RESUMO
Background: Probiotics could decrease irinotecan-induced diarrhea due to the reduction of intestinal beta-d-glucuronidase activity. This study included a combined analysis of two clinical trials aimed to determine the effectiveness of the probiotics in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer (CRC) patients. Methods: This combined analysis included 46 patients with CRC enrolled in the Probio-SK-003 (NCT01410955) and 233 patients from Probio-SK-005 (NCT02819960) starting a new line of irinotecan-based therapy with identical eligibility criteria. Patients were randomized in a ratio 1:1 to probiotic formulas vs. placebo administered for 12 and 6 weeks, respectively. Due to the different durations of study treatments, only the first 6 weeks of therapy were used for analysis. Results: In total, 279 patients were randomized, including 142 patients in the placebo and 137 participants in the probiotic arm. Administration of probiotics did not significantly reduce the incidence of grade 3/4 diarrhea compared to placebo (placebo 12.7% vs. probiotics 6.6%, p = 0.11). Neither the overall incidence of diarrhea (placebo 48.6% vs. probiotics 41.6%, p = 0.28) nor the incidence of enterocolitis (placebo 4.2% vs. probiotics 0.7%, p = 0.12) was different in the placebo vs. probiotic arm. However, subgroup analysis revealed that patients with a colostomy who received a placebo had a significantly higher incidence of any diarrhea (placebo 51.2% vs. probiotics 25.7%, p = 0.028) and grade 3/4 diarrhea (placebo 14.6% vs. probiotics 0.0%, p = 0.03) compared to the probiotic arm. Conclusions: This combined analysis suggests that probiotics could be beneficial in the prevention of irinotecan-induced diarrhea in colorectal cancer patients with colostomy.
RESUMO
Background: The incidence of irinotecan-induced diarrhea varies between 60-90%, by which the incidence of severe diarrhea is 20-40%. The objective of this phase III trial was to determine the effectiveness of the probiotic mixture containing Bifidobacterium, BB-12® and Lactobacillus rhamnosus, LGG® in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer patients due to a reduction in the activity of intestinal beta-D-glucuronidase. Methods: From March 2016 to May 2022, a total of 242 patients with colorectal cancer starting a new line of irinotecan-based therapy were registered to the study in 11 cancer centers in Slovakia. Patients were randomized in a ratio 1:1 to probiotic formula vs. placebo that was administered for 6 weeks. Each capsule of Probio-Tec® BG-Vcap-6.5 contained 2.7x109 colony-forming units (CFU) of 2 lyophilized probiotic strains Bifidobacterium, BB-12® (50%) and Lactobacillus rhamnosus GG, LGG® (50%). Results: Administration of probiotics compared to placebo was not associated with a significant reduction of grade 3/4 diarrhea (placebo arm 11.8% vs. probiotic arm 7.9%, p=0.38). Neither the overall incidence of diarrhea (46.2% vs. 41.2%, p=0.51) nor the incidence of enterocolitis (3.4% vs. 0.9%, p=0.37) was different in the placebo vs. probiotic arm. Subgroup analysis revealed that patients with colostomy had higher incidence of any diarrhea and grade 3/4 diarrhea in the placebo arm compared to the probiotic arm (48.5% vs. 22.2%, p=0.06 and 15.2% vs. 0%, p=0.06, respectively). Moreover, patients on probiotic arm had significantly better diarrhea-free survival (HR = 0.41, 95%CI 0.18 - 0.95, p=0.05) and needed less loperamide (p=0.01) compared to patients on placebo arm. We did not observe any infection caused by probiotic strains used in this study. Conclusion: This study failed to achieve its primary endpoint, and results suggest a lack of benefit of administered probiotic formula for the prevention of irinotecan-induced diarrhea. However, subgroup analysis suggests a possible benefit in patients with colostomy.
RESUMO
PURPOSE: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. METHODS: Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus™, was administered at a dose of 10×10(9)CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. RESULTS: Twenty-three 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 antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. CONCLUSIONS: Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity.