Adrien Guilloteau1,2,3, Michal Abrahamowicz4, Olayide Boussari5,6,7,8, Valérie Jooste5,6,7, Thomas Aparicio9, Catherine Quantin10,11,12,13, Karine Le Malicot5,6,8, Christine Binquet5,6,11,12. 1. INSERM, U1231, EPICAD team, Equipe EPICAD, 7, Bld Jeanne d'Arc, Dijon, France. adrien.guilloteau@chu-dijon.fr. 2. University of Bourgogne Franche-Comté, UMR "Lipides Nutrition Cancer", EPICAD team, Dijon, France. adrien.guilloteau@chu-dijon.fr. 3. Infection Control Unit, Dijon-Bourgogne University Hospital, Dijon, France. adrien.guilloteau@chu-dijon.fr. 4. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada. 5. INSERM, U1231, EPICAD team, Equipe EPICAD, 7, Bld Jeanne d'Arc, Dijon, France. 6. University of Bourgogne Franche-Comté, UMR "Lipides Nutrition Cancer", EPICAD team, Dijon, France. 7. Digestive Cancer Registry of Burgundy, Dijon-Bourgogne University Hospital, Dijon, France. 8. Fédération française de cancérologie digestive (FFCD), Biostatistics department, Dijon, France. 9. Assistance Publique - Hôpitaux de Paris, Saint-Louis Hospital, Gastroenterology and Digestive Oncology Department, Université Paris 7, Sorbonne Paris Cité, Paris, France. 10. Biostatistics and Bioinformatics (DIM), Dijon-Bourgogne University Hospital, Dijon, France. 11. Inserm, CIC1432, Clinical Epidemiology unit, Dijon, France. 12. Dijon-Bourgogne University Hospital, Centre d'investigation clinique, Module Epidémiologie Clinique/Essais cliniques Dijon, Dijon, France. 13. INSERM, U1181, Paris France ; Université Paris-Saclay, B2PHI, Paris, France.
Abstract
BACKGROUND: As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. METHODS: To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. RESULTS: After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model's fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. CONCLUSIONS: All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. TRIAL REGISTRATION: clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.
RCT Entities:
BACKGROUND: As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. METHODS: To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. RESULTS: After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model's fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. CONCLUSIONS: All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. TRIAL REGISTRATION: clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.
Entities:
Keywords:
Bevacizumab; Colorectal cancer; Survival; Time varying cumulative exposure to maintenance treatment
Authors: Krystyna M Wozniak; James J Vornov; Ying Wu; Kenichi Nomoto; Bruce A Littlefield; Christopher DesJardins; Yanke Yu; George Lai; Larisa Reyderman; Nancy Wong; Barbara S Slusher Journal: Cancer Res Date: 2016-04-13 Impact factor: 12.701
Authors: Susanna Hegewisch-Becker; Ullrich Graeven; Christian A Lerchenmüller; Birgitta Killing; Reinhard Depenbusch; Claus-Christoph Steffens; Salah-Eddin Al-Batran; Thoralf Lange; Georg Dietrich; Jan Stoehlmacher; Andrea Tannapfel; Anke Reinacher-Schick; Julia Quidde; Tanja Trarbach; Axel Hinke; Hans-Joachim Schmoll; Dirk Arnold Journal: Lancet Oncol Date: 2015-09-08 Impact factor: 41.316