Page 81 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

c.1129- 5923C>G/ haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidi nes. Cancer Chemother Pharmacol 2016;78:875- 80. PubMed PMID: 27544765.
peripheral blood mononuclear cells was determined and cDNA was analysed.
Results:
- A 47-year old female developed leukocytopenia grade 2 (2.3x109/L), neutropenia grade 2 (1.3x109/L), hand-foot syndrome grade 1, diarrhoea grade 1 and fatigue grade 1 on day 9 of neoadjuvant treatment with standard dose capecitabine (825 mg/m2 twice daily) and radiotherapy. Because the symptoms intensified, the capecitabine dose was reduced by 40% on day 15. After dose reduction, treatment was well tolerated. Five days after a dose increase by 10%, she again developed leukopenia grade 2 (2.5x109/L) and neutropenia grade 1 (1.5x109/L). Despite this, treatment could be finished at reduced dose. The patient received surgery and was disease-free four years after treatment.
The DPD activity of the patient was 41% of the normal DPD activity.
- A 67-year old male developed fatigue grade 2 on day 7 of treatment with capecitabine 850 mg/m2 on day 1-14 of the three-week cycle, docetaxel, oxaliplatin and bevacizumab. On day 11, the patient was hospitalised with neutropenia grade 2 (1.3x109/L) and fever grade 1 (38.7oC, without apparent focus). After release from hospital, he refused further treatment. Because of disease progression, capecitabine 800 mg/m2 twice daily (64% of the standard dose) was started four months later as monotherapy. The patient again developed fatigue grade 2 and refused further treatment after cycle 1.
The DPD activity of the patient was 55% of the normal DPD activity.
- A 69-year old male tolerated 4 weeks of neoadjuvant treatment with standard dose capecitabine (825 mg/m2 twice daily) and radiotherapy well. Treatment was completed without dose reductions or delays, and without adverse events and haematological changes. The patient had a relapse one year after surgery and died as a result of progressive disease before determination of DPD activity could be performed.
cDNA analysis of the first two patients showed that they produced roughly equal amounts of wild type mRNA and aberrantly spliced mRNA with a premature stop codon.
The authors indicate that the starting dose of capecitabine was relatively low in these patients (compared to the monotherapy dose of 1250 mg/m2 twice daily). So, higher doses might have resulted in more pronounced toxicity. Amstutz 2009 describes a
clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.’
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Supplement
Tolerated dose versus gene activity 2:
gene activity 1: 60%
DPD activity versus gene activity 2: gene activity 1: 48%
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