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.


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.


CONCLUSIONS
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.
de Jong
Floris A
FA
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. f.a.dejong@erasmusmc.nl
Kehrer
Diederik F S
DF
Mathijssen
Ron H J
RH
Creemers
Geert-Jan
GJ
de Bruijn
Peter
P
van Schaik
Ron H N
RH
Planting
André S Th
AS
van der Gaast
Ate
A
Eskens
Ferry A L M
FA
Janssen
Jos Th P
JT
Ruit
Jan B
JB
Verweij
Jaap
J
Sparreboom
Alex
A
de Jonge
Maja J A
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D009355:Neomycin / Q000627:therapeutic use*; D010919:Placebos; D013274:Stomach Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D000099148:UGT1A1 Enzyme
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009355:Neomycin; D010919:Placebos; D000099148:UGT1A1 Enzyme