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Small molecule receptor tyrosine kinase inhibitors (SM-TKIs) are among a group of targeted cancer therapies, intended to be more specific to cancer cells compared with treatments, such as chemotherapy, hence reducing adverse events. Unfortunately, many patients report high levels of diarrhea, the pathogenesis of which remains under investigation. In this article, we compare the current state of knowledge of the pathogenesis of chemotherapy-induced diarrhea (CID) in comparison to SM-TKI–induced diarrhea, and investigate how a similar research approach in both areas may be beneficial. To this end, we review evidence that both treatment modalities may interact with the gut microbiome, and as such the microbiome should be investigated for its ability to reduce the risk of diarrhea.

PurposeLapatinib is a small molecule tyrosine kinase inhibitor used to treat breast cancer, often in combination with chemotherapy. Diarrhoea commonly occurs in up to 78% of patients undertaking lapatinib treatment. The mechanism of this diarrhoea is currently unknown. Elsiglutide is a GLP-2 analogue known to increase cell proliferation and reduce apoptosis in the intestine.MethodsWe used a previously developed rat model of lapatinib-induced diarrhoea to determine if co-treatment with elsiglutide was able to reduce diarrhoea caused by lapatinib. Additionally, we analysed the caecal microbiome of these rats to assess changes in the microbiome due to lapatinib.ResultsRats treated with lapatinib and elsiglutide had less severe diarrhoea than rats treated with lapatinib alone. Serum lapatinib levels, blood biochemistry, myeloperoxidase levels and serum limulus amebocyte lysate levels were not significantly different between groups. Rats treated with lapatinib alone had significantly higher histopathological damage in the ileum than vehicle controls. This increase was not seen in rats also receiving elsiglutide. Rats receiving lapatinib alone had lower microbial diversity than rats who also received elsiglutide.ConclusionsElsiglutide was able to reduce diarrhoea from lapatinib treatment. This does not appear to be via reduction in inflammation or barrier permeability, and may be due to thickening of mucosa, leading to increased surface area for fluid absorption in the distal small intestine. Microbial changes seen in this study require further research to fully elucidate their role in the development of diarrhoea.

Introduction Diarrhoea caused by treatment with receptor tyrosine kinase inhibitors (TKI) targeting Epidermal Growth Factor Receptors (EGFR) is an important clinical toxicity in oncology that remains poorly understood. This study aimed to identify histological and molecular changes within the intestine following lapatinib to elucidate mechanisms of diarrhoea related to treatment with this dual EGFR TKI. Methods and materials Male albino Wistar rats were orally gavaged lapatinib at 100, 240 or 500 mg/kg daily for 4 weeks and assessed for indicators of gastrointestinal injury at the end of each week. Lapatinib in combination with weekly paclitaxel (9 mg/kg i.p.) was also assessed for cumulative injury. At each time point, blood was collected for biochemical analysis. Sections or jejunum and colon were also collected and underwent immunohistochemistry and RT-PCR to detect markers of EGFR pathway signalling, and morphometric analysis to assess changes in mucosal architecture. Results Lapatinib (with or without paclitaxel co-treatment) caused dose-dependent changes in crypt length, mitotic rate and goblet cell morphology. Jejunal crypt expression of EGFR and ErbB2 were decreased, whilst no changes in Erk1/2 were observed. Markers of apoptosis (caspase-3) and proliferation (Ki-67) were only significantly altered in rats treated with both lapatinib and paclitaxel. Conclusions In our novel rat model of lapatinib-induced diarrhoea we have shown that changes in small intestinal morphometry and expression of EGFR are associated with diarrhoea. Further research is required to test intervention agents for the prevention of diarrhoea.

Purpose A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients’ regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. Methods This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. Results Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. Conclusion This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.

PurposeThe aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM).MethodsA systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible.ResultsA total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged.ConclusionsOf the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.

Purpose A common side effect of chemotherapy treatment is diarrhoea. Unfortunately, the underlying mechanisms of chemotherapy-induced diarrhoea (CD) are poorly understood. We aimed to determine if faecal microbes of CD patients were displaced, if faecal calprotectin increased during CD and if there were alterations in circulating matrix metalloproteinases, nuclear factor kappa B (NF-κB), IL-1β and TNF. Patients and methods Twenty-six cancer patients receiving chemotherapy were enrolled and requested to provide stool samples and blood samples at various times during their chemotherapy cycle. Stool samples were analysed using conventional culture techniques and qRT-PCR. ELISA kits determined faecal calprotectin levels, levels of circulating matrix metalloproteinases and circulating NF-κB, IL-1β and TNF. Results The majority of patients with CD showed decreases in Lactobacillus spp., Bifidobacterium spp., Bacteroides spp. and Enterococcus spp. Increases were observed in Escherichia coli and Staphylococcus spp. Methanogenic archaea were also quantified, with all patients except one showing a decrease. Faecal calprotectin levels were increased in 81.25 % of patients with CD. Circulating MMP-3 and MMP-9 significantly increased following chemotherapy. Circulating levels of NF-κB, IL-1β and TNF were increased following chemotherapy, although this did not reach significance. Conclusions We demonstrated that CD is associated with marked changes in intestinal microflora, methanogenic archaea, matrix metalloproteinase and serum levels of NF-κB, IL-1β and TNF. These changes may result in diminished bacterial functions within the gut, altering gut function and initiating intestinal damage, resulting in the onset of diarrhoea. More importantly, these changes may provide clinicians with a possible new target for biomarkers of toxicity.