Page 97 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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underestimate for *1/ *2A. The 5-FU concentration 1 hour after injection was around the detection limit for *1/*1.
- The terminal half-life of 5-FU increased by 109% for the 300 mg/m2 dose (from 0.128 to 0.268 hours) and by 69% for the 450 mg/m2 dose (from 0.181 to 0.306 hours) (S)
- The maximum enzymatic metabolic capacity (Vmax) calculated in a multi-compartment model decreased by 46% for the 300 mg/m2 dose (from 1749 to 942 mg/hour) and by 34% for the 450 mg/m2 dose (from 1370 to 900 mg/hour) (S)
568 patients with advanced colorectal cancer were treated with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks, in combination with oxaliplatin and bevacizumab, with or without cetuximab. Oxaliplatin was discontinued from cycle 7 and the capecitabine dose increased to 1250 mg/m2. Grade III-IV toxicity occurred in 85% of the patients.
*1/*2A versus *1/*1:
- Factor 3.0 increase in the percentage of patients with grade III-IV diarrhoea (from 24% to 71%) (S; strong association: false discovery rate < 0.3)
The sensitivity of *2A for predicting grade III-IV diarrhoea was 4% and the specificity 100%.
- No increase in the percentage of patients with grade II-III hand-foot syndrome and no significant increase in the percentage of patients with grade III-IV toxicity (NS)
All 7 *1/*2A developed grade III-IV toxicity (including 3 women), and 1 patient died during the 3rd cycle.
- Decrease in the cumulative dose over the first 6 cycles (S): the average dose decrease increased from 10% to 51% in the lowest-dose cycle and from 10% to 44% in cycle 6.
- No difference in mortality or progression-free survival (NS)
(*1/c.1236A>G + c.1236A>G/c.1236A>G) versus *1/*1:
- Factor 2.2 increase in the percentage of patients with grade III-IV diarrhoea (from 23% to 50%) (S; strong association: false discovery rate < 0.3)
The sensitivity of c.1236G>A for predicting grade III-IV diarrhoea was 10% and the specificity 97%.
- No significant increase in the percentage of patients with grade II-III hand-foot syndrome or with grade III- IV toxicity (NS).
- No significant increase in dose decreases (NS)
- No difference in mortality or progression-free survival (NS)
*1/c.2846A>T versus *1/*1:
4
ref. 16 – CAP, comb Deenen MJ et al. Relationship between single nucleotide polymorphis ms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer.
Clin Cancer Res 2011;17:3455 -68. PubMed PMID: 21498394.
Level of evidence score: 4
gene act. 1: CTC- AE 5
(gene act. 1 + gene act. 1,5): CTC- AE 4
gene act. 1,5: CTC- AE 4
Authors’ conclusion: “Of the patients polymorphic for DPYD IVS14+1G>A, c.2846A>T, and c.1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhoea, respectively, compared with 24% in the overall population.
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DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions.
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The data suggest that initial dose reductions of 50% in IVS14+1 G>A and 25% in c.2846A>T variant allele carriers with further dose titration would significantly reduce the total number of severe toxicity events, thereby separate validation is indicated.”
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