Abstract
Current guidelines recommend pre-therapeutic UGT1A1 genotyping to guide irinotecan dosing, but the usefulness of this approach remains to be clarified. In 247 patients with advanced gastrointestinal cancers undergoing irinotecan-based chemotherapy, we prospectively performed UGT1A1*28 genotyping and we analyzed the incidence of severe neutropenia according to genotype-guided dose reductions. Overall, 28 (11.3%) and 92 (37.2%) patients were homozygous or heterozygous UGT1A1*28 carriers, respectively. Grade ≥ 3 neutropenia was reported in 39% of homozygous patients receiving an upfront dose reduction of irinotecan (median 40%, range 22–58%), in 20% of heterozygous or wild-type patients receiving full dose (ORvs*28/*28 genotype = 0.38; 95% CI: 0.14–1.03; p = 0.058), and in 15.3% of those receiving a reduced dose for clinical reasons (OR vs*28/*28 genotype = 0.28, 95% IC: 0.12–0.67; p = 0.004). Occurrence of severe neutropenia was inversely associated with dose reduction in UGT1A1*28 homozygous carriers (ORx10 unit = 0.62, 95% CI: 0.27–1.40, p = 0.249) and UGT1A1 heterozygous or wild-type patients (ORx10 unit = 0.87, 95% CI: 0.59–1.28, p = 0.478). Incidence of severe neutropenia was related to irinotecan doses and UGT1A1 polymorphisms. Upfront irinotecan dose reductions do not reduce the burden of grade ≥ 3 neutropenia in UGT1A1*28 homozygous carriers.
Highlights
Fluoropyrimidines (FP), irinotecan, and oxaliplatin are a mainstay in the systemic treatment of metastatic colorectal cancer [1] and other gastrointestinal malignancies including gastric, pancreatic, and biliary cancers
Occurrence of severe neutropenia was inversely associated with dose reduction in UGT1A1*28 homozygous carriers (ORx10 unit = 0.62, 95% confidence intervals (CI): 0.27–1.40, p = 0.249) and UGT1A1 heterozygous or wild-type patients (ORx10 unit = 0.87, 95% CI: 0.59–1.28, p = 0.478)
The most relevant finding is that the UGT1A1*28*28 genotype is associated with a substantial risk of grade ≥ 3 neutropenia despite an upfront irinotecan dose reduction
Summary
Fluoropyrimidines (FP), irinotecan, and oxaliplatin are a mainstay in the systemic treatment of metastatic colorectal cancer [1] and other gastrointestinal malignancies including gastric, pancreatic, and biliary cancers. Associations between irinotecan toxicity and the UGT1A1*28/*28 genotype have been reported in cancer patients [4,5,6], suggesting a significantly higher risk of severe neutropenia [7]. Given these premises, a pre-therapeutic screening for the homozygous carriers of the UGT1A1*28 allele before the administration of irinotecan has been recommended to reduce the risk of disproportionate and sometimes fatal toxicity [8]. UGT1A1 genotyping has not been routinely integrated into clinical practice yet To this end, we undertook an analysis on the safety of irinotecan dose reductions following UGT1A1 genotyping. Here we explored the incidence of severe neutropenia in patients with gastrointestinal malignancies being treated in a palliative setting with irinotecan-containing chemotherapy regimens
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