Page 325 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

deficient patients between study arms at baseline were detected, with more DPD deficient patients in the retrospectively screened study arm. This results in bias and could lead to the expectation of lower toxicity in the prospectively screened study arm, regardless of applying their multi-parametric approach.31 Due to the available evidence on the increased risk of toxicity in DPD deficient patients or DPYD variant allele carriers, most researchers consider it unethical to perform an RCT and no further attempts are to be expected. Therefore, evidence from an RCT will never be gathered. In addition to this, it was debated that adequate (pharmacogenetic) evidence can also be provided by small-scale, innovative, prospective interventional studies,32 and indeed, some other predictive biomarkers were previously implemented in clinical care without evidence from an RCT.29 In the study of Deenen et al, a historic cohort of patients who appeared to be carrier of DPYD*2A after treatment with fluoropyrimidines, was used to compare severe toxicity between groups.14 The use of a historic cohort was applied as well in the clinical trial presented in this thesis (chapter 5).15 Considering ethics, this study set-up is the best possible method to collect evidence in a prospective way, since an RCT is not possible.
Besides the lack of evidence from an RCT, there are other arguments against DPYD genotyping. The fear of underdosing patients is an often used argument not to implement DPYD genotyping. However, both the study of Deenen et al. and our study (chapter 5) show that DPYD variant allele carriers who received initial dose reductions have comparable 5-FU levels or 5-FU metabolite levels to DPYD wild-type patients treated with a standard dose,14,15 therefore differences in efficacy are less likely. Secondly, treating physicians could increase fluoropyrimidine dosages in DPYD variant allele carriers during treatment based on the onset of severe toxicity (dose titration). In 55% of the DPYD variant allele carriers in whom the dose was increased during treatment, treatment had to be stopped or the dose had to be reduced again due to toxicity. Lastly, a recently published matched pair analysis by Henricks et al. showed no differences in efficacy, measured as overall survival and progression-free survival, between carriers of DPYD*2A treated with a reduced dose and DPYD*2A wild-type patients.33 These results indicate that the fear of underdosing is unjustified.
13
General discussion
Many of the arguments against DPYD genotyping can be refuted with the current evidence in favour of DPYD genotyping. Unfortunately, negative opinions on DPYD genotyping will always exist and maybe not everyone can be convinced. In 2010, Ciccolini et al. already pointed out that it was time to mandate the integration of systematic prospective testing for DPYD as part of routine clinical practice in oncology.27 Yet, in order to align patient care, guidelines of health care authorities should be available.
Recommendations and guidelines
The Food and Drug Administration (FDA) state warnings or contraindications for the use of 5-FU or capecitabine in DPD deficient patients, however does not recommend to test for DPD deficiency.34 No formal recommendations on DPD deficiency testing prior to treatment are given by health authorities, regulatory agencies or guideline committees from the National Comprehensive Cancer Network (NCCN) or American Society of Clinical Oncology (ASCO). In March 2018, the European Medicine Agency (EMA) has asked the involved pharmaceutical companies to update the Summary of Product Characteristics (SPC) of capecitabine by
323