Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai

BACKGROUND: The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)(6)/(TA)(6) and (TA)(6)/(TA)(7) genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS: One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine–adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)(6)/(TA)(6) and (TA)(6)/(TA)(7) genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)(6)/(TA)(6) and (TA)(6)/(TA)(7) genotypes were analyzed statistically. RESULTS: One hundred and fourteen patients (69.51 %) were identified with the (TA)(6)/(TA)(6) genotype, forty-eight patients (29.27 %) with the (TA)(6)/(TA)(7) genotype, and two patients (1.22 %) with the (TA)(7)/(TA)(7) genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)(6)/(TA)(7) genotype group were all higher than those in (TA)(6)/(TA)(6) group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)(6)/(TA)(6) genotype. In the (TA)(6)/(TA)(7) group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)(6)/(TA)(6) genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)(6)/(TA)(7) genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)(7)/(TA)(7) cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION: The (TA)(6)/(TA)(6) genotype and (TA)(6)/(TA)(7) genotype accounted for the most, and (TA)(7)/(TA)(7) genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)(6)/(TA)(6) genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)(6)/(TA)(7) genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)(7)/(TA)(7) genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.