Abstract
We report here the case of a 19-year-old female patient who suffered from extremely severe toxicities (G4 mucitis, fever, diarrhea, alteration of general state) while undergoing low-dose capecitabine treatment for her metastatic corticosurrenaloma. The severe toxicities stopped as soon as treatment was suspended. Interestingly, this patient was not deficient in DPD, a pharmacogenetic syndrome usually associated with increased risk of developing severe/lethal toxicities in patients undergoing fluoropyrimidine therapy, and she had been treated previously with 5-FU with a good tolerance. We then hypothesized that cytidine deaminase (CDA) extensive phenotype could be responsible for the severe toxicities observed with capecitabine. CDA is affected by genetic polymorphism, with subsequent acquisition of either deficient or extensive metabolizer profile. Phenotypic investigations confirmed that CDA activity in this patient was +180% higher than the ones usually recorded in the general population. This strongly suggests that the extensive activation of triple-prodrug capecitabine could have occurred in this patient, resulting in overexposure to 5-FU and its cytotoxic metabolites eventually. This case report suggest for the first time that severe toxicities with a capecitabine-containing protocol could be, at least in part, linked with an extensive-CDA syndrome. The case reported here suggests therefore that besides DPD, screening for CDA activity could be of interest to ensure a better safety in the handling of oral capecitabine at the bedside.
References
Kirch HC, Schröder J, Hoppe H, Esche H, Seeber S, Schütte J (1998) Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro. Exp Hematol 26:421–425
Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794–1803
Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T, Maeba H, Ito T, Sasaki T, Koizumi S (2003) A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics 13:29–38
Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo N, Yoshida T, Ishii H, Furuse J, Sugiyama E, Kim SR, Kikura-Hanajiri R, Hasegawa R, Saito Y, Ozawa S, Kaniwa N, Sawada J (2005) Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin Cancer Res 11:2620–2624
Mercier C, Raynal C, Dahan L, Ortiz A, Evrard A, Dupuis C, Blesius A, Duluc M, Franceschini F, Giacometti S, Salas S, Milano G, Favre R, Seitz JF, Ciccolini J (2007) Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation. Pharmacogenet Genomics 17:841–844
Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, Di Marsico R, Antonuzzo A, Orlandini C, Ricciardi S, Del Tacca M, Peters GJ, Falcone A, Danesi R (2008) Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 14:1797–1803
Ciccolini J, Mercier C, Evrard A, Dahan L, Boyer JC, Duffaud F, Richard K, Blanquicett C, Milano G, Blesius A, Durand A, Seitz JF, Favre R, Lacarelle B (2006) A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy. Ther Drug Monit 28:678–685
Ciccolini J, Evrard A, Cuq P (2004) Thymidine phosphorylase and fluoropyrimidines efficacy: a Jekyll and Hyde story. Curr Med Chem Anti-Canc Agents 4:71–81
Maitland ML, Vasisht K, Ratain MJ (2006) TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci 27:432–437
Ciccolini J, Mercier C, Dahan L, Evrard A, Boyer JC, Richard K, Dales JP, Durand A, Milano G, Seitz JF, Lacarelle B (2006) Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 58:272–275
Mercier C, Ciccolini J (2007) Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit? Trends Pharmacol Sci 28:597–598
Mercier C, Ciccolini J (2006) Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer 6:288–296
Mercier C, Evrard A, Ciccolini J (2007) Genotype-based methods for anticipating gemcitabine-related severe toxicities may lead to false-negative results. J Clin Oncol 25(30):4855
Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N (2007) Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32–42
Saif MW, Kang SP, Ledbetter L, Steg A, Diasio R, Johnson M (2007) Long-term survival on capecitabine in two gemcitabine refractory pancreatic cancer patients. Is there a pharmacogenetic explanation? J Pancreas 8:799–805
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mercier, C., Dupuis, C., Blesius, A. et al. Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile. Cancer Chemother Pharmacol 63, 1177–1180 (2009). https://doi.org/10.1007/s00280-008-0889-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-008-0889-1