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

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.

Figure 1

Flow diagram.

Figure 2

Kaplan–Meier estimates of probabilities of diarrhea-free survival according to probiotic administration (N = 233). Patients on probiotic arm had non-significantly better diarrhea-free survival as compared to patients on placebo arm HR = 0.86, 95%CI 0.57 – 1.28, p = 0.45.

Figure 3

Kaplan–Meier estimates of probabilities of grade 3/4 diarrhea-free survival according to probiotic administration (N = 233). Patients on probiotic arm had non-significantly better diarrhea-free survival as compared to patients on placebo arm HR = 0.63, 95%CI 0.27 – 1.48, p = 0.30.

Figure 4

Kaplan–Meier estimates of probabilities of diarrhea-free survival in patients with colostomy according to probiotic administration (N = 233). Patients on probiotic arm had significantly better diarrhea-free survival as compared to patients on placebo arm HR = 0.41, 95%CI 0.18 – 0.95, p = 0.05.

Figure 5

Kaplan–Meier estimates of probabilities of grade 3/4 diarrhea-free survival in patients with colostomy according to probiotic administration (N = 233). Patients on probiotic arm had significantly better diarrhea-free survival as compared to patients on placebo arm; 6-week diarrhea-free survival for probiotics vs. placebo 100.0% vs. 80.3%, p = 0.03.