Severe irinotecan-induced toxicity in a patient with UGT1A1 28 and UGT1A1 6 polymorphisms

Abstract

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1 28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1 28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1 28 (TA 7/7), while UGT1A1 6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1 28 polymorphism (TA 6/7) as well as the UGT1A1 6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1 28 and UGT1A1 6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1 28 and UGT1A1 6 polymorphisms.

Keywords: Irinotecan; Polymorphism; Toxicity; UGT1A1*28; UGT1A1*6.

Figure 1

Plasma concentration-time profiles of SN-38 in different dose levels of irinotecan.

Figure 2

Computerized tomography scan (A) and magnetic resonance imaging (B). Before treatment (left figure) and after treatment (right figure) of the lung and the liver metastases, respectively; the response was confirmed after two additional cycles.