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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

^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

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.

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