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The Oncologist, Vol. 11, No. 8, 944-954, September 2006; doi:10.1634/theoncologist.11-8-944
© 2006 AlphaMed Press

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Symptom Management and Supportive Care

Prophylaxis of Irinotecan-Induced Diarrhea with Neomycin and Potential Role for UGT1A1*28 Genotype Screening: A Double-Blind, Randomized, Placebo-Controlled Study

Floris A. de Jonga, Diederik F. S. Kehrerb, Ron H. J. Mathijssena, Geert-Jan Creemersc, Peter de Bruijna, Ron H. N. van Schaikd, André S. Th. Plantinga, Ate van der Gaaste, Ferry A. L. M. Eskense, Jos Th. P. Janssenf, Jan B. Ruitg, Jaap Verweija, Alex Sparrebooma, Maja J. A. de Jongea

a Department of Medical Oncology, Erasmus University Medical Center Rotterdam–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; b Department of Internal Medicine, IJsselland Hospital, Capelle aan den IJssel, The Netherlands; c Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands; d Department of Clinical Chemistry and e Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; f Department of Internal Medicine, Franciscus Hospital, Roosendaal, The Netherlands; g Department of Internal Medicine, Vlietland Hospital, Schiedam/Vlaardingen, The Netherlands

Key Words. Diarrhea • Irinotecan • Neomycin • Pharmacokinetics • Pharmacogenetics • UGT1A1

Correspondence: Floris de Jong, Erasmus University Medical Center Rotterdam–Daniel den Hoed Cancer Center, Department of Medical Oncology, Room AS-15, Groene Hilledijk 301, NL-3075 EA Rotterdam, The Netherlands. Telephone: 31-10-4391-112; Fax: 31-10-4391-053; e-mail: f.a.dejong{at}erasmusmc.nl

Received February 3, 2006; accepted for publication June 20, 2006.


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
Objective. Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea.

Patients and Methods. Patients were treated with irinotecan in a multicenter, double-blind, randomized, placebo-controlled trial. Eligible patients received irinotecan (350 mg/m2 once every 3 weeks) combined with neomycin (660 mg three times daily for three consecutive days, starting 2 days before chemotherapy) or combined with placebo. Blood samples were obtained for additional pharmacokinetic and pharmacogenetic analyses.

Results. Sixty-two patients were evaluable for the toxicity analysis. Baseline patient characteristics, systemic SN-38 exposure, and UGT1A1*28 genotype status (i.e., an additional TA repeat in the promoter region of uridine diphosphate-glucuronosyltransferase isoform 1A1) were similar in both arms. Although distribution, severity, and duration of delayed-type diarrhea did not differ significantly between arms, grade 3 diarrhea tended to be less frequent in the neomycin arm. The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea. In the neomycin arm, grade 2 nausea was significantly more common.

Conclusion. Our results do not suggest a major role for neomycin as prophylaxis for irinotecan-induced delayed-type diarrhea. It is suggested that the UGT1A1*28 genotype status could be used as a screening tool for a priori prevention of irinotecan-induced delayed-type diarrhea.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
Irinotecan (Campto®, Camptosar®; Pfizer Pharmaceuticals, New York) is frequently used in first- and second-line treatment of metastatic colorectal cancer [1–4]. Clinical activity has also been demonstrated in lung, gastric, and pancreatic cancer, among others [5–7]. Regardless of its schedule of administration, myelosuppression and delayed-type diarrhea are the most common side effects seen in patients treated with this topoisomerase-I inhibitor [1, 8–10]. Irinotecan is a prodrug that needs to be metabolized through hydroxylation to form its active metabolite SN-38 [11]. Subsequently, SN-38 is detoxified in the liver by uridine diphosphate-glucuronosyltransferases, especially UGT1A1, to form an inactive glucuronide metabolite (SN-38G) [12–14]. Both SN-38 and SN-38G are excreted via the urine and bile [9, 15].

Delayed-type diarrhea, defined as diarrhea occurring more than 24 hours after administration of irinotecan [16], is probably directly mediated by high concentrations of intraluminal SN-38, which is formed partly out of SN-38G by bacterial ß-glucuronidases [17, 18]. Severe delayed-type diarrhea has been reported to occur in up to 30%–40% of patients and necessitates hospitalization for i.v. rehydration in about 10% of patients [2, 8, 16, 19–23]. Apart from morbidity, this type of diarrhea results in expanded health-care costs [24], and even mild diarrhea may influence continuation of treatment.

In recent years, several attempts have been made to prevent irinotecan-induced delayed-type diarrhea in humans [22, 25–39]. Most strategies have focused on intervening in its metabolic pathway to reduce SN-38 concentrations in the gut. However, most studies that have suggested protective effects were not randomized, did not evaluate SN-38 pharmacokinetics, and/or were not placebo controlled. Therefore, there is still no generally accepted prophylactic treatment for irinotecan-induced delayed-type diarrhea [40, 41]. In a previously performed pilot study, we reported that the aminoglycoside antibiotic neomycin prevented the recurrence of grade ≥ 2 diarrhea in six of seven patients, which was attributed to inhibition of ß-glucuronidase-producing intestinal bacteria [29]. Because no changes in systemic pharmacokinetic parameters of SN-38 with or without neomycin were observed, cotreatment with neomycin was considered safe. Moreover, fecal cultures taken during and after neomycin treatment did not reveal neomycin-resistant microorganisms, bacterial overgrowth, or toxins. Two subsequent small studies have been published since then, confirming the potential role of neomycin in preventing irinotecan-induced delayed-type diarrhea [32, 37]. Here, we present the results of a multicenter, double-blind, randomized, placebo-controlled study of irinotecan with or without neomycin, aimed to validate the previously demonstrated prophylactic effects of neomycin on irinotecan-induced delayed-type diarrhea [29].


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
Patient Eligibility
Patients were recruited from the departments of medical oncology and internal medicine of the hospitals mentioned below. The treating physicians were medical oncologists who were all familiar with the study protocol. Patients, 18 years of age or older, were required to have a confirmed malignant solid tumor for which irinotecan was considered the best available treatment option. Before randomization, eligibility was confirmed by use of a protocol-specific checklist, which included adequate hematological (absolute neutrophil count [ANC] ≥2.0 x 109/l) and hepatic (bilirubin ≤1.25 x the upper limit of normal [ULN], alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤2.5 x ULN, in cases of liver metastasis ≤5 x ULN, and alkaline phosphatase ≤5 x ULN) functions. Patients who had a World Health Organization (WHO) performance status score >2, were known to be hypersensitive to neomycin, had been treated with irinotecan before, or had had anticancer therapy or major surgery within 4 weeks prior to study entry were not eligible. Other exclusion criteria were previous abdominal radiotherapy, unresolved bowel obstruction, and chronic colic disease. Patients were not allowed to use herbal medicines/tea, dietary supplements, and grapefruit (juice) from 4 weeks before and during the study period. Use of drugs known to modulate cytochrome P450 3A (CYP3A) function or expression to a clinically significant extent was prohibited, except for necessary prophylactic antiemetics.

This study was performed in accordance with the Declaration of Helsinki (Hong Kong amendment). The institutional medical ethical board of the Erasmus University Medical Center Rotterdam, The Netherlands, and the local institutional review boards of all participating local hospitals in its referral area (Catharina Hospital in Eindhoven, the Franciscus Hospital in Roosendaal, the IJsselland Hospital in Capelle aan den IJssel, the Vlietland Hospital in Schiedam/Vlaardingen, the Van Weel Bethesda Hospital in Dirksland, and the Lievensberg Hospital in Bergen op Zoom) had approved the study protocol, which involved sampling for pharmacokinetic and pharmacogenetic purposes as well. Prior to study entry, written informed consent was obtained from all patients. Sampling for pharmacokinetic and pharmacogenetic analysis was only done if the patient had given separate and specific written consent for these procedures.

Study Design and Treatment
Once eligibility was confirmed, the patient was given an identification number according to the hospital where the patient was entered and his/her entry order in the study. Randomization was performed according to a randomized block design. Block length varied at random using a mixture of block lengths stratified for each separate institution. Patients were randomized between arm A, consisting of irinotecan given at a dose of 350 mg/m2 combined with oral neomycin (660 mg three times daily) for three consecutive days starting 2 days before chemotherapy, and arm B, consisting of the same irinotecan regimen but during the first course given with placebo. Prior to the study, a numbered randomization list with neomycin versus placebo was produced by an independent statistician and was directly provided to the involved trial pharmacist (Department of Hospital Pharmacy, Erasmus University Medical Center Rotterdam) only. Capsules containing neomycin or placebo were produced by the hospital pharmacy. The medication strips, renumbered according to the randomization list, were distributed to the participating centers. After registration, the registration officer provided the number of the strip to be used. The clinical study coordinator, the registration officer, the treating physician, and the patient were therefore not informed as to which arm of treatment the patient had been randomized.

Irinotecan hydrochloride trihydrate (Aventis Pharma, Hoevelaken, The Netherlands; Pfizer BV, Capelle aan den IJssel, The Netherlands) was administered over 90 minutes as a continuous i.v. infusion, repeated every 3 weeks. All patients received prophylactic antiemetics, including dexamethasone and 5HT3-receptor antagonists. The neomycin dosing regimen was based on a small study in healthy volunteers in which it was shown to adequately block fecal ß-glucuronidase activity for a period of at least 3 days after the last dose (unpublished data). As soon as the first liquid stool occurred, the patient had to start loperamide treatment (4 mg loperamide for the first dose, then 2 mg every 2 hours until 12 hours after the last liquid stool). If diarrhea persisted for more than 48 hours, oral antibiotic therapy with ciprofloxacin (500 mg twice a day) was prescribed.

Patients were deemed evaluable if they had taken 3 days of neomycin/placebo completely and without vomiting within 4 hours after intake (according to anamnesis), irinotecan had been adequately administered, and complete data on diarrhea toxicity were available. A full blood count, including neutrophils, was obtained once every week. Besides nadir values and percent decrease at nadir from baseline, the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0) were used for classification of severity of neutropenia and leukopenia, as well as for diarrhea, nausea, and vomiting, up to 3 weeks following administration of irinotecan. The duration of diarrhea (in days) was scored as well.

At regular intervals, the case record forms were checked against source documents and, if necessary, completed by the data manager. After closing the study, the clinical study coordinator (re-)evaluated eligibility, (recorded) toxicity, and evaluability according to the above-mentioned criteria for all patients. To assure unbiased interpretation, this was done before unblinding the study intervention, that is, the use of neomycin or placebo.

Isolation of Genomic DNA and Genotype Analysis
Genomic DNA was isolated from whole blood or plasma using the MagNA Pure LC System (Roche Molecular Biochemicals, Mannheim, Germany), after which amplification was performed using polymerase chain reaction (PCR)-based techniques. The number of TA repeats in the TATA box of the promoter region of the UGT1A1 gene was determined by sizing of the PCR products obtained with UGT1A1-specific primers, as described in detail elsewhere [42]. Genotypes were assigned as 6/6, 6/7, and 7/7 for patients homozygous for six repeats (wild-type), heterozygous patients, and patients homozygous for seven repeats (UGT1A1*28), respectively. The analysis was validated using control DNA from individuals with known 6/6, 6/7, and 7/7 genotypes.

Blood Sampling and Pharmacokinetic Analysis
Blood samples for pharmacokinetic analysis were collected at three time points: immediately prior to infusion, and at 1 and 48 hours after the end of infusion, according to a previously developed limited-sampling model to predict the area under the plasma concentration–time curve (AUC) of the active metabolite SN-38 [43, 44]. After patient approval, blood was taken from the arm that was not used for irinotecan infusion. Samples were collected in tubes containing lithium heparin and were centrifuged for 10 minutes at 3,000 x g to separate blood cells from plasma, as described in detail elsewhere [45]. Plasma was stored at –70°C until the day of analysis. Concentrations of SN-38 in plasma were determined by reversed-phase high-performance liquid chromatography with fluorescence detection [46, 47]. The AUC of SN-38 was calculated as: AUCSN-38 (ng x h/ml) = 6.588 x C1h + 146.4 x C48h + 15.53, where C1h and C48h are the plasma concentrations of SN-38 at 1 and 48 hours after the end of infusion [43].

Statistical Considerations
Initially, grade ≥2 irinotecan-induced delayed-type diarrhea was estimated to occur in half of the regularly dosed patients. Protection against this type of diarrhea by prophylactic neomycin coadministration was considered to be of clinical importance if the reduction to grade <2 diarrhea would be at least 50%. In order to detect this reduction, with a power of 80% and a significance level of 5%, it was calculated that a population of 60 patients had to be studied in a randomized, placebo-controlled design. To compare normally distributed continuous variables between two groups of patients, the Student’s t-test was used; otherwise the nonparametric Mann-Whitney U-test was chosen. In cases of two dichotomous variables, the Pearson {chi}2 test was performed, whereas Spearman’s correlation coefficient was used to relate two continuous variables. A nonparametric trend test was used if a trend over several groups of patients was expected. Statistical tests were performed using SPSS version 10.0.7 (SPSS Inc., Chicago, IL) and Stata version 9.0 (Stata, College Station, TX). Test results with a p < .05 were considered statistically significant.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
Patient Population and Treatment
Of the 75 patients enrolled in this study between December 2001 and October 2004, 62 were evaluable for analysis of the effects of neomycin on irinotecan-induced delayed-type diarrhea (Table 1Go). Thirteen patients did not fulfill all criteria: one never started, five did not complete their neomycin/placebo or irinotecan therapy, two died during follow-up, one received concurrent radiotherapy, two had a stoma, one suffered from pre-existing diarrhea, and one used lactulose. About half of the patients were included in the Erasmus University Medical Center Rotterdam, whereas the remaining patients were treated in the six local hospitals in its referral area. Patients were treated with 350 mg/m2 irinotecan (mean, 660 mg; range, 500–800 mg) during their first cycle combined with neomycin (n = 28; 45%) or with placebo (n = 34; 55%). The groups were well balanced for demographic parameters and hematological functions, bilirubin, and liver enzyme values (Table 1Go). In patients who had consented to pharmacokinetic sampling, the administered dose of irinotecan did not differ significantly between groups (mean, 640 mg vs. 679 mg; p = .09).


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  		Table 1. Patient demographicsa

 
Effect of Neomycin on Toxicity
The pattern of distribution of side effects as a function of concomitant neomycin/placebo treatment during the first cycle is given in Table 2Go. The overall incidence and severity of delayed-type diarrhea did not differ significantly between study groups (p = .33) (Fig. 1Go). Although a 45% lower incidence of grade 3 diarrhea was seen in the group receiving neomycin compared with those who received placebo (17.9% vs. 32.4%; p = .19), there was no difference between the study groups when grade 2 and 3 diarrhea were taken together (46.4% vs. 50.0%; p = .78). Treatment with neomycin did not result in a significantly shorter duration of diarrhea (4.0 vs. 4.9 days; p = .32). In both arms, approximately 75% of patients experienced any grade of nausea despite the use of prophylactic antiemetics. Patients receiving neomycin had a 4.5-fold higher risk for grade 2 nausea than those receiving placebo (39.3% vs. 8.8%; p < .01).


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  		Table 2. Effect of neomycin on irinotecan pharmacodynamics

 

Figure 1
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  		Figure 1. The effect of concomitant neomycin treatment on irinotecan-induced delayed-type diarrhea. Histogram showing the distribution of patients (percentages) receiving neo-mycin (grey) or placebo (black) by diarrhea (National Cancer Institute Common Toxicity Criteria [NCI-CTC], version 2.0). No significant effect of neomycin prophylaxis on the incidence and severity of irinotecan-induced delayed-type diarrhea was found, although the risk for grade 3 diarrhea was 45% lower in patients receiving neomycin (p = .19).

 
UGT1A1*28 Pharmacogenetics
Of the evaluable patients, 52 patients (84%) consented to pharmacogenetic blood sampling. Twenty-three patients (44.2%) were heterozygous for UGT1A1*28, three (5.8%) were homozygous variant, and 26 (50.0%) were homozygous wild type. The UGT1A1*28 allele was found to be equally distributed between patients receiving neomycin and those receiving placebo (p = .58). The presence of at least one UGT1A1*28 allele was highly related to the distribution pattern of delayed-type diarrhea (p = .03) (Table 3Go). Specifically, the incidence of grade 2–3 diarrhea was double in patients carrying at least one UGT1A1*28 allele (69.2% vs. 34.6%; p = .01), whereas patients carrying the wild-type sequence were more likely to experience only grade 0–1 diarrhea (30.8% vs. 65.4%), regardless of prophylactic neomycin coadministration. In neither genetic group was the incidence and severity of diarrhea related to the use of neomycin or placebo (p > .66).


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  		Table 3. Irinotecan pharmacodynamics in relation to UGT1A1*28 genotype

 
SN-38 Pharmacokinetics
Of the evaluable patients, 43 patients (69%) were assessable for pharmacokinetic analysis. The AUC of SN-38 did not differ between patients receiving neomycin and those receiving placebo (median, 717 ng x h/ml vs. 731 ng x h/ml; p = .80), nor did the apparent metabolic clearance (median, 884 l/h vs. 954 l/h; p = .56). The UGT1A1*28 allele was found to be equally distributed between groups (45.0% vs. 56.5%; p = .45). Overall, the presence of one UGT1A1*28 allele was associated with slower metabolic clearance of SN-38 (n = 19; median, 804 l/h) compared with wild-type patients (n = 21; median, 1,268 l/h), whereas patients who were homozygous variant (n = 2; median, 489 l/h) showed an even slower clearance (p < .01) (Fig. 2Go).


Figure 2
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  		Figure 2. UGT1A1*28 genotype and the metabolic clearance of SN-38. Boxplot showing that presence of the variant UGT1A1*28 allele is significantly related to less efficient metabolic clearance of SN-38 (p < .01). The wild-type allele of UGT1A1 is designated TA6 and the variant allele is TA7 (UGT1A1*28).

 
Patients who experienced grade 2–3 diarrhea had a significantly higher SN-38 exposure than those with grade 0–1 diarrhea (mean, 873 ng x h/ml vs. 639 ng x h/ml; p = .03), which may be explained in part by the presence of the UGT1A1*28 variant allele, because UGT1A1*28 carriers were somewhat over-represented in the patients experiencing grade 2–3 diarrhea (65.2% vs. 35%; p = .05). Patients (n = 11) who experienced grade 3–4 neutropenia had a significantly higher systemic exposure to SN-38 than those (n = 31) who experienced grade 0–2 neutropenia (median, 1,023 ng x h/ml vs. 623 ng x h/ml; p < .01). Both the ANC nadir and the percentage decrease at nadir from baseline were related to the AUC of SN-38 (rs = –0.54 and rs = 0.62, respectively; p < .01).


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
In this double-blind, randomized, placebo-controlled trial, we found no significant effect of neomycin on incidence, severity, and duration of irinotecan-induced delayed-type diarrhea. Although the incidence of grade 3 diarrhea was diminished from 32% to 18% and the average duration was shortened by almost 1 day, this was accompanied by a shift to a substantially higher incidence of grade 2 diarrhea. This finding is in contrast to the hypothesis derived from the earlier performed pilot study [29]. Our results clearly demonstrate that the combination of neomycin with irinotecan is safe and that neomycin does not affect systemic exposure to SN-38, but patients receiving neomycin had a significantly greater risk for more severe nausea, probably at least partly induced by neomycin.

Despite the fact that a high-dose loperamide regimen renders irinotecan-induced diarrhea more manageable once it has occurred [23, 48], it still remains one of its serious toxicities, occurring rather frequently and unpredictably. It was originally suggested from animal models that ß-glucuronidases produced by common intestinal microflora might play a major role in the development of delayed-type diarrhea by mediating deglucuronidation of hepatobiliary excreted SN-38G into SN-38 [17]. Indeed, data obtained in rats have indicated that antibiotics inhibited the ß-glucuronidase activity from the intestinal microflora, thereby decreasing the luminal SN-38 concentration and subsequently reducing cecal damage and ameliorating diarrhea [18, 49]. Additionally, in our pilot study mentioned before [29], we observed a reduced incidence of delayed-type diarrhea after cotreatment with neomycin in patients who had experienced grade ≥2 irinotecan-induced diarrhea in their first course.

The discrepancy between the current data and those presented earlier on the neomycin–irinotecan combination might be caused by a change in study design. In the pilot study, patients were treated with neomycin starting 5 days before irinotecan infusion and ending 2 days after infusion. Prior to embarking on the current study, the question arose whether a shorter period of treatment with neomycin would be sufficient to reduce ß-glucuronidase activity. Likewise, it was not known how soon ß-glucuronidase activity would reappear after discontinuation of the neomycin treatment. These questions were addressed in a small study in healthy volunteers (unpublished data). The obtained data revealed that 3 days of treatment with 3 times daily 660 mg neomycin adequately blocked fecal ß-glucuronidase activity for at least 3 days after the last dose, which led to the neomycin dosing regimen as prescribed in this study.

As mentioned before, in our earlier study, patients who had experienced grade ≥2 delayed-type diarrhea were selected to receive concomitant neomycin during their second chemotherapy course [29]. Six of seven patients likely benefited from neomycin prophylaxis during their second course. Although no significant prophylactic effect on the incidence and severity of irinotecan-induced delayed-type diarrhea during the first course of treatment could be demonstrated in this study, a protective effect during subsequent courses once patients have experienced grade ≥2 delayed-type diarrhea and are at higher risk for recurrence of diarrhea cannot be ruled out based on the findings presented here. However, because the natural course of diarrhea during the second administration of irinotecan was not investigated in the pilot study, an overestimation of the prophylactic neomycin effect cannot be excluded. Additionally, a synergistic effect of neomycin on the severity of delayed-type diarrhea in patients who would have encountered only mild diarrhea without neomycin prophylaxis cannot be excluded.

Although the current study might be somewhat under-powered to detect small therapeutic benefits, the general lack of a substantial clinical benefit of neomycin on irinotecan-induced delayed-type diarrhea is concordant with previously reported comparative trials of comparable size that evaluated other agents. For example, Karthaus et al. [39] performed a study in 56 patients showing that budesonide (a synthetic corticosteroid) had no significant prophylactic effect on irinotecan-induced delayed-type diarrhea. Similarly, no effect of tiorfan (racecadotril, an antidiarrheal drug that inhibits enkephalinase) was noted in a trial involving 68 patients [25]. In contrast, in a smaller, nonrandomized study, a significant effect of active charcoal was seen on the incidence of irinotecan-induced delayed-type diarrhea [22]. Specifically, the incidence of grade 3–4 diarrhea was reduced in 28 patients from 25% to 7% when combined with active charcoal. However, no pharmacokinetic analysis was performed to confirm a lack of effect of active charcoal on systemic SN-38 concentrations. Hence, partly because of its nature and the many factors involved in its pathogenesis, specific recommendations for the prophylactic treatment of irinotecan-induced delayed-type diarrhea currently cannot be provided.

As long as there are no generally accepted and undisputedly proven interventions to prevent the occurrence of irinotecan-induced delayed-type diarrhea, we have to focus on other ways of dealing with this debilitating side effect. Because it has been shown that body surface area–based dosing does not reduce interindividual pharmacokinetic and pharmacodynamic variability of irinotecan [50, 51], one approach may be to optimize dosing strategies [42]. Several pharmacokinetic and pharmacogenetic analyses have been performed in order to predict the severity and incidence of irinotecan-induced side effects, with conflicting results [9, 14, 52, 53]. Some studies have reported a correlation between delayed-type diarrhea and biliary secretion of SN-38 [54–56]. In addition, the homozygous presence of the UGT1A1*28 polymorphism, leading to less efficient glucuronidation of SN-38 [57, 58], has been identified as a potential risk factor for the occurrence of delayed-type diarrhea and grade 3–4 neutropenia [15, 59–62].

In the current study, occurrence of grade 2–3 delayed-type diarrhea was found to be strongly related to systemic SN-38 exposure, with a 37% higher AUC for those patients who experienced grade 2–3 diarrhea, which is in line with earlier findings [63]. Because pharmacokinetic information is always limited to a posteriori correlates, in clinical practice relations with exposure to SN-38 are of little value, and we should search for a priori predictors. In this study, a strong correlation between the presence of the UGT1A1*28 polymorphism and incidence and severity of irinotecan-induced delayed-type diarrhea was noted. Most studies have reported that only patients carrying two variant alleles were at risk for serious toxicity [14, 53, 60, 62]. In contrast, we found that patients carrying at least one variant allele had a double risk for grade 2–3 delayed-type diarrhea, making the presence of at least one UGT1A1*28 allele a strong predictive factor with potential clinical relevance. This is of particular interest given the availability of blood tests, such as the recently U.S. Food and Drug Administration–approved Invader UGT1A1 Molecular Assay (Third Wave Technologies, Madison, WI), which can rather easily detect this polymorphism at low cost before treatment [14].


   CONCLUSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
Disclosure of Potential...
 References
 Additional Reading
 
Based on the findings presented here, the best way to deal with irinotecan-induced delayed-type diarrhea still remains a strict loperamide regimen once it has occurred, in combination with antibiotics and rehydration if necessary. Although neomycin did not prove useful as prophylaxis, this study suggests that we can potentially reduce the a priori risk for grade ≥ 2 irinotecan-induced delayed-type diarrhea using genotyping strategies. Specifically, our data provide a strong argument to administer irinotecan only to patients who are most likely to tolerate it relatively well, such as individuals who are not carrying the UGT1A1*28 allele. Alternatively, one should opt for other proven effective chemotherapeutic agents in the first instance for patients carrying this genetic aberration, until better dosing strategies and/or prophylactic interventions aimed to lower the risk for irinotecan-induced delayed-type diarrhea have been undisputedly proven to have clinical value.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
References
 Additional Reading
 
This study was supported by a grant from Aventis Pharma (The Netherlands). Pfizer BV (The Netherlands) supported the finalization of this study.


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
We would like to thank all participating investigators and researchers at the following Dutch hospitals: the Erasmus University Medical Center Rotterdam (Center Location and Daniel den Hoed Cancer Center, Rotterdam), the Catharina Hospital (Eindhoven), the Franciscus Hospital (Roosendaal), the IJsselland Hospital (Capelle aan den IJssel), the Vlietland Hospital (Schiedam/Vlaardingen), the Van Weel Bethesda Hospital (Dirksland), and the Lievensberg Hospital (Bergen op Zoom).


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
Additional Reading
 

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   Additional Reading
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 Additional Reading
 
    Mathijssen RH, van Alphen RJ, Verweij J et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001;7:2182–2194.[Abstract/Free Full Text]

    Benson AB 3rd, Ajani JA, Catalano RB et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 2004;22:2918–2926.[Abstract/Free Full Text]

    de Jong FA, de Jonge MJ, Verweij J et al. Role of pharmacogenetics in irinotecan therapy. Cancer Lett 2006;234:90–106.[CrossRef][Medline]

    Alimonti A, Gelibter A, Pavese I et al. New approaches to prevent intestinal toxicity of irinotecan-based regimens. Cancer Treat Rev 2004;30: 555–562.[CrossRef][Medline]

    McLeod HL, King CR, Marsh S. Application of pharmacogenomics in the individualization of chemotherapy for gastrointestinal malignancies. Clin Colorectal Cancer 2004;4(suppl 1):S43–S47.[CrossRef][Medline]




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