Page 154 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
a total expected sample size of 1,100 evaluable patients. Detailed information on the sample size calculation can be found in the Supplementary methods. Patients were considered evaluable when meeting the inclusion and exclusion criteria, and if they received at least one fluoropyrimidine drug administration.
Associations between dichotomous outcomes, e.g. occurrence of severe toxicity or hospitalization, and genotype status were tested using χ2 or Fisher’s exact test (Fisher’s exact test was chosen when the smallest cell count was 5 or lower; for this test the double one- tailed exact probability was reported). Baseline characteristics between DPYD variant allele carriers and wild-type patients in the study were compared using either χ2 test, Fisher’s exact test or Kruskal-Wallis rank sum test depending on the type of variable. DPD enzyme activity was compared between carriers of individual DPYD variants and wild-type patients using Student’s t-tests. P-values <0.05 were considered statistically significant. Statistical analyses on an intention-to-treat population were performed using SPSS (version 23.0) and R (version 3.1.2). This study is registered with ClinicalTrials.gov, number NCT02324452.
Results
Patient and treatment characteristics
Between April 30th, 2015 and December 21st, 2017, a total of 1,181 patients intended to start fluoropyrimidine-based treatment were enrolled in this study. In total, 78 patients were considered non-evaluable (Figure 1), as they retrospectively were identified as not meeting the inclusion criteria (N=48), did not start fluoropyrimidine-based treatment (N=26), or were homozygous or compound heterozygous DPYD variant allele carriers (N=4). This resulted in a total of 1,103 evaluable patients, of whom 85 were heterozygous DPYD variant allele carriers (7.7%). Baseline characteristics of DPYD variant allele carriers and DPYD wild-type patients are described in Table 1 and in the Supplementary Table 1. The most common tumor type was colorectal cancer (64%). In total, 83% of patients were treated with a capecitabine-based regimen.
Mean relative dose intensities for each patient group are presented in Table 2. In general, dose recommendations as described in the study protocol were followed by the treating physicians, which resulted in mean dose intensities in the first cycle of 74%, 73%, 51%, and 50% for c.1236G>A, c.2846A>T, DPYD*2A and c.1679T>G, respectively. The performed dose reductions were therefore in line with the pre-specified dose reductions of 25% (for c.1236G>A and c.2846A>T) or 50% (for DPYD*2A and c.1679T>G). However, for four patients carrying DPYD variants, dose reductions were not applied at start of treatment (Supplementary results). One of these patients, (c.2846A>T carrier) was treated by mistake with a full capecitabine dose for the first two cycles, which resulted in fatal fluoropyrimidine- related toxicity. Although dosing recommendations were not followed in these four patients, all results were included in the analysis (intention-to-treat analysis).
Doses were escalated during treatment in eleven out of 85 DPYD variant allele carriers (13%). In five of these patients (two DPYD*2A and three c.1236G>A carriers) the higher dose was not well tolerated, leading to a dose reduction. Also, one patient (c.2846A>T carrier) discontinued treatment after the dose escalation due to toxicity. Five patients (one c.2846A>T, one c.1236G>A, one c.1679T>G, and two DPYD*2A carriers) were able to
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