Resampling the N9741 trial to compare tumor dynamic versus conventional end points in randomized phase II trials

J Clin Oncol. 2015 Jan 1;33(1):36-41. doi: 10.1200/JCO.2014.57.2826. Epub 2014 Oct 27.


Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Clinical Trials, Phase II as Topic*
  • Clinical Trials, Phase III as Topic*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Fluorouracil / administration & dosage
  • Humans
  • Irinotecan
  • Kaplan-Meier Estimate
  • Leucovorin / administration & dosage
  • Neoplasm Metastasis
  • Organoplatinum Compounds / administration & dosage
  • Oxaliplatin
  • Randomized Controlled Trials as Topic*
  • Treatment Outcome
  • Tumor Burden / drug effects


  • Organoplatinum Compounds
  • Oxaliplatin
  • Irinotecan
  • Leucovorin
  • Fluorouracil
  • Camptothecin