Role of the Gut Microbiome in Anti-tumor Therapy Induced Diarrhea

Hepatocellular carcinoma (HCC) is the 5th most common tumor worldwide and the second most frequent cause of cancer-related death globally. HCC represents about 90% of primary liver cancers and constitutes a major global health problem.Therapeutic approaches depend on the stage of the disease. In the last decade systemic therapy approaches complement surgical and locoregional treatment in advanced disease stages.

The current first-line drug class used to treat locally advanced and metastasized HCC are tyrosine kinase inhibitors (TKIs). At the moment the multikinase inhibitors sorafenib, lenvatinib and regorafenib are licensed in Austria for treatment of HCC: TKIs are a class of small molecule drugs that block the intracellular signals which drive proliferation in many malignant cells by specifically inhibiting the kinase function of individual intracellular pathways involved in receptor-mediated growth signaling.Diarrhea is one of the most common side effects of TKIs, that often prevents optimal dosage and thereby limits efficacy of systemic cancer therapy. Mechanisms of TKI induced diarrhea are largely unknown, speculations span from induction of exocrine pancreatic insufficiency leading to vitamin malabsorption and hypophosphatemia to enterocyte malfunction. Recently, accumulating data suggest that the composition of gut microbiome may also affect efficacy and toxicity of cancer therapy. In a small pilot study (n=25) patients who did not develop diarrhea under TKI had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae. To the best of our knowledge, microbiome composition in patients with TKI induced diarrhea has not been studied in detail yet. However, this information is of clinical relevance since the manipulation of the gut microbiota through antibiotics, probiotics, prebiotics or fecal transplantation is an interesting strategy to improve efficacy and mitigate toxicity of anticancer drugs such as TKI. Probiotics for example have been shown to be able to prevent and treat diarrhea and may therefore be a valuable option to prevent or treat TKI-induced side effects.

In 2019 around 5000 Austrian citizens were diagnosed with lung cancer. The diagnosis is associated with a very poor prognosis compared to other malignant diseases. However, the introduction of checkpoint inhibitors has led to a revolutionary improvement in prognosis for those that respond.

Immune-Checkpoints are immunologic pathways that are used by tumor cells to evade destruction by immune cells. The most important checkpoints to date are programmed death ligand 1 (PDL-1), cytotoxic T lymphocyte antigen-4 (CTLA-4) and TIGIT. Antagonization of these check points by monoclonal antibodys can largely improve antineoplastic efficacy of immune cells.

These immune checkpoint inhibitors (ICI) are essential part of modern neoadjuvant, adjuvant and palliative oncologic therapy concepts. ICI-treatment may lead to remarkable responses. However, 60 to 80 percent of patients do not respond to therapy.Although Tumor-PDL-1 level has shown some predictive value and is therefore used in clinical praxis it cannot predict response reliably.

Many preclinical and clinical trials showed evidence of relevant impact of the composition of the microbiome of the gut and response to ICI. Therefore, the microbiome of the gut may be promising biomarker and even possible target for intervention to predict and improve ICI response in the future. However, the exact optimal composition of the gut microbiome and the strategies for intervention are still unclear.

• stool zonulin [Time frame: 4-12 weeks]
• stool calprotectin [Time frame: 4-12 weeks]
• serum lipopolysaccharide binding protein [Time frame: 4-12 weeks]
• serum soluble cluster of differentiation (CD)14 [Time frame: 4-12 weeks]
• Bristol stool scale (BSS) [Time frame: 4-12 weeks]
• gastrointestinal quality of life (GIQLI) [Time frame: 4-12 weeks]