Page 152 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
Patients and methods
Study design and participants
This study was a prospective multicenter clinical trial in which 17 hospitals in the Netherlands participated. The study was approved by the institutional review board of The Netherlands Cancer Institute, Amsterdam, the Netherlands, and approval from the board of directors of each individual hospital was obtained for all participating centers. All patients provided written informed consent before enrollment in the study. Additional informed consent was obtained for DPYD variant allele carriers who participated in pharmacokinetic and DPD enzyme activity measurements.
The study population consisted of adult cancer patients (≥18 years) intended to start with a fluoropyrimidine-based anticancer therapy, either as single agent or in combination with other chemotherapeutic agents and/or radiotherapy. Patients with all tumor types for which fluoropyrimidine-based therapy was considered in their best interest could be included. Prior chemotherapy was allowed, except for prior use of fluoropyrimidines. Patients had to have a WHO performance status of 0, 1 or 2, a life expectancy of at least 12 weeks, and acceptable safety laboratory values (Supplementary methods). There were no restrictions on comorbidities, except for diseases expected to interfere with study or the patient’s safety. Full inclusion and exclusion criteria can be found in the Supplementary methods.
Procedures
Treatment
Patients were genotyped before start of fluoropyrimidine therapy for the previously mentioned four DPYD variants. Heterozygous DPYD variant allele carriers received an initial dose reduction of either 25% (for c.2846A>T and c.1236G>A) or 50% (for DPYD*2A and c.1679T>G), in line with current recommendations from Dutch and international pharmacogenomic guidelines.13,16 To achieve a maximal safe exposure, dose escalation was allowed after the first two cycles provided that treatment was well tolerated, and the decision to escalate was left to the discretion of the treating physician. The dose of other anticancer agents or radiotherapy were left unchanged at start of treatment. Homozygous or compound heterozygous DPYD variant allele carriers were excluded from the study and could be treated with personalized regimens outside this protocol.17 Non-carriers of the above mentioned DPYD variants are considered wild-type patients in this study and were treated according to existing standard of care.
Assessments
Toxicity was graded by participating centers according to the National Cancer Institute common terminology criteria for adverse events (CTC-AE),18 and severe toxicity was defined as grade 3 or higher. Patients were followed for toxicity during the entire treatment period and until toxicity was resolved. Toxicity scored by the treating physician or qualified nurse practitioner as possibly, probably or definitely related to fluoropyrimidine-treatment was considered treatment-related toxicity (definitions in the Supplementary methods). Toxicity- related hospitalization and treatment discontinuation due to adverse events were also investigated. Standard laboratory assessments were performed prior to start of treatment
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