Lisa is a woman in her early 70s who was experiencing constipation with some urinary and fecal incontinence (inability to control urinating or defecating). A year later, she was found to have a rectal tumour and underwent transanal endoscopic microsurgery to have it removed. Examination of the removed tumour revealed that it was an invasive cancer. After 17 months, her tumour came back and had also spread to her liver. Lisa started her first chemotherapy cycle, followed by a dose of 5-fluorouracil and then continuous infusion of 5-fluorouracil for 48 hours.
On day 6 of the treatment, Lisa was admitted to the emergency department after several days of vomiting and diarrhea, being unable to tolerate food or drink and having general discomfort. She developed mucositis, an inflammation of the mucous membranes that line the digestive tract and is a side effect of some cancer treatments. Mucositis can cause pain, problems eating, diarrhea, and can increase the risk of infection due to sores.
Lisa also developed grade 3 neutropenia, an abnormally low number of white blood cells, and developed grade 4 thrombocytopenia, an abnormally low number of platelets in the blood, for which she received a platelet transfusion. The diarrhea persisted throughout this time. Her neutropenia worsened and she developed fever, necessitating further antibiotics.
Unfortunately, Lisa developed septic shock, a life-threatening condition where an infection can cause dangerously low blood pressure. Sadly, despite medical care, she passed away 16 days after her first dose of 5-fluorouracil.
Through a pharmacogenetic test, Lisa was found to be a poor metabolizer of 5-fluorouracil, meaning that she had a reduced clearance of 5-fluorouracil. Patients with reduced clearance of 5-fluorouracil are at increased risk of 5-fluorouracil toxicity, including diarrhea, myelosuppression, mucositis and neurotoxicity.
Borràs, E. et al. (2013). High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity. Front Genet 3, 312.
Caudle, K.E. et al. (2013) Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing. Clin Pharmacol Ther. Epub ahead of print.
NHS Choices. Mucositis. October 26, 2012. https://www.nhs.uk/Conditions/Mucositis/Pages/Introduction.aspx. Accessed September, 2013.
PharmGKB. Dutch Pharmacogenetics Working Group Guideline for fluorouracil and DPYD. https://www.pharmgkb.org/guideline/PA166104939. Accessed September, 2013.