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The Role of UGT1A1*28 Polymorphism in the Pharmacodynamics and Pharmacokinetics of Irinotecan in Patients With Metastatic Colorectal Cancer

Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona, Antonio Russo, Angela Buonadonna, Mario D'Andrea, Lara Maria Pasetto, Sergio Pessa, Domenico Errante, Vincenzo De Pangher, Mauro Giusto, Michele Medici, Fernando Gaion, Paolo Sandri, Enzo Galligioni, Salvatore Bonura, Massimo Boccalon, Paola Biason, Sergio Frustaci

From the Experimental and Clinical Pharmacology Unit and the Medical Oncology unit of "Centro di Riferimento Oncologico," National Cancer Institute, Aviano; the Medical Oncology Units of: Ospedale "Pierfortunato Calvi," Noale; Oncologia Medica, "Istituto Oncologico Veneto," Padova; Ospedale "Ca’ Foncello," Treviso; Division of Medical Oncology, Ospedale Civile di Vittorio Veneto (TV); Ospedale di Gorizia and Monfalcone; Ospedale "San Martino," Belluno; Ospedale "S.S. Giovanni e Paolo," Venezia; Ospedale Civile, Camposampiero; Ospedale "S. Maria Dei Battuti," San Vito al Tagliamento; Ospedale di Trento; Ospedale Civile, Latisana; Ospedale "S. Maria degli Angeli," Pordenone; and the Epidemiology Service, "Azienda Sanitaria Locale Città di Milano," Italy

Address reprint requests to Giuseppe Toffoli, MD, Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, National Cancer Institute, via Pedemontana Occidentale, 12, 33081, Aviano, Italy; e-mail: gtoffoli{at}cro.it

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 TA₆/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.

Authors' disclosures of potential con- flicts of interest and author contributions are found at the end of this article.

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