Page 128 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
A large study found that the *2A allele only increased the risk of grade ≥ 3 toxicity in men (OR = 41.8) and not in women. Other studies did not find any differences between men and women.
When the dose was guided by toxicity, the average dose in the sixth cycle was 56% of the standard dose in seven patients with genotype *1/*2A. Dose reduction down to 40% or 50% of the standard dose was not adequate in two *1/*2A patients in another study. There was no difference in grade ≥ 3 toxicity between 18 patients with genotype *1/*2A at ≤ 50% of the standard dose and non-selected patients on the standard dose. In another study, four patients with genotype *1/*2A did not develop grade ≥ 3 toxicity at 50% of the standard dose. One of them had previously developed grade ≥ 3 toxicity during the first cycle at
the standard dose. One of them tolerated a dose increase to 60%, the other two did not tolerate a dose increase to 80% and 100% respectively. Of the three patients with genotype c.1236G>A/c.1236G>A, one tolerated a standard dose. A second patient tolerated the treatment after dose reduction to 60% of the standard dose. Another study found a mean tolerated dose of 55% of the standard dose for 2x c.1236G>A/c.1236G>A, 1x c.1236G>A/ c.2846A>T and 1x c.2846A>T/c.2846A>T, although in this study a strong variation between patients (and genotypes) was found (17-100% of the standard dose).
Predicted phenotype: Gene activity score 1.5 Ref. 3-5,8-12,14-16,20,21,25-27,33,38-41
Therapeutic recommendation
Rationale of
the therapeutic recommendation
Kinetic consequence
Clinical consequence
Start with 75% of the standard dose or choose an alternative.
Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
For *1/c.2846A>T, the weighted average of the calculated dose adjustments was a reduction to 55%. However, Deenen 2011 investigated 8 patients with *1/c.2846A>T and found a toxicity-guided dose reduction to 74% of the standard dose. In addition, Lunenburg 2016 found no grade ≥ 3 toxicity when treating five patients with *1/c.1236G>A with an initial dose of 75% of the standard dose. As oncolytic under dosing should be avoided, the dose adjustment determined in clinical practice has been included in the recommendation. Instead of dose adjustment, physicians may also choose an alternative.
40-58% decrease in clearance.
Four of the five studies and one meta-analysis found an increased risk of grade ≥ 3 toxicity. Increased grade ≥ 3 toxicity: OR = 4.42-9.35. The percentage of patients with grade ≥ 3 toxicity was 109-1175% higher. One patient (*1/496G) died due to toxicity.
No association with grade ≥ 3 toxicity was found in one small study of 21 patients with grade ≥ 3 toxicity.
When the dose for eight patients with genotype *1/c.2846A>T was guided by toxicity, the average dose in the sixth cycle was 76% of the standard dose. Five patients with genotype *1/c.1236G>A did not develop grade ≥ 3 toxicity at 75 % of the standard dose. The two patients for who the dose was then increased tolerated the standard dose. One patient with genotype *1/c.1236G>A, who was started at the standard dose, developed grade 3-4 toxicity in the first cycle.
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