Neomycin as secondary prophylaxis for irinotecan-induced diarrhea

Irinotecan-based chemotherapy is widely used for colorectal cancer (CRC) and small-cell lung cancer (SCLC). Irinotecan-associated diarrhea can be dose limiting and sometimes necessitates termination of chemotherapy. Loperamide at high doses can ameliorate irinotecan-associated diarrhea, but in large trials the rate of grade III/IV diarrhea remains 16–22% [1Go, 2Go]. Irinotecan is hydrolyzed in vivo to form SN38, the active metabolite. SN38 is inactivated by UDP-glucuronyltranferase to form SN38-G, which is excreted biliarily [3Go]. Intestinal bacterial ß-glucuronidases can deglucuronate SN38-G into active SN38, which causes mucosal damage in the small intestine resulting in toxic diarrhea. An earlier study demonstrated that oral neomycin (3 x 1000 mg daily) effectively inhibits fecal ß-glucuronidase activity, resulting in a reduction of diarrhea in patients treated with irinotecan 350 mg/m2, without affecting systemic SN38 levels [4Go].

We assessed the efficacy of loperamid plus oral neomycin as secondary prophylaxis of diarrhea. Patients with CRC received irinotecan 80 mg/m2 plus leucovorin (LV) 200 mg/m2 over 2 h plus 5-fluorouracil (5-FU) 2000 mg/m2 over 24 h weekly for 6 weeks. Patients with SCLC received irinotecan 50 mg/m2 weekly plus carboplatin area under the concentration–time curve (AUC) 5 or 6 on day 1 of a 4-week cycle. In cases of grade III or IV diarrhea, patients were treated with loperamide 4 mg orally followed by 2 mg every 2 h until termination of diarrhea. Chemotherapy was postponed until the patients were at least 3 days without diarrhea and neomycin was administered orally in all subsequent cycles at a dose of 2 x 500 mg as secondary prophylaxis until the end of treatment.

Four of 14 patients receiving irinotecan–5-FU–LV treatment experienced grade III diarrhea. In all patients chemotherapy was postponed and loperamide was given until termination of diarrhea. In one patient therapy was not continued because of disease progression. Three other patients received secondary prophylaxis with neomycin and two additional cycles of chemotherapy could be administered at full dose in one case and with a 20% dose reduction according to the study protocol in two other cases without evidence of grade > I diarrhea. Therefore, in these two patients the relative contribution of neomycin as secondary prophylaxis cannot be assessed.

Three of 17 patients who were treated with irinotecan plus carboplatin for SCLC experienced grade III or IV diarrhea which was treated with loperamide. The first patient died within 24 h due to febrile neutropenia and septic organ failure after the first treatment cycle. In two other patients loperamide terminated diarrhea within 2 and 6 days, respectively. Neomycin prophylaxis was initiated and three additional cycles of irinotecan plus carboplatin could be administered at full dose without recurrent diarrhea.

In addition to the report by Kehrer et al. [4Go], a second study reported on the efficacy of a combination of neomycin plus bacitracin in patients with diarrhea during irinotecan plus 5-FU–FA therapy (Saltz regimen) [5Go]. We have demonstrated that neomycin was effective as secondary prophylaxis for irinotecan-induced diarrhea in three patients, and may have contributed to the prevention of diarrhea in a further two patients. The results have to be confirmed in larger studies.

A. Schmittel*, K. Jahnke, E. Thiel and U. Keilholz

Charité, Campus Benjamin Franklin, Department of Medicine III (Hematology, Oncology and Transfusion Medicine), Hindenburgdamm 30, D-12200 Berlin, Germany

* E-mail: alexander.schmittel{at}charite.de

References

1. Noda K, Nishiwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small lung cancer. N Engl J Med 2002; 346: 85–91.[Abstract/Free Full Text]

2. Saltz LB, Cox JV, Blanke C et al. Irinotecan and fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905–914.[Abstract/Free Full Text]

3. Iyer L, King CD, Whitington PF et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101: 847–854.[Abstract/Free Full Text]

4. Kehrer DF, Sparreboom A, Verweij J et al. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 2001; 7: 1136–1141.[Abstract/Free Full Text]

5. Alimonti A, Satta F, Pavese I et al. Prevention of irinotecan plus 5-fluorouracil/leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol 2003; 14: 805–806.[Free Full Text]





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