Page 68 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
a systematic review of literature was performed and relevant articles were summarized by a scientist of the Royal Dutch Pharmacists Association (MN). The performed search strategy can be found in Supplementary Material 1. Each article was provided with two scores: 1) quality of evidence and 2) clinical impact. The quality of evidence was scored on a 5-point scale ranging from 0 (lowest; data on file) to 4 (highest; well performed controlled studies or meta-analysis) and the clinical impact of clinical effect was scored on a 7-point scale ranging from AA# (positive effect) to F (highest negative effect). The criteria used to develop these scores have been published in detail previously.2,7 This clinical impact scale (AA#─F) runs parallel to the common terminology criteria for adverse events (CTC-AE); where CTC-AE grade 5 severity is equal to clinical relevance score F (death) and CTC-AE grade 1 severity is equal to clinical relevance score B. The clinical relevance score additionally includes the scores AA#, AA and A, since these do not exist in the CTC-AE. These regard “Positive clinical effect”, “No clinical or kinetic effect”, and “Significant kinetic effect or not clinically relevant effect”, respectively. The summaries of articles, and their respective scores, reviewed to devise this guideline can be found in the Supplementary Table 1 and 2. The summaries of each article and their respective scores were checked by two independent DPWG members.
For 5-FU/capecitabine, the initial literature search was performed on March 24th 2009, followed by a second search on July 9th 2014. To update this guideline to the current date, an additional literature search was performed on October 19th 2017, resulting in eleven additional papers. Case reports concerning systemic 5-FU or capecitabine therapy were excluded in this literature review, due to a large number of case reports and other available publications of greater evidentiary quality. Kinetic studies from 2009 onwards were only included if the kinetic parameters were given per genotype. Clinical studies were only included if the patient numbers exceeded 500 (from 2009 onwards) or 1,000 (from May 2014 onwards) and the patient numbers with partially functional activity were at least ten or if the study investigated a variant for which no studies were as yet included or if the study investigated the effect of dose adjustment. From 2009, articles investigating the effect of a group containing both polymorphisms known to increase the risk of toxicity and polymorphisms not known to increase the risk of toxicity were not included. If more than one article described data of the same patient group and the same polymorphisms, only the article with data from the largest amount of patients was included.
For tegafur, the initial literature search was performed on August 20th 2009, followed by a second and third search on October 2nd 2012 and July 27th 2015. To update this guideline to current date, an additional literature search was performed on October 19th 2017, resulting in no additional papers.
General conclusion of evidence
In the systematic review performed for 5-FU/capecitabine, 16 of 18 studies and all three meta-analyses found an increased risk of grade ≥3 toxicity (either overall toxicity or at least one specified type of toxicity) for patients carrying variants resulting in reduced DPD enzyme activity (ranging from gene activity score 0 to 1.5). This increased risk was shown separately for patients assigned DPYD-gene activity scores 1 and 1.5, but gene activity scores 0 and 0.5 were only investigated when grouped with patients assigned other gene activity
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