Page 112 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Supplementary Table 2. Literature review of DPYD/[tegafur with DPD inhibitor] interactions to support the therapeutic dose guidelines to optimize dose
Reference
ref. 1
Cubero DI et al. Tegafur-uracil is
a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle.
Ther Adv Med Oncol 2012;4:167- 72.
PubMed PMID: 22754590.
Code
Level of evidence score: 2
gene act. AA
1:
Effect
Four patients with colorectal cancer developed grade 3-4 toxicity after the first cycle of chemotherapy with 5-FU (intravenous bolus of 425 mg/m2 on days 1 and 5, in combination with folinic acid). They were found to be *1/*2A. After recovery, treatment with tegafur- uracil in combination with folinic acid was initiated. A full dose (100%) was tegafur 100 mg/m2 three times daily for 21 days followed by a week-long rest period. Doses were rounded down to multiples of 100 mg tegafur. Doses were guided by adverse events.
The first patient received 60% in the first cycle, 80% in the second cycle, 100% in the third cycle and 90% in the fourth and fifth cycles of the full dose of tegafur without development of grade 3-4 toxicity. This patient had developed grade 4 mucositis, diarrhoea and myelotoxicity on 5-FU.
The following 3 patients received 90% of the full dose of tegafur during 5 cycles without development of grade 3-4 toxicity in any of the cycles. Of the three patients, one developed grade 4 diarrhoea and grade 3 mucositis on 5-FU, the second grade 3 diarrhoea and myelotoxicity, and the third grade 3 mucositis, diarrhoea and myelotoxicity.
The best response in the first and the last patient, who both had metastatic disease, was achieving stable disease. The second and third patients receiving adjuvant chemotherapy were disease-free two years after the therapy.
- One patient developed severe abdominal cramps, grade 4 diarrhoea, grade 4 neutropenia, dehydration and severe mucositis 10 days after initiation of capecitabine 1000 mg/m2 BSA twice daily (in combination with oxaliplatin and bevacizumab).
She recovered after discontinuation of capecitabine and 25 days at the hospital. A few months later
she received tegafur-uracil 300 mg/m2 per day in combination with folinic acid. After 10 days, she developed severe diarrhoea, mucositis, fever, dehydration and grade 4 neutropenia. She recovered after 25 days at the hospital.
The patient was *1/*2A.
- Three other patients requiring hospitalisation due to severe toxicity on 5-FU or capecitabine therapy also developed severe toxicity following treatment with standard-dose tegafur-uracil. The patients were *1/*2A, *1/c.2846A>T and *1/c.1236G>A respectively. The DPD activity was approximately 50% in the latter two patients. This confirms that
Comments
Authors’ conclusion: “Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.”
ref. 2
Deenen MJ et al. Standard-dose tegafur combined with uracil is not safe treatment after severe toxicity from 5-fluoro-uracil or capecitabine. Ann Intern Med 2010;153:767-8. PubMed PMID: 21135311.
Level of evidence score: 2
gene act.
gene act. 1,5: E
1: E
Authors’ conclusion: “The standard dose
of UFT is not safe after severe toxicity to 5-FU or capecitabine in DPD-deficient patients.”
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