OBJECTIVE: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. STUDY DESIGN AND SETTING: The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. RESULTS: R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. CONCLUSION: These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed.
OBJECTIVE: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. STUDY DESIGN AND SETTING: The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. RESULTS: R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. CONCLUSION: These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed.
Authors: Lucas Moreno; Andrew D J Pearson; Xavier Paoletti; Irene Jimenez; Birgit Geoerger; Pamela R Kearns; C Michel Zwaan; Francois Doz; Andre Baruchel; Josef Vormoor; Michela Casanova; Stefan M Pfister; Bruce Morland; Gilles Vassal Journal: Nat Rev Clin Oncol Date: 2017-05-16 Impact factor: 66.675
Authors: Philip S Boonstra; Jincheng Shen; Jeremy M G Taylor; Thomas M Braun; Kent A Griffith; Stephanie Daignault; Gregory P Kalemkerian; Theodore S Lawrence; Matthew J Schipper Journal: J Natl Cancer Inst Date: 2015-02-20 Impact factor: 13.506
Authors: Marcin Waligora; Malgorzata M Bala; Magdalena Koperny; Mateusz T Wasylewski; Karolina Strzebonska; Rafał R Jaeschke; Agnieszka Wozniak; Jan Piasecki; Agnieszka Sliwka; Jerzy W Mitus; Maciej Polak; Dominika Nowis; Dean Fergusson; Jonathan Kimmelman Journal: PLoS Med Date: 2018-02-20 Impact factor: 11.069