Introduction

Diarrhea is one of the most common adverse events of cancer therapies and, when severe, it may even cause the temporary suspension or the interruption of these drugs, limiting the treatment chances and potentially the survival of patients¹. Moreover, immune-checkpoint inhibitors (ICI) are often associated to a more severe clinical picture of inflammatory condition (ICI-related colitis), which may require immunosuppressive treatments and hospitalization.²
An increasing body of evidence suggests that the manipulation of gut microbiome, mainly fecal microbiota transplantation (FMT), but also antibiotics and pre-probiotics, may represent a promising therapeutic strategy for diarrhea and colitis associated with cancer therapies, but these options are rarely applied into clinical practice.

Aims & Methods

Our aim is to evaluate whether an approach based on the modulation of gut microbiome can be an effective strategy for the treatment of diarrhea and colitis related to ICI treatment in cancer patients.
In this study, carried out from January 2023 to January 2024, we evaluated the efficacy of microbiome-modulating therapeutics (antibiotics, probiotics, FMT) in cancer patients referred to our Microbiome Clinic, under indication of their oncologists, for diarrhea and colitis related to ICI.
All patients underwent first a clinical evaluation to establish the severity of the symptoms and the oncological history, and then received a microbiome-modulating therapy. All patients were followed up to at least 4 weeks after the prescription of the therapy. We collected the following data of patients: age, gender, type of cancer, oncological therapy and its suspension, severity of diarrhea (graded via CTCAE) and its onset since the start of the oncological therapy.

Results

Overall nineteen patients were enrolled in the study period (6 males, 13 females, mean age 54 years-old). Of them, 10 (53%) had Breast cancer, 3 (16%) Lung cancer, 2 (10%) Non-Melanoma Skin Cancer, 2 (10%) Kidney cancer, 1 (5%) Melanoma and 1 (5%) Cervix cancer. All the patients were treated with ICI (12 Pembrolizumab, 2 Atezolizumab, 1 Trastuzumab, 1 Nivolumab, 1 Mogamulizumab, 1 Cemiplimab, 1 Ipilimumab). Four patients had a G1 diarrhea (21%), seven (37%) G2, and eight (42%) G3. Twelve (63%) patients had to interrupt their immunotherapy due to diarrhea.
Multi-species probiotics were given in 10 (59%) patients, rifaximin in 6 (35%). Systemic steroids were necessary only in 10 patients (59%). At 4-week follow-up, 16 patients (94%) had a resolution of the diarrhea (G0), and 50% of the patients who had to interrupt their oncological therapy because of the diarrhea severity were then able to continue the treatment.
Moreover, two patients, referred from another Centre (Pavia University) for ICI-related colitis refractory to steroids and biologics, were successfully treated with FMT, and were able to continue ICI.

Conclusion

An approach based on gut microbiome modulation can be an effective strategy to treat ICI-related diarrhea and colitis, and may potentially reduce the need for steroids. Our preliminary findings should be confirmed by more consolidated and well designed studies.

References

1. He, Y., Zheng, J., Ye, B., Dai, Y. & Nie, K. Chemotherapy-induced gastrointestinal toxicity: Pathogenesis and current management. Biochem Pharmacol 216, 115787 (2023).
2. Adiwinata, R. et al. Immune Checkpoint Inhibitor Colitis, a Rising Issue in Targeted Cancer Therapy Era: A Literature Review. Rom J Intern Med (2024) doi:10.2478/rjim-2024-0015.
3. Hoang, J. et al. Preliminary Analysis of Gut Microbiome and Gastrointestinal Symptom Burden in Breast Cancer Patients Receiving Chemotherapy Compared to Healthy Controls. Biol Res Nurs 26, 219–230 (2024).

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.