Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study.
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/m(2) 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.
|Keywords||Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents/*therapeutic use, Antineoplastic Agents, Phytogenic/*adverse effects/therapeutic use, Camptothecin/adverse effects/*analogs & derivatives/therapeutic use, Colorectal Neoplasms/complications/*drug therapy/genetics, Diarrhea/chemically induced/*drug therapy, Double-Blind Method, Drug Therapy, Combination, Female, Genotype, Glucuronosyltransferase/*genetics, Humans, Male, Mass Screening, Middle Aged, Neomycin/*therapeutic use, Placebos, Stomach Neoplasms/complications/*drug therapy/genetics|
|Persistent URL||dx.doi.org/10.1634/theoncologist.11-8-944, hdl.handle.net/1765/14085|
de Jong, F.A., Kehrer, D.F.S., Mathijssen, A.H.J., Cremers, G.J., de Bruijn, P., van Schaik, R.H.N., … de Jonge, M.J.A.. (2006). Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study.. The Oncologist, 11(8), 944–954. doi:10.1634/theoncologist.11-8-944