E M Holmes1, I Bradbury1, L S Williams2, L Korde3, E de Azambuja4, D Fumagalli5, A Moreno-Aspitia6, J Baselga7, M Piccart-Gebhart8, A C Dueck9, R D Gelber10. 1. Frontier Science (Scotland), Kincraig, Kingussie. 2. Novartis Pharmaceuticals UK Limited, Frimley, UK. 3. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA. 4. Medical Support Team of the Academic Promoting Team, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), Brussels. 5. Breast International Group (BIG), Brussels, Belgium. 6. Alliance for Clinical Trials in Oncology (formerly North Central Cancer Treatment Group), Mayo Clinic, Jacksonville. 7. AstraZeneca, Gaithersburg, USA. 8. Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), Brussels, Belgium. 9. Alliance Statistics and Data Center, Mayo Clinic, Scottsdale. 10. Department of Data Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, Frontier Science and Technology Research Foundation, Boston, USA. Electronic address: gelber@jimmy.harvard.edu.
Abstract
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.
RCT Entities:
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.
Authors: Gunter von Minckwitz; Marion Procter; Evandro de Azambuja; Dimitrios Zardavas; Mark Benyunes; Giuseppe Viale; Thomas Suter; Amal Arahmani; Nathalie Rouchet; Emma Clark; Adam Knott; Istvan Lang; Christelle Levy; Denise A Yardley; Jose Bines; Richard D Gelber; Martine Piccart; Jose Baselga Journal: N Engl J Med Date: 2017-06-05 Impact factor: 91.245
Authors: Martine Piccart-Gebhart; Eileen Holmes; José Baselga; Evandro de Azambuja; Amylou C Dueck; Giuseppe Viale; Jo Anne Zujewski; Aron Goldhirsch; Alison Armour; Kathleen I Pritchard; Ann E McCullough; Stella Dolci; Eleanor McFadden; Andrew P Holmes; Liu Tonghua; Holger Eidtmann; Phuong Dinh; Serena Di Cosimo; Nadia Harbeck; Sergei Tjulandin; Young-Hyuck Im; Chiun-Sheng Huang; Véronique Diéras; David W Hillman; Antonio C Wolff; Christian Jackisch; Istvan Lang; Michael Untch; Ian Smith; Frances Boyle; Binghe Xu; Henry Gomez; Thomas Suter; Richard D Gelber; Edith A Perez Journal: J Clin Oncol Date: 2015-11-23 Impact factor: 44.544
Authors: Alvaro Moreno-Aspitia; Eileen M Holmes; Christian Jackisch; Evandro de Azambuja; Frances Boyle; David W Hillman; Larissa Korde; Debora Fumagalli; Miguel A Izquierdo; Ann E McCullough; Antonio C Wolff; Kathleen I Pritchard; Michael Untch; Sébastien Guillaume; Michael S Ewer; Zhimin Shao; Sung Hoon Sim; Zeba Aziz; Georgia Demetriou; Ajay O Mehta; Michael Andersson; Masakazu Toi; Istvan Lang; Binghe Xu; Ian E Smith; Carlos H Barrios; Jose Baselga; Richard D Gelber; Martine Piccart-Gebhart Journal: Eur J Cancer Date: 2021-03-23 Impact factor: 9.162