Page 203 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Fluoropyrimidine dosages in chemoradiation therapy
Case description
To illustrate the importance of dose reductions in DPYD variant allele carriers, we have shown the course of one DPYD*2A carrier in Figure 2. This patient was excluded from the statistical analyses due to a substantially increased dose during treatment. Being one of the first DPYD variant allele carriers who received 50% dosed CRT, it was decided that the fluoropyrimidine dose would be titrated up to 100% if the patient would have no side-effects after two weeks. However, diarrhoea grade 1─2 was present, and the dose was increased to 83%. After four weeks, severe toxicity (diarrhoea, vomiting, nausea grade 3 and dermatitis grade 2) occurred and chemotherapy, and later radiotherapy, was stopped prematurely. The patient was hospitalised for 31 days, of which three days at the intensive care unit. After hospitalisation, the patient had to recover completely from toxicity for 39 days in a nursing home (rehabilitation). Although it cannot be excluded that toxicity would have evolved in the severity as was now shown at an 83% dose level when treated entirely with a 50% dose level, it is clear that the dose increase was most likely a reason for the development of severe toxicity.
Figure 2. Course of treatment and toxicity
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Shown is the course of an ideal treatment, and the treatment and toxicity for one patient (#1). The patient is a carrier of the DPYD*2A variant and started therapy on a 50% dose. After two weeks, the dose was increased to 83%. Thereafter, the patient developed severe toxicity, and therapy was discontinued. The patient was hospitalised for 31 days (including three days at the intensive care unit) and had to recover completely from toxicity for 39 days in a nursing home (rehabilitation). Abbreviations: CT: chemotherapy; RT: radiotherapy.
Discussion
Fluoropyrimidine dosages are lower in CRT compared with other fluoropyrimidine treatment regimens, and it is unclear if pharmacogenetic dose adjustments should be made for DPYD variant allele carriers receiving CRT. Dose titration in CRT is more difficult compared with other treatment regimens where the schedule contains so-called stop weeks. To our knowledge, this is the first study specifically investigating DPYD pharmacogenetics of fluoropyrimidines in CRT. DPYD variant allele carriers treated with standard fluoropyrimidine dosages in CRT showed a significantly increased risk to develop severe toxicity compared with wild-type patients. This indicates the need for pharmacogenetic dose reductions in CRT, despite the
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