Dose adaptation of capecitabine based on individual prediction of limiting toxicity grade: evaluation by clinical trial simulation View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2011-08-02

AUTHORS

Ines Paule, Michel Tod, Emilie Hénin, Benoit You, Gilles Freyer, Pascal Girard

ABSTRACT

PurposeAnticancer drugs often show a narrow therapeutic index and high inter-patient variability, which can lead to the need to adjust doses individually during the treatment. One approach to doing this is to use individual model predictions. Such methods have been proposed to target-specific drug concentrations or blood cell count, both of which are continuous variables. However, many toxic effects are evaluated on a categorical scale. This article presents a novel approach to dose adjustments for reducing a graded toxicity while maintaining efficacy, applied to hand-and-foot syndrome (HFS) induced by capecitabine.MethodsA mixed-effects proportional odds Markov model relating capecitabine doses to HFS grades was individually adjusted at the end of each treatment cycle (3 weeks) by estimating subject-specific parameters by Bayesian MAP technique. It was then used to predict the risk of intolerable (grade ≥ 2) toxicity over the next treatment cycle and determine the next dose accordingly, targeting a predefined tolerable risk. Proof of concept was given by simulating virtual clinical trials, where the standard dose reductions and the prediction-based adaptations were compared, and where the therapeutic effect was simulated using a colorectal tumor inhibition model. A sensitivity analysis was carried out to test various specifications of prediction-based adaptation.ResultsIndividualized dose adaptation might reduce the average duration of intolerable HFS by 10 days as compared to the standard reductions (3.8 weeks vs. 5.2 weeks; 27% relative reduction) without compromising antitumor efficacy (both responder rates were 49%). A clinical trial comparing the two methods should include 350 patients per arm to achieve at least 90% power to show a difference in grade ≥2 HFS duration at an alpha level of 0.05.ConclusionsThese results indicate that individual prediction-based dose adaptation based on ordinal data may be feasible and beneficial. More... »

PAGES

447-455

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00280-011-1714-9

DOI

http://dx.doi.org/10.1007/s00280-011-1714-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1029124441

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21809035


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89 model predictions
90 narrow therapeutic index
91 need
92 next dose
93 next treatment cycle
94 novel approach
95 ordinal data
96 parameters
97 patients
98 power
99 prediction
100 proof
101 proof of concept
102 reduction
103 results
104 risk
105 scale
106 sensitivity analysis
107 simulations
108 specification
109 standard dose reductions
110 standard reduction
111 subject-specific parameters
112 such methods
113 syndrome
114 technique
115 therapeutic effect
116 therapeutic index
117 tolerable risk
118 toxic effects
119 toxicity
120 toxicity grade
121 treatment
122 treatment cycles
123 trial simulations
124 trials
125 variability
126 variables
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