Fluoropyrimidine toxicities prompt call for pharmacogenomic screening

Cancer care

By Mardi Chapman

10 Jul 2024

The incidence of severe toxicity in patients treated with standard doses of fluoropyrimidine (FP) chemotherapies for solid organ cancers warrants the use of pharmacogenomic testing and other measures to improve patient safety, Australian clinicians say.

A study, published in the Internal Medicine Journal [link here], evaluated grade 3–5 toxicities in a cohort of 500 adults receiving FP chemotherapies within the Hunter-New England Local Health District from June 2020 to June 2022.

Most patients (78.5%) received intravenous 5-fluorouracil and 24.2% received oral capecitabine.

The majority of patients (78.6%) received FP in combination with other chemotherapy or targeted agents while 17.8% received FP as a single agent and 3.6% as a single agent in combination with radiotherapy.

The study found 150 documented toxicities in 111 patient presentations for management of Grades 3–5 toxicities in the first 60 days of FP exposure.

These included 122 requiring hospital admissions and 28 requiring ED presentations but not admission.

Diarrhoea/colitis and nausea/vomiting were the most common toxicity events.

The average length of hospital admission was 4.9 days with four patients admitted to ICU and four toxicity-related deaths during admission.

The study found 16% of lower GI cancer patients and 21% of the upper GI cancer patients presented with Grade 3–5 toxicity.

“The higher incidence of G3–5 toxicity in the UGI cancer group possibly reflects triplet chemotherapy regimen use in this cohort,” the investigators said.

Toxicities led to treatment delay in 22% of patients, dose reductions in 21.4%, and discontinuation in 7.8%.

The investigators, led by medical oncologist Dr Cassandra White, said their toxicity frequency findings were consistent with the global literature.

“These data are important as they identify the scope of toxicity in Australia and form a historical cohort to compare with interventions that seek to reduce early FP toxicity, such as DPYD genotyping and variant-specific dose adjustments,” they said.

“Such interventions improve FP tolerability for patients who carry clinically significant variants and reduce the overall toxicity burden, which in turn reduces financial strain on health management systems.”

They said “pure FP toxicity” was difficult to gauge given that most FP regimens were administered in combination with other chemotherapies such as oxaliplatin or irinotecan.

And they found an increased toxicity with doublet and triplet chemotherapy combinations as compared to single-agent regimens.

“This suggests some additional toxicity from accompanying agents and may be an area that is targetable with an extended prospective pharmacogenomic panel, including genotyping for DPYD for those receiving FP chemotherapies and uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) for patients receiving chemotherapies targeting topoisomerase 1, such as irinotecan.”

The study concluded that the findings will form an important comparative baseline to allow for the investigation of utility and cost-effectiveness of pharmacogenomic screening interventions to improve patient safety and effectiveness of FP prescribing in Australia,”

As previously reported in the limbic [link here], the RCPA recommends genetic testing for DPYD alleles before initial prescribing of fluorouracil and capecitabine, or  if severe adverse effects were suspected in a person taking the drugs.

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