Prophylaxis of Irinotecan‐Induced Diarrhea with Neomycin and Potential Role for UGT1A128 Genotype Screening: A Double‐Blind, Randomized, Placebo‐Controlled Study

• Published in: The oncologist (Dayton, Ohio) Ohio), 2006-09, Vol.11 (8), p.944-954
• Main Authors: de Jong, Floris A., Kehrer, Diederik F. S., Mathijssen, Ron H. J., Creemers, Geert‐Jan, de Bruijn, Peter, van Schaik, Ron H. N., Planting, André S. Th, van der Gaast, Ate, Eskens, Ferry A. L. M., Janssen, Jos Th. P., Ruit, Jan B., Verweij, Jaap, Sparreboom, Alex, de Jonge, Maja J. A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents - therapeutic use; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - therapeutic use; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Colorectal Neoplasms - complications; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Diarrhea; Diarrhea - chemically induced; Diarrhea - drug therapy; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Glucuronosyltransferase - genetics; Humans; Irinotecan; Male; Mass Screening; Middle Aged; Neomycin; Neomycin - therapeutic use; Pharmacogenetics; Pharmacokinetics; Placebos; Stomach Neoplasms - complications; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; UGT1A1
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.11-8-944

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.