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News in Pharmacovigilance N° 50
REGIONAL CENTRE OF PHARMACOVIGILANCE – ANGERS, FRANCE
Pharmacology-Toxicology Department
Focus: 5-Fluorouracil and capecitabine: avoiding potentially lethal toxicities
5-fluorouracil (5-FU) and capecitabine (Xeloda ®) (pro-drug of 5-FU) are both derived from pyrimidines
and quite often used in the treatment of gastrointestinal and breast cancers. Over the last thirty years
numerous publications have discussed the severe, sometimes lethal, toxic effects which occur in a seemingly
unpredictable manner in patients treated with fluoropyrimidines. These toxicities have been retrospectively
linked to a partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, which is
the limiting factor in the catabolism of 5-FU. Different research teams consequently focused their work on
exploring the relationship between the severity of the toxic effects of 5-FU and DPD activity, then
subsequently developing pharmacogenetic and pharmacokinetic data on the inter-patient variability of the
enzyme.
A 75-year-old patient with a good performance status with an adenocarcinoma (classified as pT4 pM1) began a FOLFOX6 protocol, associating oxaliplatin (85 mg/m²), folic acid (200 mg/m²) and 5-FU (2400 mg/m² over 48 hours). As of the second day of treatment the patient complained of pain when swallowing and his performance status degraded extremely quickly, with severe stomatitis and diarrhea. He was hospitalized on day 7 with dehydration and functional renal failure. The initial diagnosis of septic shock required rehydration, a wide-spectrum antibiotic and dopamine. The following day, renal function continued to deteriorate, and severe neutropenia and thrombocytopenia appeared. Despite aggressive treatment in the intensive care unit, he died ten days after initial admission. This patient was retrospectively diagnosed with complete DPD deficiency [1].
A 70-year-old patient with an lieberkunien adenocarcinoma (classified as T3N0) was included in the Accord trial, and given neoadjuvant radiotherapy with capecitabine (1300 mg twice a day / 5 days per week). At day eleven of treatment patient presented with diarrhea (4 bowel movements per day) and cramping, symptoms which deteriorated and led to hospitalization twenty-four days after the beginning of treatment. Symptoms included profuse diarrhea, vomiting, mucositis grade IV, febrile neutropenia grade IV, hand-foot syndrome and asthenia, lactic acidosis and acute renal insufficiency. Many other complications were noted during the hospitalization of this patient which lasted a total of five months. These symptoms being evocative of toxicity related to capecitabine, the patient was screened for DPD deficiency and was found to have significantly low DPD enzyme activity [2].
The current technique for pre-therapeutic DPD deficiency screening practiced by the laboratory of onco-pharmacology in ICO Paul Papin uses both genotyping and phenotyping. The phenotype measures the plasma concentration levels of endogenous substrates of DPD, uracil (U) and its metabolite dihydrouracil (UH2). The ratio of UH2/U (metabolism index) is used to provide a reflection of the activity of the DPD enzyme, which is otherwise quite difficult to measure directly. The genotype concentrates on the DYPD gene (encoding for DPD production and activity) and the principal polymorphisms (both homozygous and heterozygous) which have been associated with decreased DPD activity and/or increased risks of toxicity to fluoropyrimidines. Using these two approaches together is essential to arrive at significant specificity and sensibility which are respectively 98% and 82% [3]. The frequencies of partial and complete DPD deficits in the general population are estimated respectively at 3-5% and 0,2% [4].
These types of severe adverse events are hard to accept in terms of quality of life for any patient and are completely unacceptable in the adjuvant setting. Although not suggested currently in multidisciplinary meetings regarding the use of these two anticancer drugs, t he pretreatment s creening f or DPD de ficiency must become a necessity i n order to ver ly onset grade III or IV toxicities or death related to toxicities Bibliography
1.Mounier-Boutoille H, Boisdron-Celle M, Cauchin E at al. nucleotide polymorphisms on 5-fluorouracil tolerance. Mol
Lethal outcome of 5-fluorouracil infusion in a patient with a
total DPD deficiency and a double DPYD and UTG1A1 gene mutation. Br J Clini Pharmacol 2010; 70;280-3
2.Coursier S, Martelet S, Guillermet A at al. Severe toxicity NB: The reference made to ICO and Michèle Boisdron-Celle
following capecitabine administration because of
also defacto refers to the company ODPM, which markets
the calculator developed by the Gamelin team at ICO, which
is honored to have Dr. Boisdron-Celle as its President and
co-Founder, along with Drs. Gamelin and Morel.
Morel A, Boisdron-Celle M, Fey L at al. Clinical relevance of Contact ODPM: Linda Rattner Celle linda.celle@odpm.fr
different dihydropyrimidine dehydrogenase gene single

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