Page 109 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Supplement
ref. 36 – FU, cutaneous Johnson MR et al.
Life- threatening toxicity in a dihydropyrimi dine dehydrogenas e-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999;5:2006- 11.
ref. 37 – FU SPC Fluorouracil PCH 15-10-12.
ref. 38 – FU SPC Efudix (fluorouracil) crème 07-09- 16.
Level of evidence score: 2
gene act. 0: CTC- AE 3
A 76-year-old white man developed severe stomatitis, severe inflammatory colitis, erythematous rash, neutropenia 0.6x109/L and thrombocytopenia 57x109/L one week after initiation of 5% FU cream twice daily on the scalp for the treatment of basal cell cancer. FU was discontinued and the patient made a gradual recovery over 3 weeks.
The patient was *2A/*2A and had no detectable DPD enzyme activity in peripheral mononuclear blood cells.
Assuming 10% cutaneous absorption, the authors estimate that application of 2 g of 5% FU cream leads to a total absorbed dose of ~20 mg/day (~0.33 mg/kg for this patient). This is much lower than the IV bolus FU dose of 500-550 mg/kg that is generally used for chemotherapy.
Warning: There have been reports of increased 5-FU toxicity in patients with partially functional or non- functional dihydropyrimidine dehydrogenase (DPD). If appropriate, DPD enzyme activity should be determined prior to treatment with 5- fluoropyrimidines.
Warning: Individuals with a defective dihydropyrimidine dehydrogenase (DPD) enzyme may be susceptible to severe systemic toxicity on use of standard doses of Efudix due to an increased systemic 5-FU concentration. Evaluation of DPD activity may be considered in patients with confirmed or suspected systemic toxicity. Due to the relationship between DPD deficiency and systemic toxicity, individuals known to have DPD enzyme deficiency should be intensively monitored for systemic toxicity during Efudix treatment.
Adverse events: Frequency not known: haematological conditions, such as pancytopenia, neutropenia, thrombocytopenia, leukocytosis; haemorrhagic diarrhoea, diarrhoea, vomiting, stomach pain, stomatitis, rash, nasal mucositis.*
* Haematological conditions, stomatitis, rash, nasal mucositis (associated with systemic toxicity to medicinal products).
Contraindications: Patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.
Authors’ conclusion:
“This study
represents the first characterization of a
DPD deficient patient
who developed life- threatening toxicity
after exposure to
topical 5-FU.
Considering the 4 previously reported
low cutaneous absorption rate (~10%) of topical 5- FU, we suggest that life-threatening toxicity in the population of patients receiving topical 5-FU will be limited to profoundly DPD-deficient patients (no measurable DPD enzyme activity).”
Level of evidence score: 0
gene act. 0-1,5: CTC-AE 4 Level of evidence score: 0
gene act. 0-1,5: CTC-AE 4
ref. 39 - CAP
Level of evidence score: 0
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