Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics

J Clin Oncol. 2009 Sep 1;27(25):4103-8. doi: 10.1200/JCO.2008.21.0807. Epub 2009 Jul 27.


Purpose: We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.

Methods: We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.

Results: The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine.

Conclusion: The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.

MeSH terms

  • Antimetabolites, Antineoplastic / therapeutic use*
  • Capecitabine
  • Clinical Trials, Phase II as Topic*
  • Clinical Trials, Phase III as Topic*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / pathology
  • Computer Simulation
  • Decision Support Techniques
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / therapeutic use
  • Humans
  • Models, Biological*
  • Randomized Controlled Trials as Topic*
  • Reproducibility of Results
  • Retrospective Studies
  • Survival Analysis
  • Time Factors
  • Treatment Outcome


  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • Capecitabine
  • Fluorouracil