Page 78 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 2 – CAP, comb Henricks LM et al. Capecitabine- based treatment of a patient with a novel DPYD
Level of evidence score: 2
gene act. 0: Clinical Relevanc e Score A
Authors’ conclusion: ‘This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with
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well without occurrence of severe toxicity and surgery was performed after treatment. The dose- corrected AUC of 5-FU in this patient was 866% of that of control patients.
The mean DPD activity in these patients was 40%. There was a large variance in DPD activity between these patients (10-79%).
- The patient with genotype *2A/*2A had undetectable DPD activity and tolerated monotherapy with 0.65% of the normal capecitabine dose (65 mg/m2 every 5 days) for 1 month after which grade 2 diarrhoea developed. After a rest period of 3 weeks, treatment was restarted with the same dose, but every third gift was skipped (0.43% of the normal dose). The patient tolerated this dose also after addition of oxaliplatin and bevacizumab as originally planned and had stable metastatic colorectal carcinoma as best treatment response.
The dose-corrected AUC of 5-FU in this patient was 13.812% of that of control patients.
- The carrier of both c.1236A>G and c.2846A>T had 45% of the normal DPD activity, corresponding to gene activity score 1 (variants on different alleles). He was treated with 51% of the normal capecitabine dose in cycle 1 (daily dose of 900 mg/m2 in combination with oxaliplatin), which was tolerated without toxicity. Increase to 71% of the planned dose (daily dose of 1250 mg/m2) in cycle 2 resulted in grade 3 thrombocytopenia. The dose was reduced to 57% of the normal dose (1000 mg/m2 daily), which was continued during cycle 3. However, because grade 2 thrombocytopenia developed after 8 days, the dose was reduced to 29% of the normal dose (500 mg/m2 daily) for the rest of the cycle, resulting in platelets to increase to normal values. Progression of metastatic colorectal cancer was established after 3 cycles and capecitabine treatment was discontinued.
The dose corrected AUC of 5-FU in this patient was 227% of that of control patients.
NOTE: Patients were genotyped for *2A, *13, c.2846A>T and c.1236G>A.
A 59-year-old women with 0.5% of the normal DPD activity tolerated adjuvant chemotherapy with 0.8% of the normal capecitabine dose (77 mg/m2 on days 1 and 6 of the first cycle and on days 1, 6 and 11 of the following cycles) in combination with oxaliplatin for eight cycles. Capecitabine-related toxicity like diarrhoea, hand-foot syndrome or leukopenia did not occur. However, sensory neuropathy developed during the first cycle, and became more severe (grade
DPD activity compared to gene activity 2:
gene act. 1: 41% gene act. 0: 0%
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