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- Title
Early Trial Discontinuation in Toxicity-Driven, Dose-Escalating, Phase I Cancer Trials: Occurrence, Outcomes and Predictive Factors.
- Authors
Cousin, Sophie; Cassier, Philippe; Gomez-Roca, Carlos; Isambert, Nicolas; Kotecki-Borghesi, Nuria; Zanetta, Sylvie; Tassy, Louis; Simonet-Lamm, Anne-Laure; Maio, Eleonora; Terret, Catherine; Bouchet, Juliette; Delord, Jean-Pierre; Penel, Nicolas
- Abstract
Introduction: The selection of patients for phase I cancer trials remains challenging. Patients who dropout of the trial before completion need to be replaced and this can result in significant delays to trial completion. Objective: The objective of this study was to identify patients enrolled in phase I oncology trials who were unable to complete the minimum evaluation period of the trial, and to use these data to develop a predictive model of risk factors for patient replacement. Patients and Methods: We retrospectively reviewed all consecutive patients who were enrolled in dose-escalating phase I cancer trials at four medical centers in France between May 2003 and May 2013. Replacement was defined as trial discontinuation before 6 weeks, without the occurrence of dose-limiting toxicity. Using logistic regression and decision-tree analyses, we developed a predictive model to identify patients who were at high risk for replacement, and also their common risk factors. This model was designed to provide maximum specificity and a negative predictive value. Results: Of 332 patients enrolled in the study, 16 had to be replaced (4.8 %). The median overall survival time was 45 days for the patients who were replaced versus 480 days for the patients who were not replaced ( p < 0.0001). In the univariate analysis, the risk factors for replacement included Eastern Cooperative Oncology Group performance status (ECOG-PS) = 2 [odds ratio (OR) 11], Royal Marsden Score (RMS) = 3 (OR 29), and enrollment in a study investigating multiple agents (OR 7). Multivariate analysis retained PS ≥2 and RMS = 3 as independent predictive factors for replacement. The following two patient subgroups were identified: low risk of replacement (RMS ≤2 and PS ≤1) and high risk of replacement (RMS = 3 or PS ≥2). The rates of replacement were 8/312 (2.5 %) and 8/20 (40.0 %) for low- and high-risk patients, respectively, and the specificity and negative predictive values of our model were 96.2 and 97.5 %, respectively. Conclusions: Approximately 5 % of enrolled patients were replaced, and these patients experienced very poor outcomes. To minimize trial delays, enrolling patients who have an RMS = 3 or PS ≥2 should be avoided.
- Subjects
ONCOLOGY research; CLINICAL trials; CANCER; PREDICTION models; TOXICOLOGY
- Publication
Pharmaceutical Medicine, 2016, Vol 30, Issue 1, p49
- ISSN
1178-2595
- Publication type
Article
- DOI
10.1007/s40290-015-0120-8