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 ShanghaiReportar como inadecuado




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 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 9, pp 1579–1589

First Online: 28 July 2013Received: 10 March 2013Accepted: 16 July 2013DOI: 10.1007-s00432-013-1480-7

Cite this article as: Cai, X., Cao, W., Ding, H. et al. J Cancer Res Clin Oncol 2013 139: 1579. doi:10.1007-s00432-013-1480-7

Abstract

BackgroundThe 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 TA6-TA6 and TA6-TA7 genotypes treated with CPT-11 as first-line chemotherapy in Shanghai.

MethodsOne 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 TA6-TA6 and TA6-TA7 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 TA6-TA6 and TA6-TA7 genotypes were analyzed statistically.

ResultsOne hundred and fourteen patients 69.51 % were identified with the TA6-TA6 genotype, forty-eight patients 29.27 % with the TA6-TA7 genotype, and two patients 1.22 % with the TA7-TA7 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 TA6-TA7 genotype group were all higher than those in TA6-TA6 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 TA6-TA6 genotype. In the TA6-TA7 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 TA6-TA6 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 = 17.18, p = 0.00 with a relatively high incidence of Grade I-II° myelosuppression; for the TA6-TA7 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 = 1.38, p = 0.24, but the former had a higher incidence of Grade III-IV° mucositis and delayed diarrhea. For 2 TA7-TA7 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.

ConclusionThe TA6-TA6 genotype and TA6-TA7 genotype accounted for the most, and TA7-TA7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the TA6-TA6 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 TA6-TA7 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 TA7-TA7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

KeywordsColonic neoplasms Drug metabolism Genetic polymorphism Irinotecan Uridine diphosphate glucuronosyl transferase AbbreviationsHPLCHigh-performance liquid chromatography

PFSProgression-free survival

mPFSMedian PFS

OSOverall survival

mOSMedian OS

UGT1A1Uridine diphosphate glucuronosyl transferase 1A1

SN-387-ethyl-10-hydroxycamptothecin

SN-38GSN-38 glucuronide

AUCSN-38Area under the curve of SN-38

AUCSN-38G-AUCSN-38The ratio of area under the curve of SN-38G and SN-38

SAPShrimp alkaline phosphatase

ISInternal standard

RECISTThe response evaluation criteria in solid tumors

CTCAENational Cancer Institute common terminology criteria for adverse events

hCESHuman carboxylesterase

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Autor: Xun Cai - Weiguo Cao - Honghua Ding - Tianshu Liu - Xinli Zhou - Mei Wang - Ming Zhong - Ziyi Zhao - Qing Xu - Liwei Wan

Fuente: https://link.springer.com/



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