Toxicity and Efficacy of 5-Fluorouracil and Capecitabine in a Patient With TYMS Gene Polymorphism: A Challenge or a Dilemma?

• Published in: Clinical colorectal cancer 2009-10, Vol.8 (4), p.231-234
• Main Authors: Shahrokni, Armin, Rajebi, Mohammad Reza, Saif, Muhammad Wasif
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Capecitabine; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dihydropyrimidine dehydrogenase; Fluorouracil - administration & dosage; Fluorouracil - analogs & derivatives; Foot Dermatoses - chemically induced; Foot Dermatoses - therapy; Gastroenterology and Hepatology; Genotype; Hand Dermatoses - chemically induced; Hand Dermatoses - therapy; Hand-foot syndrome; Hematology, Oncology and Palliative Medicine; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Male; Middle Aged; Pharmacogenetic; Polymorphism, Genetic; Thymidylate synthase; Thymidylate Synthase - genetics; Treatment Outcome
• ISSN: 1533-0028; 1938-0674
• DOI: 10.3816/CCC.2009.n.039

Abstract 5-Fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS), thus preventing DNA synthesis, which leads to imbalanced cell growth and ultimately cell death. 5-FU and its oral prodrug capecitabine are used in the treatment of a number of solid tumors, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and alopecia. Hand-foot syndrome (HFS) is a relatively common side effect of cytotoxic chemotherapy. It is more frequently associated with 5-FU, capecitabine, and cytarabine. This article reports on the case of a 55-year-old black man with metastatic colorectal carcinoma that was refractory to recommended treatment measures who developed grade 3 HFS after treatment with modified FOLFOX6 (leucovorin [LV]/5-FU/oxaliplatin) and bFOL (bolus 5-FU/LV/oxaliplatin) regimens. Treatment was discontinued despite excellent response to chemotherapy. The patient had progression of disease on IROX (irinotecan/oxaliplatin) and irinotecan/cetuximab regimens. He was started on gemcitabine/capecitabine and developed HFS again, which was controlled with aggressive skin care and vitamin B 6 treatment. Full sequencing of the dihydropyrimidine dehydrogenase ( DPYD ) gene and analysis of the human TS gene ( TYMS ) promoter region was performed. Pharmacogenetic testing revealed 2R/2R genotype of TYMS gene, which is associated with up to a 2.5-fold risk of toxicity to 5-FU therapy. Hand-foot syndrome has proven to be a dose-limiting toxicity of 5-FU, especially of capecitabine, leading to significant morbidity. Hand-foot syndrome seems to be dose dependent, and both peak drug concentration and total cumulative dose determine its occurrence. Genetic variations such as polymorphic abnormality of TYMS are potential causative factors for a significant portion of serious adverse reactions to 5-FU–based therapy.