Value of plasma SN-38 levels and DPD activity in irinotecan-based individualized chemotherapy for advanced colorectal cancer with heterozygous type UGT1A1*6 or UGT1A1*28

Purpose: The relationship between the pharmacokinetics of irinotecan and outcomes of advanced colorectal cancer is unclear, and few studies have examined individualized irinotecan-based chemotherapy depending on plasma 7-ethyl-10-hydroxy camptothecin (SN-38) levels and dihydropyrimidine dehydrogenase (DPD) activity, particularly for the UGT1A1*6 or UGT1A1*28 heterozygous type. Methods: This study retrospectively explored the relationship among plasma SN-38 level 1.5 hours after critical enzyme for irinotecan (CPT-11) administration (CSN-38 1.5h), plasma SN-38 level 49 hours after CPT-11 administration (CSN-38 49h), DPD activity, and clinical outcomes for the UGT1A1*6 and UGT1A1*28 heterozygous types. Results: CSN-38 1.5h and CSN-38 49h of the UGT1A1*6 or UGT1A1*28 heterozygous type were close to those of UGT1A1*6 and UGT1A1*28 wild-types; some of those with relatively high CSN-38 1.5h levels obtained better median progression-free survival (mPFS), whereas others with higher CSN-38 49h concentrations showed a relatively high incidence of adverse reactions possibly because of the decreased activity of DPD. Conclusion: Increasing the dosage of CPT-11 according to CSN-38 1.5h may improve the efficacy in patients with lower CSN-38 1.5h levels. For cases with comparably low DPD activity, advisable primary and subsequent dose adjustment of 5-fluorouracil based on plasma 5-fluorouracil levels may be a practical strategy for reducing the occurrence of adverse reactions for personalized treatment of the UGT1A1*6 or UGT1A1*28 heterozygous type.