TOPLINE:

In a retrospective study at Dutch hospitals, dosing irinotecan based on UGT1A1 genotype normalized the risk of severe toxicity and hospitalization in patients who were poor metabolizers of the drug.

METHODOLOGY:

• Irinotecan is a cornerstone treatment for patients with colorectal or pancreatic cancer, but severe diarrhea and neutropenia are common side effects. About 10% to 20% of patients carry two copies of dysfunctional variants in the UGT1A1 gene that make them poor metabolizers of the drug and put them at high risk for severe toxicity.
• Guidelines in some countries recommended UGT1A1 genotype-guided dosing of irinotecan, while FDA labeling advises genotyping on a case-by-case basis. But real-world evidence is lacking. To investigate, researchers conducted a retrospective study of patients who received genotype-guided dosing at six Dutch hospitals between December 2020 and April 2024. Per practice in the Netherlands, poor metabolizers started at 70% of the standard irinotecan dose.
• A total of 501 patients were included in the primary analysis: 447 (89.2%) were intermediate or normal metabolizers who started on full-dose irinotecan, and 54 (10.8%) were poor metabolizers who received 70% dosing for at least the first treatment cycle.
• The primary endpoint was the incidence of early severe toxicity, defined as grade 3 or worse neutropenia, febrile neutropenia, or diarrhea, or toxicity-related hospitalization during the first three treatment cycles.

TAKEAWAY:

• Overall, severe toxicity occurred in 29.6% of poor metabolizers, compared with 34% of intermediate/normal metabolizers — a difference that was not statistically significant. (P = .520).
• Rates of toxicity-related hospitalization were 14.8% among poor metabolizers and 21.7% in the comparison group (P = .240). Similarly, there were no statistically significant differences in rates of grade 3 or higher febrile neutropenia (3.7% vs 5.8%), neutropenia (17% vs 17.8%), or diarrhea (13% vs 15%).
• Poor metabolizers were less likely to need early toxicity-related dose reductions compared with intermediate/normal metabolizers (18.8% vs 37.7%; P = .010).
• A secondary analysis looked at an additional nine poor metabolizers who inadvertently received a full irinotecan starting dose. More than three-quarters of those patients (77.8%) experienced severe toxicity — underscoring the necessity of upfront dose reduction, the study authors noted.

IN PRACTICE:

"Overall, our real-world data support the implementation of routine UGT1A1 genotyping and upfront UGT1A1 genotype–guided irinotecan dose reductions," the authors wrote. A 70% starting dose, they added, appears sufficient to reduce poor metabolizers' risk of severe toxicity to that of other patients receiving standard dosing.

SOURCE:

The study, led by Niels Heersche, MD, of Erasmus Medical Center Cancer Institute, in Rotterdam, the Netherlands, was published online in Journal of the National Comprehensive Cancer Network.

LIMITATIONS:

The retrospective real-world setting may have introduced potential information bias. Primary granulocyte colony-stimulating factor prophylaxis was administered more frequently to patients who were intermediate or normal metabolizers, which likely reduced their neutropenia rates (though neutropenia incidence was no higher among poor metabolizers who had their irinotecan dose reduced).

DISCLOSURES:

One co-author reported receiving institutional grant and research support from Astellas, Bayer, Boehringer Ingelheim, and other commercial sources. The remaining authors reported no relevant financial relationships.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.