Page 195 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Fluoropyrimidine dosages in chemoradiation therapy
Introduction
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are the backbone of chemotherapy regimens for solid tumours such as colorectal and breast cancer.1-3 Since the 90’s, 5-FU has been in use in neoadjuvant chemoradiation therapy (CRT) for patients with stages 2-3 rectal cancer.4,5 Fluoropyrimidines affect nucleotide metabolism and inhibit the repair of radiation-induced DNA damage in patients and act as a radiation sensitiser.6 Fluoropyrimidines in combination with radiotherapy are used at lower dosages than those in other treatment regimens. An example; for patients with advanced colorectal cancer capecitabine, dosages are usually 1,250 mg/m2 bid (twice daily) for two weeks followed by one week rest, repeated every three weeks.7 In combination with radiotherapy, a continuous regimen is preferred to optimise radio-sensitisation. The maximum tolerated dose of capecitabine was 825 mg/m2 bid for patients with rectal cancer.8,9
Adverse events are well known in fluoropyrimidine treatment and differ between treatment regimens. Severe (grade ≥3) side-effects in stage 3 or 4 colorectal cancer patients 7 treated with capecitabine monotherapy dosed 1,250 mg/m2 bid in three-week cycles,
were hand-foot syndrome (~18%), diarrhoea (~14%), stomatitis (~3%), vomiting (~3%)
and neutropenia (~3%).10-12 Severe side-effects in locally advanced rectal cancer patients treated with CRT, including 825 mg/m2 capecitabine continuously for five weeks, were grade
≥3 radiation dermatitis (~9%), diarrhoea (~2-7%), fatigue (~2%), neutropenia (~2%) and anaemia (~2%).13,14
Over 80% of 5-FU is degraded into inactive metabolites by the key enzyme dihydropyrimidine dehydrogenase (DPD).15 DPD is encoded by the gene DPYD. DPD and variants in DPYD are associated with the onset of severe fluoropyrimidine-induced toxicity. To prevent severe fluoropyrimidine-induced toxicity prospective DPYD genotyping is increasingly used in clinical practice, followed by dose reductions in patients who carry a DPYD variant. For four variants (DPYD*2A, c.1905+1G>A, rs3918290; DPYD*13, c.1679T>G, rs55886062; c2846A>T, rs67376798; c.1236G>A/HapB3, rs56038477) individual dosing guidelines are currently given by the Dutch Pharmacogenetics Working Group and Clinical Pharmacogenetics Implementation Consortium.16,17 Dosing guidelines advise that DPYD variant allele carriers should receive a percentage of the standard dose, for example 50 or 75%, depending on the specific variant.18 These guidelines do not distinguish between treatment regimens in which different fluoropyrimidine dosages are given. Because fluoropyrimidine dosages in CRT regimens are lower than those in other treatment regimens, it is questioned if dose adjustments in dosing guidelines should be applied in patients receiving fluoropyrimidines in CRT. The objective of this study was to investigate the frequency of severe treatment- related toxicity in DPYD variant allele carriers receiving reduced or standard fluoropyrimidine dosages in CRT, to determine whether dose reductions are required.
Methods
Study population
The study population consisted of three combined databases. All patients were treated with fluoropyrimidine-based CRT according to the various tumour types and were genotyped for the aforementioned four variants in DPYD.
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