title: Converging or Crossing Curves: Untie the Gordian Knot or Cut it? Appropriate Statistics for Non-Proportional Hazards in Decitabine DACO-016 Study (AML).
abstract: BACKGROUND
  Among patients with acute myeloid leukemia (AML), the DACO-016 randomized study showed reduction in mortality for decitabine [Dacogen(®) (DAC), Eisai Inc., Woodcliff Lake, NJ, USA] compared with treatment choice (TC): at primary analysis the hazard ratio (HR) was 0.85 (95% confidence interval 0.69-1.04; stratified log-rank P = 0.108). With two interim analyses, two-sided alpha was adjusted to 0.0462. With 1-year additional follow-up the HR reached 0.82 (nominal P = 0.0373). These data resulted in approval of DAC in the European Union, though not in the United States. Though pre-specified, the log-rank test could be considered not optimal to assess the observed survival difference because of the non-proportional hazard nature of the survival curves.
  
  
  METHODS
  We applied the Wilcoxon test as a sensitivity analysis. Patients were randomized to DAC (N = 242) or TC (N = 243). One-hundred and eight (44.4%) patients in the TC arm and 91 (37.6%) patients in the DAC arm selectively crossed over to subsequent disease modifying therapies at progression, which might impact the survival beyond the median with resultant converging curves (and disproportional hazards).
  
  
  RESULTS
  The stratified Wilcoxon test showed a significant improvement in median (CI 95%) overall survival with DAC [7.7 (6.2; 9.2) months] versus TC [5.0 (4.3; 6.3) months; P = 0.0458].
  
  
  CONCLUSIONS
  Wilcoxon test indicated significant increase in survival for DAC versus TC compared to log-rank test.
  
  
  BACKGROUND
  Janssen-Cilag GmbH.
authors.affiliation: Janssen-Cilag GmbH, Neuss, Germany. jtomeczk@its.jnj.com.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tomeczkowski
authors.affiliation: Center for Health Economics Research Hannover, Leibniz University Hannover, Hannover, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Lange
authors.affiliation: Janssen-Cilag GmbH, Neuss, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Güntert
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Pushpike
authors.initials: P
authors.lastname: Thilakarathne
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Diels
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xiu
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.affiliation: Janssen-Cilag GmbH, Neuss, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tapprich
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077209:Decitabine; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D016016:Proportional Hazards Models; D013223:Statistics as Topic; D015996:Survival Rate; D014481:United States
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine
keywords: Acute myeloid leukemia; Dacogen®; Decitabine; Log-rank test; Non-proportional hazards; Oncology; Wilcoxon test