Randomized double-blind, placebo-controlled multicenter phase III study of prevention of irinotecan-induced diarrhea by a probiotic mixture containing Bifidobacterium BB-12®Lactobacillus rhamnosus LGG® in colorectal cancer patients

Michal Mego; Radoslav Danis; Jozef Chovanec; Silvia Jurisova; Branislav Bystricky; Stefan Porsok; Peter Konkolovsky; Vladimir Vaclav; Maria Wagnerova; Marian Streško; Bibiana Brezinova; Mária Rečková; Dagmar Sutekova; Natalia Pazderova; Mária Novisedlakova; Eva Zomborska; Sona Ciernikova; Daniela Svetlovska; Lubos Drgona

doi:10.3389/fonc.2023.1168654

Randomized double-blind, placebo-controlled multicenter phase III study of prevention of irinotecan-induced diarrhea by a probiotic mixture containing Bifidobacterium BB-12^®Lactobacillus rhamnosus LGG^® in colorectal cancer patients

Front Oncol. 2023 Aug 4:13:1168654. doi: 10.3389/fonc.2023.1168654. eCollection 2023.

Authors

Michal Mego¹, Radoslav Danis², Jozef Chovanec³, Silvia Jurisova¹, Branislav Bystricky⁴, Stefan Porsok¹, Peter Konkolovsky⁵, Vladimir Vaclav⁶, Maria Wagnerova⁷, Marian Streško⁸, Bibiana Brezinova⁹, Mária Rečková¹⁰, Dagmar Sutekova¹¹, Natalia Pazderova¹, Mária Novisedlakova^{1

6}, Eva Zomborska¹, Sona Ciernikova¹², Daniela Svetlovska¹, Lubos Drgona¹

Affiliations

¹ Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia.
² Faculty of Medicine, Comenius University, Bratislava, Slovakia.
³ Department of Oncology, St. Jacob Hospital, Bardejov, Slovakia.
⁴ Department of Oncology, Faculty Hospital, Trencin, Slovakia.
⁵ Department of Oncology, Regional Cancer Center, Komarno, Slovakia.
⁶ Department of Oncology, University Hospital Milosrdni Bratia, Bratislava, Slovakia.
⁷ Department of Oncology, East Slovakia Comprehensive Cancer Center, Kosice, Slovakia.
⁸ Department of Oncology, Faculty Hospital, Trnava, Trebisov, Slovakia.
⁹ Department of Oncology, Trebisov Hospital, Trnava, Slovakia.
¹⁰ Department of Oncology, Regional Cancer Center, Poprad, Slovakia.
¹¹ Department of Oncology, University Hospital Martin, Martin, Slovakia.
¹² Biomedical Center, Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.

Abstract

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.

Keywords: beta-glucuronidase; colorectal cancer; diarrhea; irinotecan; probiotics.

Copyright © 2023 Mego, Danis, Chovanec, Jurisova, Bystricky, Porsok, Konkolovsky, Vaclav, Wagnerova, Streško, Brezinova, Rečková, Sutekova, Pazderova, Novisedlakova, Zomborska, Ciernikova, Svetlovska and Drgona.

Grants and funding

This study was funded by S&D Pharma, Slovakia. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.