TY - JOUR
T1 - The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer
AU - Toffoli, Giuseppe
AU - Cecchin, Erika
AU - Corona, Giuseppe
AU - Russo, Antonio
AU - Buonadonna, Angela
AU - D'Andrea, Mario
AU - Pasetto, Lara Maria
AU - Pessa, Sergio
AU - Errante, Domenico
AU - De Pangher, Vincenzo
AU - Giusto, Mauro
AU - Medici, Michele
AU - Gaion, Fernando
AU - Sandri, Paolo
AU - Galligioni, Enzo
AU - Bonura, Salvatore
AU - Boccalon, Massimo
AU - Biason, Paola
AU - Frustaci, Sergio
PY - 2006/7/1
Y1 - 2006/7/1
N2 - Purpose: UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent. Patients and Methods: In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy. Results: UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA 6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant. Conclusion: The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.
AB - Purpose: UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent. Patients and Methods: In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy. Results: UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA 6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant. Conclusion: The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.
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U2 - 10.1200/JCO.2005.05.5400
DO - 10.1200/JCO.2005.05.5400
M3 - Article
C2 - 16809730
AN - SCOPUS:33745972934
VL - 24
SP - 3061
EP - 3068
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 19
ER -