title: The power of phase II end-points for different possible mechanisms of action of an experimental treatment.
abstract: BACKGROUND
  The high failure rate in phase III oncology trials is partly because the signal obtained from phase II trials is often weak. Several papers have considered the appropriateness of various phase II end-points for individual trials, but there has not been a systematic comparison using simulated data to determine which end-point should be used in which situation.
  
  
  METHODS
  In this paper we carry out simulation studies to compare the power of several Response Evaluation Criteria in Solid Tumours (RECIST) response-based end-points for one-arm and two-arm trials, together with progression-free survival (PFS) and testing the tumour-shrinkage directly for two-arm trials. We consider six scenarios: (1) short-term cytotoxic therapy; (2) continuous cytotoxic therapy; (3+4) cytostatic therapy; (5+6) delayed tumour-shrinkage effect (seen in some immunotherapies). We also consider measurement error in the assessment of tumour size.
  
  
  RESULTS
  Measurement error affects the type-I error rate and power of single-arm trials, and the power of two-arm trials. Generally no single end-point performed well in all scenarios. Best observed response rate, PFS and directly testing the tumour-shrinkages performed best for a number of scenarios. PFS performed very poorly when the effect of the treatment was short-lived. In scenario 6, where the delay in effect was long, no end-point performed well.
  
  
  CONCLUSIONS
  A clinician setting up a phase II trial should consider the likely mechanism of action the drug will have and choose an end-point that provides high power for that scenario. Testing the difference in tumour-shrinkage is often powerful. Alternative end-points are required for therapies with a long delayed effect.
authors.affiliation: MRC Biostatistics Unit, Cambridge, United Kingdom. Electronic address: james.wason@mrc-bsu.cam.ac.uk.
authors.forename: J M S
authors.initials: JM
authors.lastname: Wason
authors.affiliation: Department of Brain and Behavioral Sciences, University of Pavia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Dentamaro
authors.affiliation: Cambridge Clinical Trials Centre, Cambridge Biomedical Research Centre, United Kingdom.
authors.forename: T G
authors.initials: TG
authors.lastname: Eisen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D018572:Disease-Free Survival; D023381:Endpoint Determination / Q000379:methods* / Q000592:standards; D006801:Humans; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D012107:Research Design; D066066:Response Evaluation Criteria in Solid Tumors; D035703:Therapies, Investigational; D047368:Tumor Burden / Q000187:drug effects
keywords: Measurement error; Phase II cancer trial; Progression-free-survival; RECIST; Response
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