodology and Biostatistics Unit, Oscar Lambret Cancer Center, Lille.|SIRIC OncoLille, Lille.
authors: A
authors: A
authors: Kramar
authors: Department of Medical Oncology, Nîmes University Hospital, Nîmes, France nadine.houede@chu-nimes.fr.
authors: N
authors: N
authors: Houédé
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D035843:Biomedical Research / Q000706:statistics & numerical data*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D018450:Disease Progression; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents
keywords: clinical trial; end point; phase II; time to progression; trial design