Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines.

PURPOSE: The 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). METHODS: A 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. RESULTS: A 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. CONCLUSIONS: Of 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.

Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer.

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model.

BACKGROUND: The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. OBJECTIVES: The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. METHODS: Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. RESULTS: AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. CONCLUSIONS: This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling.

Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats.

Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 µM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC-dextran 2 hr before cull, and serum levels of FITC-dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT-PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.

Tight junction defects are seen in the buccal mucosa of patients receiving standard dose chemotherapy for cancer.

PURPOSE: Oral mucositis is one of the most common and debilitating side effects of chemotherapy treatment. Patients are often unable to eat and drink, which can lead to poor clinical outcomes and extensive resource utilisation. The primary aim of this study was to determine the molecular integrity of oral epithelial tight junctions in patients undergoing chemotherapy. The secondary aim was to correlate these changes with proinflammatory cytokines and matrix metalloproteinase profiles. METHODS: Patients (n = 23) were recruited from the Royal Adelaide Hospital between 2000 and 2003. Reach patient underwent two oral buccal mucosa biopsies (4 mm): one prior to chemotherapy treatment and a second one after chemotherapy treatment. Oral buccal mucosa biopsies were also taken from seven healthy volunteers with no history of cancer, chemo- or radiotherapy treatment or inflammatory disorders. Routine haematoxylin and eosin staining was performed to determine epithelial thickness. Immunohistochemical staining was performed for claudin-1, zonular occludens-1, occludin, interleukin-1ß, tumour necrosis factor, interleukin-6, matrix metalloproteinase-2 and metalloproteinase-9. RESULTS: Patients receiving standard dose chemotherapy had significant epithelial atrophy. Elevations in all cytokines and matrix metalloproteinases were seen, with significant lamina propria staining for interleukin-6 and tumour necrosis factor. Matrix metalloproteinase-2 appeared most upregulated within the oral epithelium. These changes coincided with altered tight junction staining properties. Changes in the staining intensity and localisation were both noted, with clear cytoplasmic staining for zonular occludens-1 and claudin-1 in patients treated with chemotherapy. CONCLUSIONS: Chemotherapy causes defects in oral tight junctions, coupled with altered cytokine and matrix metalloproteinase profiles. Tight junction disruption in the epithelium may contribute to ulcer development or lead to poor tissue integrity, and the timing of these events may be a target for preventative treatment.

Management of Mucositis During Chemotherapy: From Pathophysiology to Pragmatic Therapeutics.

Chemotherapy-induced mucositis is a common condition caused by the breakdown of the mucosal barrier. Symptoms can include pain, vomiting and diarrhoea, which can often necessitate chemotherapy treatment breaks or dose reductions, thus compromising survival outcomes. Despite the significant impact of mucositis, there are currently limited clinically effective pharmacological therapies for the pathology. New emerging areas of research have been proposed to play key roles in the development of mucositis, providing rationale for potential new therapeutics for the prevention, treatment or management of chemotherapy-induced mucositis. This review aims to address these new areas of research and to comment on the therapeutics arising from them.

Guidelines for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a systematic review of murine transplantation protocols.

Fecal microbiota transplant (FMT) is a powerful tool used to connect changes in gut microbial composition with a variety of disease states and pathologies. While FMT enables potential causal relationships to be identified, the experimental details reported in preclinical FMT protocols are highly inconsistent and/or incomplete. This limitation reflects a current lack of authoritative guidance on reporting standards that would facilitate replication efforts and ultimately reproducible science. We therefore systematically reviewed all FMT protocols used in mouse models with the goal of formulating recommendations on the reporting of preclinical FMT protocols. Search strategies were applied across three databases (PubMed, EMBASE, and Ovid Medline) until June 30, 2020. Data related to donor attributes, stool collection, processing/storage, recipient preparation, administration, and quality control were extracted. A total of 1753 papers were identified, with 241 identified for data extraction and analysis. Of the papers included, 92.5% reported a positive outcome with FMT intervention. However, the vast majority of studies failed to address core methodological aspects including the use of anaerobic conditions (91.7% of papers lacked information), storage (49.4%), homogenization (33.6%), concentration (31.5%), volume (19.9%) and administration route (5.3%). To address these reporting limitations, we developed theGuidelines for Reporting Animal Fecal Transplant (GRAFT) that guide reporting standards for preclinical FMT. The GRAFT recommendations will enable robust reporting of preclinical FMT design, and facilitate high-quality peer review, improving the rigor and translation of knowledge gained through preclinical FMT studies.

Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome.

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.

Prophylactic probiotics for cancer therapy-induced diarrhoea: a meta-analysis.

PURPOSE OF REVIEW: Strong preclinical data support prophylactic probiotics as an effective preventive strategy for diarrhoea secondary to anticancer therapies. To determine the composite evidence that this approach translates to the clinic, we performed a meta-analysis of randomized controlled trials (RCTs) of prophylactic probiotics for the prevention of cancer therapy-induced diarrhoea. RECENT FINDINGS: A three-step search strategy was used to identify relevant studies (1 June 2000-1 June 2017) investigating probiotic intervention for diarrhoea secondary to any cancer therapy (cytotoxic, targeted and immunotherapies). RCTs across PubMed, Embase, CINAHL and CENTRAL were assessed for eligibility and assessed using RevMan 5.3 (The Cochrane Collaboration). Seven trials with a total of 1091 patients were included in this meta-analysis. Compared with placebo, prophylactic probiotics did not prevent or reduce the overall incidence of diarrhoea or severe CTCAE Grade at least 3 diarrhoea [relative risk (RR) = 0.81, 95% confidence interval (95% CI) = 0.60-1.09, Z = 1.41, P = 0.16; RR = 0.54, 95% CI = 0.25-1.16, Z = 1.58, P = 0.11], nor did it influence the use of rescue medication (RR = 0.93, 95% CI = 0.53-1.65, Z = 0.24, P = 0.81). SUMMARY: Current evidence does not support widespread implementation of probiotics for diarrhoea secondary to cytotoxic therapy and the tyrosine kinase inhibitor, dacomitinib. Research efforts should be diverted to pair specific forms of gastrointestinal toxicity and their unique microbial phenotype to develop the ideal microbial protectant.

Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report.

PURPOSE: Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth. METHODS: Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4× per day up to 72 h post-treatment. RESULTS: At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan-induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001). CONCLUSIONS: (-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation.

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea.

We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4-/-) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4-/- BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4-/- BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4-/- mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm2; P = 0.0008). No change was seen in Tlr4-/- mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4-/- mice at 24 hours (wild-type: 100.35 ± 18.37 µA/cm2; P = 0.022; Tlr4-/-: 102.72 ± 18.80 µA/cm2; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767-79. ©2016 AACR.

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms.

Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (-/-) BALB/c mice weighing between 18 and 25 g (10-13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4(-/-billy) mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4(-/-billy) (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4(-/-billy) mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376-86. ©2016 AACR.

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis.

Diarrhoea is a common, debilitating and potentially life threatening toxicity of many cancer therapies. While the mechanisms of diarrhoea induced by traditional chemotherapy have been the focus of much research, the mechanism(s) of diarrhoea induced by small molecule ErbB TKI, have received relatively little attention. Given the increasing use of small molecule ErbB TKIs, identifying this mechanism is key to optimal cancer care. This paper critically reviews the literature and forms a hypothesis that diarrhoea induced by small molecule ErbB TKIs is driven by intestinal chloride secretion based on the negative regulation of chloride secretion by ErbB receptors being disrupted by tyrosine kinase inhibition.

Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity.

Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits.