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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

	ABSTRACT

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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.

	INTRODUCTION

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Combinations of irinotecan, fluorouracil (FU), and leucovorin (LV) in a regimen (FOLFIRI) demonstrated superiority in overall response and survival as compared with FU/LV alone.¹

Marked interpatient variability has been reported for the frequency of toxicity to FOLFIRI.² This may be due to the variability in levels of the active irinotecan metabolite SN38 in plasma and/or at the site of toxicity (ie, bone marrow). Several factors determine SN38 levels. In particular, the conversion of irinotecan to SN38 by the carboxylesterase enzymes³ and the glucuronidation of SN38 to the inactive SN38 glucuronide (SN38G) by uridine diphosphate glucuronosyltransferase, most notably UGT1A1, the same enzyme that conjugates bilirubin.⁴ Other metabolic or transport pathways can affect irinotecan and SN38 disposition; in particular, cytochrome p450 isoforms 3A4, 3A5,⁵ and the adenosine triphosphate–binding cassette transporters.⁶ The distribution qualities of SN38 versus irinotecan may also play an important role.

Impaired glucuronidation activity of the UGT1A1 enzyme, possibly due to the genetic polymorphism of the UGT1A1 gene, has been thought to have a crucial role in the variable toxicity reported. More than 50 genetic variations in the promoter and coding regions of the UGT1A1 gene are currently known.⁷ In particular, UGT1A1*28 (also known as TA indel) polymorphism, characterized by an extra TA repeat in the promoter region of the gene [A(TA)₇TAA] is believed to be involved in irinotecan toxicity. This polymorphism is believed to be associated with reduced glucuronidation of SN38 compared with wild-type UGT1A1 [A(TA)₆TAA], possibly resulting in variable SN38 pharmacokinetics.^8-10

The aim of this study was to investigate prospectively the role of UGT1A1*28 polymorphism in the development of toxicity in colorectal cancer (CRC) patients treated with the FOLFIRI regimen as first-line treatment for their metastatic disease. Furthermore, the study also investigated the effects of UGT1A1*28 genotype on irinotecan pharmacokinetics and tumor response.

	PATIENTS AND METHODS

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Study Design and Patient Eligibility
This prospective interinstitutional study involved 13 centers in Northeast Italy. The primary objective was to assess the relationship between the UGT1A1*28 allele and toxicity. Secondary objectives included investigation of the relationship between UGT1A1*28 and tumor response (complete response [CR], CR + partial response [PR]), clinical benefit (CR + PR + stable disease [SD]), time to progression (TTP), overall survival, and the pharmacokinetics of irinotecan. The study was coordinated and sponsored by the Centro di Riferimento Oncologico, National Cancer Center of Aviano (Aviano, Italy). The institutional review board of each participating institution approved the study protocol, and all patients signed a written informed consent before entering the study.

Eligibility criteria included histologically metastatic CRC; no prior chemotherapy for metastatic disease (adjuvant chemotherapy was allowed, except for irinotecan); age between 18 and 75 years; absolute neutrophil count 2,000 µL; platelets 100,000 µL; performance status (WHO) of 0 to 2; life expectancy more than 3 months; at least one measurable cancer lesion; normal renal function (creatinine clearance > 65 mL/min by Cockcroft formula)¹¹; ALT and AST less than 2.0x the upper limit of normal and total serum bilirubin less than 1.25x the upper limit of normal.

Treatment
Patients were treated with either the modified FOLFIRI regimen (> 90% of patients) as described by Tournigand¹² (irinotecan 180 mg/m² intravenously for 2 hours on day 1 + FU 400 mg/m² bolus followed by FU 2,400 mg/m² continuous infusion during 46 hours + LV 200 mg/m² on day 1 every 2 weeks) or the FOLFIRI regimen (irinotecan 180 mg/m² intravenously for 2 hours on day 1 + FU 400 mg/m² bolus followed by FU 600 mg/m² continuous infusion during 22 hours on days 1 and 2 + LV 200 mg/m² on days 1 and 2 every 2 weeks).¹ Before starting irinotecan administration, patients were treated with atropine 0.5 mg, dexamethasone 8 mg, and granisetron 3 mg or ondansetron 8 mg. Diarrhea was treated promptly with loperamide 4 mg at the onset, and then with 2 mg every 2 hours until the patient was diarrhea free for at least 12 hours.

Efficacy and Toxicity Assessment
Objective clinical evaluation, blood counts, and hepatic and renal function tests were performed within 48 hours before each cycle. Patients were questioned specifically about nausea and vomiting, mucositis, diarrhea, malaise, and appetite at every cycle. Computed tomography scans of measurable lesions were assessed at baseline and then repeated at least every four cycles. Objective tumor response and duration of response were assessed by WHO criteria.¹³ Patients with progressive disease (PD) could be dismissed from the study or could continue chemotherapy for two additional cycles according to the physician's decision.

Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria.¹⁴ A single cycle of chemotherapy administration was considered sufficient for evaluation of acute toxicity, whereas response to treatment was evaluated only in patients who had received at least four cycles of chemotherapy. Clinical evaluations were performed blindly with respect to the genetic results, and clinical data were monitored by the study sponsor.

Chemotherapy was delayed until recovery if neutrophils were 1,500 µL or in the presence of significant, persisting, nonhematologic toxicity. In the event of grade 3 or 4 neutropenia, thrombocytopenia, and diarrhea, the irinotecan dose was reduced (from 180 mg/m²) to 90 to 150 mg/m² based on the physician's assessment. Treatment was discontinued in the event of repeated grade 3 to 4 toxicity, despite dose reduction, or because of patient refusal.

UGT Genotyping Assays
Pyrosequencing (Biotage, Uppsala, Sweden) was used for genotyping genomic DNA extracted from peripheral blood using the High Pure PCR Template Preparation Kit (Roche Diagnostics GmbH, Mannheim, Germany). We used a reverse 5'-biotinylated PCR primer, 5'-GGC-AAA-GCC-ACA-GGT-CAG-C-3', and a forward primer, 5'-TTT-TGG-CTC-GTG-CAG-GGT-GGA-C-3'. The reaction was performed in a 50-µL volume with 2 mmol/L MgCl₂, deoxynucleotide triphosphates 125 µmol/L each, 200 nmol/L each primer, and 1 unit of Taq polymerase for 35 cycles of amplification (15 seconds at 94°C, 30 seconds at 53.5°C, and 30 seconds at 72°C) obtaining a 98- to 100-bp fragment. The sequencing primer was 5'-GTG-GAC-TGG-CCT-CCT-TC-3'.

Drug Assays and Pharmacokinetic Analysis
Centro di Riferimento Oncologico and Noale Hospital participated in the collection of samples for pharmacokinetic evaluation in 71 patients (all treated with the modified FOLFIRI regimen). Heparinized serial blood samples were collected before drug administration, and at 0.5, 1.0, 1.5, 2.0, 2.25, 2.50, 2.75, 3.0, 3.50, 4.0, 6.0, 8.0, 10.0, 14.0, 26.0, and 50.0 hours after the start of the irinotecan infusion. Plasma was obtained immediately by centrifugation of the blood samples at 3,000 x g for 15 minutes at 4°C, and stored at –80°C. The total plasma concentration of irinotecan (lactone plus carboxylate) and its metabolites, SN38 and SN38G, were determined using high-performance liquid chromatography as described.^15,16 The intra- and interday variability was less than 10% for irinotecan and other metabolites.

Noncompartmental analysis was used for pharmacokinetics analysis. The apparent terminal elimination rate constant (k) was determined by log-linear regression analysis of the terminal phase of the plasma concentration–time curve. The terminal half-life was calculated as 0.693/k. A linear-log trapezoidal numerical integration method was used to calculate the area under the irinotecan, SN38, and SN38G plasma concentration–time curve (AUC_{0 to last}) from time 0 to the last sampling time (C_last). Area under the irinotecan, SN38, and SN38G plasma concentration–time curves to infinite time (AUC) were calculated by adding C_last/k to AUC_{0 to last}.

The extent of glucuronidation of SN38 to SN38G in plasma was defined as the ratio of SN38G AUC/SN38 AUC (glucuronidation ratio [GR]). The biliary index (BI) was defined as the product of the irinotecan AUC and the ratio of the SN38 AUC over the SN38G AUC.

Statistical Methods
Unconditional logistic regression models were used to assess the relative risk of clinical benefit/response and grade 3 to 4 toxicity between patients with different UGT1A1*28 polymorphic statuses and to control for confounding factors (including all available prognostic factors: sex, age, primary tumor sites, and prior adjuvant chemotherapy). The overall survival and TTP were estimated using the Kaplan and Meier product limit method. Cumulative survival probability was calculated at 24 months within each of the three genotypes. Differences were tested using the log-rank test.

To assess the relative excess risk of progression/death between patients with different UGT1A1*28 genotypes and to control for confounding factors, proportional hazards models (including sex, age, primary sites, and adjuvant chemotherapy) were fitted computing hazard ratios (HRs) and the corresponding 95% CIs. The proportional assumption was examined with log-log survival plots or by adding time-dependent interaction terms into the model.

Differences between pharmacokinetic parameters by genotype, clinical toxicity, and therapeutic outcome were assessed by the nonparametric Wilcoxon or Kruskal-Wallis tests.

	RESULTS

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Patient Characteristics, Treatment Tolerance, and Response
From July 2002 to October 2005, 267 white patients were enrolled. After the Monitoring Committee evaluation, 250 patients were found eligible and included in the final analysis (Table 1). In total, 2,151 2-week cycles were administered (median, eight; range, one to 20).

UGT1A1*28 Genotype Relationship to Toxicity, Response, and Survival
Homozygous TA₇/TA₇, heterozygous TA₆/TA₇, and wild-type TA₆/TA₆ genotype frequencies were 8.8% (n = 22), 45.6% (n = 114), and 45.6% (n = 114), respectively. Allele frequencies of TA₆ and TA₇ were 68.4% and 31.6%, respectively. No TA₅ or TA₈ alleles were detected.

During the first cycle of therapy, a significant association was observed between the TA₇ allele and grade 3 to 4 hematologic toxicity (Table 3). Patients with TA₇/TA₇ genotype had more than eight-fold increased risk of developing grade 3 to 4 hematologic toxicity as compared with TA₆/TA₆ patients (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55). Grade 3 to 4 neutropenia occurred in two of 114 (1.7%) TA₆/TA₆, six of 114 (5.3%) TA₆/TA₇, and three of 22 (13.6%) TA₇/TA₇ patients.

In contrast to what was observed during the first cycle, evaluation of the hematologic and nonhematologic toxicities throughout the entire course of treatment (including toxicity during the first cycle and subsequent cycles) did not reveal any clear association with UGT1A1*28 polymorphism. In particular, grade 3 to 4 neutropenia occurred in four of 22 (18.2%) TA₇/TA₇, 20 of 114 (17.5%) TA₇/TA₆, and 11 of 114 (9.6%) TA₆/TA₆ patients. Grade 3 to 4 diarrhea occurred in one of 22 (4.5%) TA₇/TA₇, 14 of 114 (12.3%) TA₇/TA₆, and six of 114 (5.3%) TA₆/TA₆ patients.

Dose reduction occurred in 20 of 114 (17.5%), 26 of 112 (23.2%), and four of 22 (18.2%) of TA₆/TA₆, TA₇/TA₆, and TA₇/TA₇ patients, respectively, with no significant association with genotypes.

To assess the risk of toxicity after the first cycle of therapy and its relation to UGT1A1 polymorphism under more homogeneous conditions, the cumulative toxicity between cycle 2 and 6 was compared with that observed during cycle 1. No significant association was found between the TA₇ allele and grade 3 to 4 toxicity occurring during the second to sixth cycles of therapy (Table 3).

The UGT1A1 TA₇/TA₇ genotype seemed to be associated with increased clinical benefit and tumor response. Homozygous TA₇/TA₇ patients had a significantly reduced risk of PD or SD compared with the wild-type genotype (OR, 0.32; 95% CI, 0.12 to 0.86). Considering clinical benefit, the homozygous TA₇/TA₇ patients had a significantly lower risk of experiencing progression (OR, 0.19; 95% CI, 0.04 to 0.89; Table 4). Analysis of TTP showed a significant reduction for patients with the variant allele TA₇/TA₇ (HR, 0.52; 95% CI, 0.31 to 0.90) and TA₆/TA₇ (HR, 0.73; 95% CI, 0.55 to 0.98) compared with the wild-type genotype. Median TTPs were 316, 239, and 226 days for UGT1A1 TA₇/TA₇, TA₆/TA₇, and TA₆/TA₆ patients, respectively.

UGT1A1*28 Polymorphism and Pharmacokinetics and Pharmacodynamics Relationships
Pharmacokinetic analyses were performed during the first cycle. Patients who experienced grade 3 to 4 toxicity of any type (hematologic and nonhematologic) after the first chemotherapy cycle were characterized by a significantly lower level of GR (P = .01) and an increased BI (P = .003) compared with those with grade 0 to 2 toxicity (Table 5). No statistically significant associations were seen between toxicity and irinotecan AUC, SN38 AUC, or SN38G AUC. Sixty-six of the 71 patients undergoing pharmacokinetic analysis were assessable for tumor response. GR and BI (P < .01 by Kruskal-Wallis test) but not irinotecan AUC, SN38 AUC, or SN38G AUC were found to be significantly associated with tumor response (Table 5).

Table 5 also summarizes the differences in the relevant irinotecan pharmacokinetic parameters as a function of the UGT1A1*28 genotype for the 71 patients investigated. A significant correlation was found between lower GR (P = .01) and higher BI (P = .007) and UGT1A1*28 polymorphism.

	DISCUSSION

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UGT1A1*28 polymorphism has been reported to be associated with an increased toxicity after irinotecan chemotherapy.⁹ However, results from the studies conducted to date have been conflicting and often have generated opposite conclusions. This is most likely a consequence of the relatively low number of patients included in these studies, the different schedules of irinotecan treatment used, the patient type, or the use of retrospective analyses.^9,17,18 In light of the conflicting results, our trial was conducted prospectively in a homogeneous patient population and single treatment regimen. This trial constitutes the largest prospective study conducted to date to investigate the relationship between UGT1A1 polymorphism and irinotecan used in the FOLFIRI regimen. Overall, the incidence of toxicity observed in our study was lower than that reported by Douillard et al,¹ but well in agreement with that published for the FOLFIRI schedule.^12,19 We observed a significantly increased risk of developing severe hematologic toxicity (primarily grade 3 to 4 neutropenia) among patients carrying the TA₇ allele, which was only relevant for the first cycle and not seen throughout the whole treatment period. This finding suggests that UGT1A1*28 polymorphism may be important in the development of hematologic toxicity at the beginning of therapy, but becomes less important during subsequent cycles. Other effects can result from the continuous administrations of irinotecan. The increased probability that normal cells will be exposed to the drug during DNA replication and/or clinical measures (ie, supportive therapy) may overcome the effects of UGT1A1*28 polymorphism.

It is also noteworthy that there was no apparent association between TA₇/TA₇ genotype and diarrhea during any cycle of treatment. This last finding is consistent with previous studies.¹⁷

The overall response rate achieved in our study was quite comparable to previously published data on irinotecan and FU combinations.¹ A better tumor response (CR + PR) and a reduced PD in patients with the TA₇/TA₇ genotype was seen in the present study. However, the positive effect on tumor response of the TA₇/TA₇ genotype had a nonsignificant impact on patient survival. The advantage was approximately 2 months comparing TA₇/TA₇ versus TA₆/TA₆.

The association of TA₇/TA₇ genotype with a higher response rate could be explained by a different pharmacokinetics. In our study, the TA₇/TA₇ genotype was associated with a significant decrease (approximately 50%) in GR compared with the wild-type (TA₆/TA₆) and heterozygous (TA₆/TA₇) genotypes, in accordance with previous studies.^10,20 We also found significant association between TA₇/TA₇ genotype and higher BI, but not with SN38 AUC, probably due to the complex pathways leading to SN38 production. It must be considered that BI takes into account SN38 AUC, SN38G AUC, and irinotecan AUC, and therefore could be a better predictive marker for irinotecan metabolism and hence a surrogate marker of toxicity and tumor response. A significant correlation was in fact observed between BI, toxicity, or response rate, respectively.

No additional information can be derived from our study about the role of other promoter variants linked in a disequilibrium with UGT1A1*28 (–3156G > A, –3279G > T) or the promoter haplotype and diplotype compositions that result from UGT1A1. A superimposable pattern of correlation, although less significant, was found between these polymorphisms/haplotypes and the toxicity or response to therapy compared with that found for UGT1A1*28 and the associated pharmacokinetics. The 3156G > A polymorphism had the same trend of correlation, whereas the 3279G > T was inversely associated with UGT1A1*28 (data not shown).

In conclusion, data from our study indicate that the UGT1A1*28 genotype was significantly associated with hematologic toxicity only during the first cycle of chemotherapy. However, this association seems to have marginal clinical implications, given that the observed toxicities can be managed during the course of chemotherapy. It has been suggested that genetic testing for UGT1A1*28 polymorphism may have utility as a predictor of toxicity in patients receiving irinotecan.⁹ Drawing a definite conclusion on the role of UGT1A1*28 polymorphism, as a predictor of irinotecan toxicity in CRC patients, would require a randomized trial, aimed at assessing whether genotype-adjusted dosages of this drug could help establish not only a well-tolerated dose, but also an effective dose for tumor response in patients with TA₆/TA₆, TA₆/TA₇, and TA₇/TA₇ genotypes. Data reported from the literature and the data from this study are still insufficient for recommending specific dose adjustments in patients treated with any irinotecan-containing regimen, including the FOLFIRI regimen used in this trial, based on UGT1A1 genotype. The observed increased response rate in patients with lower GR and increased BI (indicative of a biochemical effect of a reduced UGT enzyme activity) and the trend toward increased tumor response and survival in TA₇/TA₇ patients suggest the need for careful consideration before irinotecan dose reduction in patients carrying the polymorphic TA₇ allele is recommended.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Giuseppe Toffoli CRO-National Cancer Institute (B) Giuseppe Corona CRO-National Cancer Institute (A) Mario D'Andrea CRO-National Cancer Institute (A) Lara Maria Pasetto CRO-National Cancer Institute (A) Sergio Pessa CRO-National Cancer Institute (A) Domenico Errante CRO-National Cancer Institute (A) Vincenzo De Pangher CRO-National Cancer Institute (A) Salvatore Bonura CRO-National Cancer Institute (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Giuseppe Toffoli Provision of study materials or patients: 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, Sergio Frustaci Collection and assembly of data: Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona, 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 Data analysis and interpretation: Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona, Antonio Russo, Paola Biason Manuscript writing: Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona Final approval of manuscript: 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, Sergio Frustaci

 

	NOTES

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

	REFERENCES

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9. Innocenti F, Undevia SD, Iyer L, et al: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382-1388, 2004[Abstract/Free Full Text]

10. Iyer L, Das S, Janisch L, et al: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43-47, 2002[CrossRef][Medline]

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15. Poujol S, Pinguet F, Malosse F, et al: Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva: Application to pharmacokinetic studies. Clin Chem 49:1900-1908, 2003[Abstract/Free Full Text]

16. Saltz LB, Kanowitz J, Kemeny NE, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996[Abstract]

17. Carlini LE, Meropol NJ, Bever J, et al: UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 11:1226-1236, 2005[Abstract/Free Full Text]

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19. Teufel A, Steinmann S, Siebler J, et al: Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer. BMC Cancer 4:38, 2004[Medline]

20. Paoluzzi L, Singh AS, Price DK, et al: Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. J Clin Pharmacol 44:854-860, 2004[Abstract/Free Full Text]

Submitted January 19, 2006; accepted April 13, 2006.

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