Prevention of Irinotecan Induced Diarrhea by Probiotics
Prevention of Irinotecan Induced Diarrhea by Probiotics
Diarrhea is a relatively common complication in patients with cancer. At its inception,
 several mechanisms participated; malabsorption on the basis of mucositis induced by
 chemotherapy, dysbiosis induced by broad-spectrum antibiotics and predisposition to
 infectious diarrhea in immunocompromised patients. Some cytostatics and their metabolites can
 also induce diarrhea directly due to effect on the intestinal mucosa.

 Use of probiotics in prevention and treatment of diarrhea relies on both the theoretical
 assumptions and the results of several clinical trials. Lactic acid bacteria involved in the
 treatment of dysbiosis, compete for substrate with pathogenic bacteria, produce
 bacterio-cins, increase transepithelial resistance. Their enzymatic activity affects
 activation or deactivation of metabolites which cause diarrhea. Production of short chain
 fatty acids, which are important for the maintenance of intestinal mucosal cells also
 contributes to their antidiarrhoeal effect.

 This randomized, double-blind, placebo controlled, multicentre trial was designed to evaluate
 potential of probiotics to prevent grade 3-4 diarrhea in patients treated by irinotecan based
 chemotherapy during first 6 weeks of irinotecan based chemotherapy
In preventing antibiotic-induced diarrhea in double blind placebo controlled clinical trials
 it was found protective effect of probiotics containing S. boulardii and Enterococcus
 faecium. Also in preventing infectious diseases associated with Clostridium difficile,
 administration of probiotics resulted in a significant decrease in disease recurrence.
 Duration of rotavirus diarrhea, in children and in immunocompromised HIV-positive patients
 was significantly shortened after administration of strains of Lactobacilli and S. boulardii
 respectively.

 Meta-analysis of 9 randomized, placebo-controlled trials showed significant reduction in the
 incidence of antibiotic associated diarrhea in children. Another meta-analysis in which 23
 studies were included showed significant reduction in risk of infectious diarrhea. Most of
 these studies was carried out with the probiotic strain Lactobacillus rhamnosus GG®.

 The incidence of diarrhea during treatment of acute leukemia is between 15 to 80%. Severe
 diarrhea level 3 to 4 is present in 8-20% and is much more common during the induction phase
 of chemotherapy. In phase II study performed in NCI Slovakia preventive administration of
 Enterococcus faecium probiotic strain M-74 with selenium was associated with low incidence
 (14%) and severity (all grade 1) diarrhea, despite the fact that half of the patients
 received induction therapy. The investigators noted safety of probiotic strain during 370
 days of severe neutropenia Gr 3-4.

 The incidence of irinotecan induced diarrhea varies between 60-90%, by which the incidence of
 severe diarrhea is 20-40%. In phase II studies, its incidence was 17% in NCI Slovakia, but
 irinotecan dose was reduced by 25% in all patients. Diarrhea is an important factor in
 morbidity and mortality during irinotecan based chemotherapy. Predisposing factors are age
 over 65 years, ECOG (Eastern Cooperative Oncology Group) PS (Performance status) of 1 and
 previous abdominopelvic radiation. One of irinotecan metabolites, SN-38 (7-ethyl-10
 hydroxycamptothecin), which is glucuronidated in the liver and subsequently expelled into
 intestine is main cause of diarrhea. Due to the bacterial enzyme beta-D-glucuronidase it is
 deconjugated in intestinal lumen again. This form causes direct damage to intestinal mucosa
 associated with malabsorption of water, electrolytes and development of diarrhea.

 Reduction of activity of intestinal beta-D-glucuronidase using broad-spectrum antibiotics
 and/or beta-D-glucuronidase inhibitors is one of the ways to avoid irinotecan induced
 diarrhea. It is also possible to modulate metabolism of irinotecan using cyclosporine and
 phenobarbital to reduce biliary excretion of SN-38 and induction of glucuronidation.
 Promising results were shown using activated charcoal, which has resulted in the absorption
 of SN-38. Also other methods were tested: oral alkalization, thalidomide, amifostine, but
 without success. These procedures have been studied only in phase II trials. It is known that
 some probiotic bacteria, reduce activity of intestinal beta-D-glucuronidase and therefore
 these bacteria could be applied in the prevention of diarrhea in patients treated by
 irinotecan based therapy.

 Results of phase III study, that was prematurely terminated due to poor accrual showed
 benefit of Colon Dophilus on irinotecan induced gastrointestinal toxicity. In this trial, 46
 patients with colorectal cancer starting a new line of irinotecan based therapy were
 enrolled. 5-fluorouracil/capecitabine along with irinotecan was administered to 26 (56.5%)
 patients and 22 (47.8%) patients received biological therapy as well. Patients were
 randomized 1:1 to probiotic (PRO) or placebo arm (PLA). Probiotic formula Colon Dophilus, was
 administered at a dose of 10x109 CFU (colony forming unit) of bacteria tid, orally for 12
 weeks of chemotherapy. Primary endpoint was incidence of grade 3/4 diarrhea. 23 patients were
 randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo
 led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4%
 for PLA, p = 0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO
 vs. 60.9% for PLA, p = 0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA).
 Patients on PRO used less loperamide compared to PLA (mean duration of loperamide use: 4.5
 days for PRO vs. 10.4 days for PLA, p = 0.45; mean number of loperamide tablets: 5.9 for PRO
 vs. 37.7 for PLA, p = 0.49). There was no infection caused by probiotic strains recorded.

 Two recent studies in murine model showed, that bacteria in the gut enhance the body's immune
 response to cancer, mobilizing immune cells to kill cancer cells, not just in the gut but
 throughout the body as well. The researchers also found that the bacteria affect the efficacy
 of three different cancer treatments.

 Given their low toxicity, good tolerability, probiotics may be an important part of
 supportive therapy and moreover they can enhance efficacy of anticancer therapy. The
 objective of this phase III. trial is to determine effectiveness of the probiotic formula
 PROBIO-FIX INUM® in the prophylaxis of irinotecan induced diarrhea due to reduction
 intestinal beta-D-glucuronidase activity and further biochemical and physiological actions of
 specific strains Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus
 GG®, LGG® that are active substances of used food supplement - PROBIO-FIX INUM®. Both of
 strains are well-documented. LGG® has been studied in more over 800 scientific publications.
 Studies have found that LGG® supports immunity, enhances antibody formation during viral
 infection, and decreases incidence of gastrointestinal infections, antibiotic associated
 diarrhoea, and respiratory infections. In addition to its well-researched health benefits,
 the safety of LGG® has been more widely studied than any other probiotic bacterium. It has a
 safe history of use in foods and is extensively documented in more over 200 clinical studies.

 The large number of clinical studies and scientific publications indicate that the BB-12®
 probiotic strain - alone or in combination with other of probiotic strains (e.g. LGG®) - may
 have beneficial effects regarding the gastrointestinal and immune areas. BB-12® is considered
 to be best studied probiotic bifidobacteria, described in more than 360 scientific studies.
Inclusion Criteria:

 -  signed written informed consent

 -  age > 18 years

 -  histologically proven colorectal cancer patients starting new line of chemotherapy
 based on irinotecan

 -  ECOG PS 0 - 1 at study entry

 -  life expectancy more than 3 months

 -  absence of any psychological, familial, sociological or geographical condition
 potentially hampering compliance with the study protocol and follow-up schedule;

 Exclusion Criteria:

 -  impossibility to take oral medication

 -  active infection treated by antibiotic therapy

 -  ileostoma

 -  hypersensitivity to study drug

 -  any concurrent malignancy other than non-melanoma skin cancer, no other cancer in past
 5 years.

 -  serious concomitant systemic disorders or diseases incompatible with the study (at the
 discretion of investigator )