Page 204 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 7
lower standard dosages.
Although over 800 patients are considered, the number of patients with a DPYD variant
remains limited due to the low prevalence of DPYD variants. We were unable to show that the risk of toxicity in DPYD variant allele carriers who received dose reductions was equivalent to the risk of wild-type patients. Also, 85% of the DPYD variant allele carriers treated with a standard dose were carriers of the c.1236G>A and c.2846A>T variants. DPYD*2A and DPYD*13 carriers have a higher risk of toxicity when treated with standard dosages compared with c.1236G>A and c.2846A>T carriers. Therefore, it is possible that more toxicity could have occurred in this group if DPYD variants would have been equally distributed, increasing the difference in toxicity compared with the other study groups. Moreover, in the DPYD group with initial dose reductions, DPYD variants and corresponding dose reductions (25 versus 50%) were equally distributed.
Noteworthy, the number of hospitalisations due to toxicity was similar in both groups of DPYD variant allele carriers, yet the duration of hospitalisation was significantly shorter in DPYD variant allele carriers treated with a reduced fluoropyrimidine dose. A possible explanation for this could be that treating physicians are alarmed of a potentially increased risk of toxicity because of DPD deficiency and more rapidly decide to hospitalise a patient in response to signs of potential toxicity. A second explanation is that DPYD variant allele carriers who received dose reductions recovered faster of toxicity.
In two DPYD variant allele carriers who received initially reduced dosages and did not experience (severe) toxicity, the dose was increased during treatment. This shows that physicians might still have fear of underdosing patients and reducing efficacy of the treatment.
Grouped diagnosis was significantly associated to severe haematological toxicity, with more severe toxicity in pelvic malignancies. A possible explanation may be that more bone marrow is exposed to radiation in the pelvic area compared with other areas, increasing the chance of myelosuppression.
With over 800 patients included, this study provides a large amount of toxicity data of wild-type patients and DPYD variant allele carriers receiving CRT. However, our study has several limitations. First, three databases were combined and were partly retrospective, possibly introducing bias. However, each database included patients in each study group, limiting bias. General differences in scoring toxicity per database could exist; however, criteria for toxicity grades are well marked and should therefore be limited. One database used the new version of CTC-AE; however, updates did not influence the grading of toxicity of interest for this study.
Second, not all databases contained the full toxicity spectrum of interest in this study (e.g. nausea, vomiting, radiation dermatitis, fatigue); therefore, overall toxicity consisted of different toxicities per original database and was not used as a primary end-point.
And third, pharmacokinetic sampling was not executed in this study, which could have shown that dose reductions in DPYD variant allele carriers result in equivalent fluoropyrimidine metabolite plasma levels compared with wild-types treated with standard dosages, as was done previously for DPYD*2A variant allele carriers.19
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