title: Resampling the N9741 trial to compare tumor dynamic versus conventional end points in randomized phase II trials.
abstract: OBJECTIVE
  The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]).
  
  
  METHODS
  Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS.
  
  
  RESULTS
  For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm.
  
  
  CONCLUSIONS
  TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.
authors.affiliation: Manish R. Sharma, Elizabeth Gray, and Theodore G. Karrison, University of Chicago, Chicago, IL; Richard M. Goldberg, Ohio State University, Columbus, OH; and Daniel J. Sargent, Mayo Clinic, Rochester, MN. msharma@medicine.bsd.uchicago.edu.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Sharma
authors.affiliation: Manish R. Sharma, Elizabeth Gray, and Theodore G. Karrison, University of Chicago, Chicago, IL; Richard M. Goldberg, Ohio State University, Columbus, OH; and Daniel J. Sargent, Mayo Clinic, Rochester, MN.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.affiliation: Manish R. Sharma, Elizabeth Gray, and Theodore G. Karrison, University of Chicago, Chicago, IL; Richard M. Goldberg, Ohio State University, Columbus, OH; and Daniel J. Sargent, Mayo Clinic, Rochester, MN.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: Manish R. Sharma, Elizabeth Gray, and Theodore G. Karrison, University of Chicago, Chicago, IL; Richard M. Goldberg, Ohio State University, Columbus, OH; and Daniel J. Sargent, Mayo Clinic, Rochester, MN.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.affiliation: Manish R. Sharma, Elizabeth Gray, and Theodore G. Karrison, University of Chicago, Chicago, IL; Richard M. Goldberg, Ohio State University, Columbus, OH; and Daniel J. Sargent, Mayo Clinic, Rochester, MN.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin