UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer.

BACKGROUND

Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.

METHODS

All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.

RESULTS

A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m(2), respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16-2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22-4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24-2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05-3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08-2.18; p = 0.0176) were also identified as significant risk factors.

CONCLUSION

The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.