Page 95 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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ref. 13 – FU/CAP, comb Magnani E et al. Fluoropyrimid ine toxicity in patients with dihydropyrimi dine dehydrogenas e splice site variant: the need for further revision of dose and schedule. Intern Emerg Med 2013;8:417- 23. PubMed PMID: 23585145.
Level of evidence score: 2
gene act. 1: CTC- AE 4
Increased risk of grade III-V diarrhoea (OR = 6.04; 95% CI: 1.77-20.66) (S)
c.2846A>T had a sensitivity of 5.4% (95% CI: 1.7-16.1) and a specificity of 99.1% (95% CI: 98.7-99.4) for predicting grade III-V toxicity (S)
The sensitivity was 11.2% for studies that showed less than 40% grade III-V toxicity (95% CI: 2.8-35.1) (S). There was heterogeneity between the studies. c.2846A>T had a sensitivity of 4.6% (95% CI: 2.2-9.4) for predicting grade III-V diarrhoea (S)
3 patients with genotype *1/*2A with gastrointestinal or head and neck tumours received 5-FU or capecitabine-based therapy (adjuvant or metastatic therapy). A 4th patient with genotype *1/*2A was not given adjuvant therapy.
A 43-year-old colon cancer patient was given adjuvant therapy with capecitabine/oxaliplatin and a 50% dose of capecitabine (500 mg/m2 twice daily for 14 days, followed by a week-long rest period). The patient developed diarrhoea, grade 4 neutropenia and grade 3 thrombocytopenia after 19 days. The adjuvant therapy was discontinued.
A 71-year-old colon cancer patient received the same adjuvant therapy including 40% of the normal capecitabine dose (400 mg/m2 twice daily). After 1 day, the patient started vomiting and developed grade 3 abdominal pain. The adjuvant therapy was discontinued.
A 68-year-old patient with metastatic maxillary sinus cancer initially received 5-FU/carboplatin/folinic acid with standard-dose 5-FU (3000 mg/m2 continuous infusion + 400 mg/m2 bolus every 3 weeks). After 15 days, he developed grade 4 neutropenia and thrombocytopenia, and grade 3 sepsis and ulceration of the palate. After recovery, the treatment was restarted at 44% of the original dose (1500 mg/m2 by continuous infusion) and prophylactic growth factors. There was no toxicity for 2 cycles. In the third cycle, the dose was increased to 59% of the standard dose (2000 mg/m2 bolus) and no growth factors were given. After 14 days, the patient developed grade 4 febrile neutropenia and grade 2 anaemia. He was henceforth given non-fluoropyrimidine-based therapy.
The authors indicated that a 50% dose decrease in gene activity score 1 is not always adequate.
1012 breast cancer patients received neoadjuvant/adjuvant therapy with 5-FU, epirubicin and cyclophosphamide. The 5-FU dose was 500 mg/m2 every 3 weeks with a maximum of 1000 mg (n=902) or 600 mg/m2 with a maximum of 1200 mg (n = 110).
Authors’ conclusion: “Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1 G>A mutations.”
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ref. 14 – FU, comb Vulsteke C et al. Genetic variability in the multidrug
Level of evidence score: 4
gene act. 1: Clinical
Authors’ conclusion: “In our study, we did not observe any association with toxicity and IVS14+1 G>A. The absence of
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