Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.
BACKGROUND
Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups.


DESIGN AND METHODS
In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting.


RESULTS AND CONCLUSIONS
We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question.


TRIAL REGISTRATION
clinicaltrials.gov Identifier NCT00490139.
['Holmes|E M|EM|', 'Bradbury|I|I|', 'Williams|L S|LS|', 'Korde|L|L|', 'de Azambuja|E|E|', 'Fumagalli|D|D|', 'Moreno-Aspitia|A|A|', 'Baselga|J|J|', 'Piccart-Gebhart|M|M|', 'Dueck|A C|AC|', 'Gelber|R D|RD|', '|||']
D000328:Adult D000368:Aged D000971:Antineoplastic Combined Chemotherapy Protocols D001943:Breast Neoplasms D018572:Disease-Free Survival D005260:Female D006801:Humans D053208:Kaplan-Meier Estimate D000077341:Lapatinib D008875:Middle Aged D016016:Proportional Hazards Models D018719:Receptor, ErbB-2 D000068878:Trastuzumab
proportional hazards early breast cancer accelerated failure time models power family-wise type 1 error stopping boundaries