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Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics.
Anticancer Drugs 2019; 30(4):431-434AD

Abstract

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. TYMS gene encodes for the human thymidylate synthase, and is considered a candid factor for toxicity and efficacy of 5-FU and capecitabine. However, TYMS polymorphism has been associated previously with capecitabine-induced neurotoxicity. We report here a 31-year-old patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine who developed acute cerebellar syndrome during cycle 5. MRI did not show any abnormalities. We performed pharmacogenetic studies related to capecitabine including DPD deficiency and TYMS polymorphism. DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved his neurotoxicity in 9 days. No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. To the best of our knowledge, this is the first patient in the literature who developed acute cerebellar syndrome following capecitabine and was found to have mutations of TYMS. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose.

Authors+Show Affiliations

Department of Medicine, Zucker School of Medicine, Northwell Health Cancer Institute, Lake Success, New York, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30875351

Citation

Saif, Muhammad W.. "Capecitabine-induced Cerebellar Toxicity and TYMS Pharmacogenetics." Anti-cancer Drugs, vol. 30, no. 4, 2019, pp. 431-434.
Saif MW. Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. Anticancer Drugs. 2019;30(4):431-434.
Saif, M. W. (2019). Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. Anti-cancer Drugs, 30(4), pp. 431-434. doi:10.1097/CAD.0000000000000737.
Saif MW. Capecitabine-induced Cerebellar Toxicity and TYMS Pharmacogenetics. Anticancer Drugs. 2019;30(4):431-434. PubMed PMID: 30875351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. A1 - Saif,Muhammad W, PY - 2019/3/16/entrez PY - 2019/3/16/pubmed PY - 2019/3/16/medline SP - 431 EP - 434 JF - Anti-cancer drugs JO - Anticancer Drugs VL - 30 IS - 4 N2 - Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. TYMS gene encodes for the human thymidylate synthase, and is considered a candid factor for toxicity and efficacy of 5-FU and capecitabine. However, TYMS polymorphism has been associated previously with capecitabine-induced neurotoxicity. We report here a 31-year-old patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine who developed acute cerebellar syndrome during cycle 5. MRI did not show any abnormalities. We performed pharmacogenetic studies related to capecitabine including DPD deficiency and TYMS polymorphism. DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved his neurotoxicity in 9 days. No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. To the best of our knowledge, this is the first patient in the literature who developed acute cerebellar syndrome following capecitabine and was found to have mutations of TYMS. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose. SN - 1473-5741 UR - https://www.unboundmedicine.com/medline/citation/30875351/Capecitabine_induced_cerebellar_toxicity_and_TYMS_pharmacogenetics_ L2 - http://dx.doi.org/10.1097/CAD.0000000000000737 DB - PRIME DP - Unbound Medicine ER -