Chemotherapy-induced Diarrhea Research Articles

Efficacy of long-acting release octreotide for preventing chemotherapy-induced diarrhoea: protocol for a systematic review

IntroductionDiarrhoea is a common adverse effect induced by chemotherapy that can reduce the dose of chemotherapeutic drugs or interrupt the chemotherapy schedule. The current treatment strategies have various limitations. It...

Cannabinoids as gastrointestinal anti-inflammatory drugs.

In this mini-review, we focus on the potential of the endocannabinoid system as a target for novel therapies to treat gastrointestinal (GI) inflammation. We discuss the organization of the endocannabinoid signaling and present possible pharmacological sites in the endocannabinoid system. We also refer to recent clinical findings in the field. Finally, we point at the potential use of cannabinoids at low, non-psychoactive doses to counteract non-inflammatory pathological events in the GI tract, like chemotherapy-induced diarrhea, as evidenced by Abalo etal. in the rat model.

A prospective study of nutritional supplementation for preventing oral mucositis in cancer patients receiving chemotherapy.

Patients undergoing chemotherapy often develop distressing adverse effects such as oral mucositis and diarrhea. Nutritional support with elemental diet is effective against various gastrointestinal complications and may exert protective effects against adverse effects induced by chemotherapy. To evaluate the influence of elemental diet on chemotherapy-induced oral mucositis and diarrhea, we conducted a randomized control trial in patients with esophageal cancer undergoing chemotherapy. Twenty esophageal cancer patients receiving chemotherapy with 5-fluorouracil plus cisplatin were assigned randomly to one of the following two groups: (1) receiving elemental diet with Elental (one pack per day) for 14 days and (2) not receiving Elental during chemotherapy. The severity of oral mucositis and diarrhea was graded using clinical examination by doctors and a standard questionnaireon days 1-14. Based on the analysis of the standard questionnaire, the distribution of the maximum severity of oral mucositis showed a statistically significant reduction in the Elental group (p=0.020), while clinical examination showed insignificant reduction but shift toward lower grade. In the Elental group, the incidence of oral mucositis (grade >=2) reduced consistently and the median grade was lower at all-time points. Regarding diarrhea, no difference was observed between the two groups based on the analysis of the standard questionnaire and clinical examination results. This study illustrates the effectiveness of oral elemental diet in preventing oral mucositis during chemotherapy. This is a preliminary report and further study with larger patients groups should be devoted to optimization of efficacy.

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5mgkg-1 injection-1 , 1 injection day-1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2days, animals received also saline or 5-FU (150mgkg-1 injection-1 , cumulative dose of 300mgkg-1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.

HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens

Approximately 40% to 80% of patients receiving pertuzumab-directed therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer will develop chemotherapy-induced diarrhea (CID). Loperamide and octreotide are frequently used to treat CID after diarrhea occurs, but neither is used prophylactically or targets the underlying mechanism. Previous studies suggest blocking epidermal growth factor receptor may cause excess chloride secretion, resulting in diarrhea. Crofelemer is derived from the red latex of the Croton lechleri tree, blocks gastrointestinal cystic fibrosis transmembrane regulator and calcium-activated chloride channels, and is U.S. Food and Drug Administration approved for relief of diarrhea in HIV/AIDS patients on anti-retroviral therapy. Crofelemer is not systemically absorbed, has relatively few side effects, and presents a targeted approach at preventing CID in patients receiving pertuzumab-based therapy.HALT-D (DiarrHeA Prevention and ProphyLaxis with Crofelemer in HER2-Positive Breast Cancer Patients Receiving Trastuzumab, Pertuzumab, and Docetaxel or Paclitaxel with or without Carboplatin, NCT02910219) is a phase II, randomized, open-label trial that aims to recruit 46 patients from 3 MedStar sites. Adults with HER2-positive breast cancer being treated with trastuzumab, pertuzumab, and docetaxel or paclitaxel (THP) or trastuzumab, pertuzumab, docetaxel, and carboplatin (TCHP) will be randomized to receive crofelemer or no medication for diarrhea prophylaxis. The primary endpoint is incidence of all grade diarrhea for ≥ 2 consecutive days during cycles 1 to 2 of THP or TCHP. Secondary endpoints include overall incidence, duration, and severity of diarrhea; time to onset of diarrhea; use of other anti-diarrheal medications; stool frequency and consistency; and quality of life.HALT-D will provide important information about the feasibility and tolerability of crofelemer in preventing diarrhea for patients receiving THP or TCHP.

Diarrhea in Multiple Myeloma: A Review of the Literature.

One of the most common and inadequately managed symptoms that patients with multiple myeloma (MM) experience as a result of cancer treatment is diarrhea. Diarrhea in patients with MM often is severe enough to warrant dose reduction, delays, or discontinuation of chemotherapy. Short-term diarrhea can occur as a side effect of drugs, such as bortezomib (Velcade®) or panobinostat (Farydak®). Late-onset diarrhea from lenalidomide (Revlimid®) can occur 17-24 months after the start of therapy. Treatment of diarrhea is often by dose reduction and discontinuation of the offending drug. However, the symptom fails to entirely resolve with these interventions and dose reductions place the individual at risk for disease progression. Best practices for diarrhea management in MM are poorly understood, but diarrhea symptoms impede patient adherence and undermine quality of life. The purpose of this article is to review the etiology of the symptom of diarrhea in people with cancer, specifically MM. Management strategies also are discussed. A comprehensive review of CINAHL®, MEDLINE®, and PubMed databases was performed using the search terms diarrhea, chemotherapy, multiple myeloma, and cancer. Research studies, guidelines, and papers from peer-reviewed publications were considered. Although general guidelines from the American Society of Clinical Oncology and Oncology Nursing Society exist that suggest best practices in the management of chemotherapy-induced diarrhea, best practices to identify and manage diarrhea symptoms in patients with MM are lacking.

Diarrhea prevention and prophylaxis with crofelemer in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and docetaxel or paclitaxel with or without carboplatin.

TPS628Background: Chemotherapy-induced diarrhea (CID) occurs in 40-80% of breast cancer patients on HER2 directed therapy with THP or TCHP. In the CLEOPATRA trial, 67% of patients who received THP ...

Effect of Diversion Ileostomy on the Occurrence and Consequences of Chemotherapy-Induced Diarrhea.

The benefits of adjuvant chemotherapy in the treatment of colorectal cancer are well established. Chemotherapy-induced diarrhea is a common adverse effect of these regimens. The occurrence of chemotherapy-induced diarrhea not only directly affects patient health but may also compromise treatment efficacy because of consequent dosing alterations or discontinuation. This study aimed to investigate the effect of diverting loop ileostomy during chemotherapy on the occurrence and consequences of chemotherapy-induced diarrhea. This was a retrospective evaluation of a prospective surgical database. This was a single-institution retrospective study. All patients receiving curative adjuvant chemotherapy after anterior resection for colorectal cancer at Auckland Hospital from 2002 to 2013 were retrospectively evaluated. Patient-, perioperative-, and chemotherapy-related variables were collected. Chemotherapy-induced diarrhea occurrence was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events. Logistic regression analysis was performed to identify independent predictors for chemotherapy-induced diarrhea occurrence, treatment modifications, and hospital admission. A total of 109 identified patients received 691 chemotherapy cycles; 84% of patients with a diverting ileostomy experienced chemotherapy-induced diarrhea compared with 47% in those who were not defunctioned (p < 0.01). On logistic regression analysis, the presence of a diverting ileostomy during chemotherapy was an independent predictor of chemotherapy-induced diarrhea grade 3 or higher (OR, 13.6 (95% CI: 1.2-150.9); p = 0.02), the need for a dosing reduction (OR, 4.0 (95% CI: 1.3-12.4); p = 0.02), and the need for any modification in the chemotherapy regimen (OR, 3.4 (95% CI: 1.2-9.6); p = 0.02). This study is limited by its retrospective design, potentially limiting the accuracy of chemotherapy-induced diarrhea grade reporting. The presence of an ileostomy during adjuvant chemotherapy is a predictor of severe chemotherapy-induced diarrhea and the need for modifications in the chemotherapy regimen. This may have important consequences for long-term survival. Prospective investigation is needed to further assess the impact of diverting ileostomy on the delivery of chemotherapy and oncologic outcomes.

Pharmacologic Agents for Chronic Diarrhea.

Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

Bacterial Etiology of Diarrhea in Children Admitted in Hematologic Unit in a Tertiary Care Hospital

Introduction: Diarrhea is a frequent complication observed in patients with hematologic cancer. The normal fecal micro flora changes in chemotherapy-induced diarrhea, which shows a higher proportion of aerobic and oxygentolerant bacteria. Hence the causative bacterial pathogens maybe different than the usual etiology. Objectives: Therefore, the objective of the study was to find outthe etiology of diarrhea in children suffering from hematological malignancy and who are on chemotherapy. Material and Methods: A retrospective study was carried out on patients in hematologic unit of pediatric ward over a period of one and half years at a tertiary care hospital in Mumbai. A total of 55 stool samples from patients of hematological malignancy who presented with diarrhea, were included in this study. The samples were processed as per standard techniques and the bacterial pathogens were identified by standard biochemical tests. Results: Growth of pathogenic bacteria was seen in 15 (27.27%) stool samples, of which 13 patients had acute lymphatic leukemia(ALL) and only two patients had acute myeloid leukemia (AML). Among 15 growths, 11 grew Pseudomonas aeruginosa, two grew Morganella morganii and one each grew Aeromonas hydrophila and Klebsiella pneumoniae. Conclusion: Organisms usually considered as non pathogenic may cause disease in immunocompromised patients. Stool specimens of all leukemic patients suffering from diarrhea and on chemotherapy, should be sent routinely for culture, so as to find out the exact cause of diarrhea.

Oral-ingestion-of-spondias-pinnata-bark-extract-trim-down-severity-of-small-intestinal-mucositis

Chemotherapy-induced diarrhea (CID) is a common side effect of cancer treatment and can cause significant morbidity and mortality. The experimental procedure included an oral treatment with S. pinnata bark extract prior (100 mg/Kg/day) or after (100 and 200 mg/ kg body wt.) the induction of a rat mucositis model by injecting a single dose of etoposide (i.p) and treated with S. pinnata bark extract (100 and 200 mg/ kg body wt.) for next 72 hrs. Treatment efficacy was determined by changes in the intestinal morphology and biochemical parameters such as intestinal TNF-α, Interleukin-6 (IL-6) and sodium potassium ATPase after 72 hr, with and without intervention. There was a significant increase in the IL-6 and TNF-α levels and a significant decrease in sodium potassium ATPase activities in intestinal tissue after etoposide injection. However, in the post treatment groups (in both 100 and 200 mg), IL-6 and TNF-α levels reverted back to that of normal. In study group, the animals exposed to Pre and post treatment with S. pinnata extract (100 mg/kg body wt), histological studies showed that S. pinnata bark extract intervention was able to restore the normal morphology and intestinal sodium potassium ATPase activity. The results suggest that S. pinnata bark extract has potentials to prevent the toxic effects of etoposide which expedites to mucositis.

Exogenous IL-1Ra attenuates intestinal mucositis induced by oxaliplatin and 5-fluorouracil through suppression of p53-dependent apoptosis.

Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of many chemoagents, resulting in weight loss, diarrhea, and even death. The current treatments for CIM are palliative and have limited benefit. Interleukin-1 receptor antagonist is a natural antagonist of interleukin-1. Our previous studies showed the protective effect of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on the intestine in mice after 5-fluorouracil chemotherapy. In this study, we further evaluated rhIL-1Ra in the treatment of CIM induced by different chemoagents and their combination. Normal as well as tumor-bearing mice were administered oxaliplatin (L-OHP), 5-fluorouracil, or their combination to induce intestinal mucositis and mortality. rhIL-1Ra administered after the chemotherapy, but not after the onset of diarrhea, significantly improved mouse survival, attenuated body weight loss, and reduced the incidence, severity, and duration of diarrhea. Histological examination showed that rhIL-1Ra-treated mice had a relatively intact mucosa structure, more proliferating crypt cells, and higher acid mucin content than the vehicle-treated mice. rhIL-1Ra suppressed crypt apoptosis by reducing the levels of proapoptotic proteins in wild-type, but not in IL-1RI or p53 mice. In addition, rhIL-1Ra was as effective as octreotide acetate in the treatment of chemotherapy-induced diarrhea, but with the advantage of reducing the epithelial apoptosis, the major cause of CIM. Importantly, the tumor sensitivity to chemotherapy was not affected by rhIL-1Ra. Thus, our data strongly suggest that rhIL-1Ra may be useful for the treatment of intestinal mucositis and improving the quality of life for cancer patients on chemotherapy.

Oral Hydration As a Post-Hydration Method for Cisplatin (Cddp) Administration in Patients with Lung Cancer: a Prospective Multicenter Trial

ABSTRACT Aim: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous (IV) hydration after CDDP administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years, and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant and dexamethasone. CDDP was administered after IV pre-hydration with MgSO4 (8 mEq) and KCL. Five hundred milliliters of commercially available oral hydration solution (OS-1®: Otsuka Pharmaceutical Factory, Inc., Japan) was used as a substitute for IV post-hydration and was administered orally within an hour after CDDP administration. OS-1® contains 50 mEq/L of NaCl, 20 mEq/L of K and 2 mEq/L of MgSO4. The primary endpoint was the proportion of patients without a grade (G) 2 or higher creatinine (Cr) elevation after the first cycle of chemotherapy. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 64 (33-74) years were enrolled from three institutions. Of these, 5 received adjuvant chemotherapy, 17 received definitive chemoradiotherapy, and 24 received chemotherapy for advanced diseases. All the patients were able to consume OS-1® within 1 hour without requiring IV post-hydration. The median (range) number of chemotherapy cycles was 4 (3-5). Seven patients received additional IV hydration on day 2 or later, with a median duration (range) of 2 (1-19) days, mainly because of chemotherapy-related anorexia. After the first cycle of CDDP administration, none of the patients experienced a Cr elevation of G 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%) completed the CDDP-based chemotherapy without G 2 or higher renal dysfunction. The only patient who experienced a G 2 elevation in Cr (maximum value, 1.97 mg/dL) experienced G 3 chemotherapy-induced diarrhea and exhibited a prompt improvement in the Cr level to 1.11 mg/dL after the resolution of the diarrhea. Conclusions: Oral hydration can be used as a safe and convenient substitute for IV post-hydration for CDDP administration at the standard dose. Disclosure: K. Kubota: Honoraria from TAIHO PHARMACEUTICAL CO., LTD.; All other authors have declared no conflicts of interest.

Risk and outcomes of chemotherapy-induced diarrhea (CID) among patients with colorectal cancer receiving multi-cycle chemotherapy.

Diarrhea is a common toxicity of chemotherapy, but the practice of reporting only severe grades (≥ 3) in clinical trials results in misleading conclusions of significance. Epidemiology remains poorly described, and effects of multi-cycle regimens have not been investigated. To better understand the risks, symptom burden and consequences of CID, we studied patients receiving chemotherapy for colorectal cancer (CRC). One hundred and fourteen patients receiving FOLFOX (95 patients, 530 cycles), FOLFOX + monoclonal antibodies (10 patients, 49 cycles) or FOLFIRI (9 patients, 50 cycles) were enrolled. CID was identified from diaries at baseline and daily during up to 8 chemotherapy cycles using supplemental questions on the Oral Mucositis Daily Questionnaire, a valid tool for collecting patient-reported outcomes of regimen-related mucosal injury. Patients scored CID severity from 0 "none" to 10 "worst possible," and quantity from "little" to "severe" on a 5-point scale. Quality of life was measured using the FACT-G, and fatigue using the FACIT fatigue scale. CID occurred in 89% of patients on FOLFIRI, 50% on FOLFOX + monoclonal antibodies and 56% on FOLFOX alone. The risk of a first episode was highest during Cycle 1 (35 %) and dropped to <10% during Cycles 3-5. Patients with CID reported poorer quality of life scores than those without CID (77.1 vs 80.7). Diarrhea occurs more commonly than typically appreciated during chemotherapy for CRC. Risk is highest during first exposure, suggesting variable susceptibility. Identification of this high-risk subgroup for prophylaxis could improve the quality of life.

Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications.

Gastrointestinal mucositis is defined as inflammation and/or ulcers of the gastrointestinal tract occurring as a complication of chemotherapy and radiation therapy, and affects about 50% of all cancer patients. To assess the role of gut microbiota in the pathogenesis of gastrointestinal mucositis and the potential for manipulations of the microbiota to prevent and to treat mucositis. Search of the literature published in English using Medline, Scopus and the Cochrane Library, with main search terms 'intestinal microbiota', 'bacteremia', 'mucositis', 'chemotherapy-induced diarrhoea', 'chemotherapy-induced mucositis', 'radiotherapy-induced mucositis'. The gut microbiota plays a major role in the maintenance of intestinal homoeostasis and integrity. Patients receiving cytotoxic and radiation therapy exhibit marked changes in intestinal microbiota, with most frequently, decrease in Bifidobacterium, Clostridium cluster XIVa, Faecalibacterium prausnitzii, and increase in Enterobacteriaceae and Bacteroides. These modifications may contribute to the development of mucositis, particularly diarrhoea and bacteraemia. The prevention of cancer therapy-induced mucositis by probiotics has been investigated in randomised clinical trials with some promising results. Three of six trials reported a significantly decreased incidence of diarrhoea. One trial reported a decrease in infectious complications. The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms. Better knowledge of these effects may lead to new therapeutic approaches and to the identification of predictive markers of mucositis.

Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil

Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.

IL-1Ra selectively protects intestinal crypt epithelial cells, but not tumor cells, from chemotoxicity via p53-mediated upregulation of p21WAF1 and p27KIP1

Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect, resulting from the nonspecific cytoablative actions of chemoagents, including 5-fluorouracil (5-FU) and irinotecan (CPT-11). Preventive strategies are urgently needed for the predictable CIM. Previously, we have demonstrated an important role of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) in the prevention of cyclophosphamide-induced mucositis in mice. In this study, the preventive role of rhIL-1Ra was further evaluated in 5-FU- and CPT-11-induced mucositis mouse models. rhIL-1Ra pretreatment reduced the incidence, severity, and duration of chemotherapy-induced diarrhea, through attenuating crypt apoptosis and improving crypt survival in wild-type mice, but not in IL-1RI−/−, p53−/−, and p21−/− mice. Further studies demonstrated that rhIL-1Ra promoted the cell cycle arrest of intestinal crypt epithelia (ICE) through elevating the cellular level of p21WAF1 and p27KIP1, which was abolished in IL-1RI−/− and p53−/− mice, and in p21WAF1 and p27KIP1 silenced IEC-6 cells. Importantly, the tumor growth and sensitivity to chemotherapy were not affected by rhIL-1Ra in cultures of tumor cell lines and in a syngeneic tumor-transplantation mouse model. The present study demonstrated that rhIL-1Ra effectively and specifically protected ICE from chemotoxicity through reversible reduction of the basal level of IL-1 signaling to promote normal cell cycle arrest, but not tumor cells. Our findings support the clinical development of rhIL-1Ra in the prevention of CIM.

Randomized Phase III Trial Exploring the Use of Long-Acting Release Octreotide in the Prevention of Chemotherapy-Induced Diarrhea in Patients With Colorectal Cancer: The LARCID Trial

Chemotherapy-induced diarrhea (CID) is a relatively common adverse event in the treatment of patients with colorectal cancer. The LAR for Chemotherapy-Induced Diarrhea (LARCID) trial evaluated the efficacy and safety of long-acting release octreotide (octreotide LAR) for the prevention of CID in this population. Patients with colorectal cancer starting adjuvant or first-line treatment with a chemotherapy combination containing fluorouracil, capecitabine, and/or irinotecan were randomly assigned to receive octreotide LAR 30 mg intramuscularly every 4 weeks (experimental arm) or the physician's treatment of choice in case of diarrhea (control arm). A total of 139 patients were randomly assigned, most of whom received fluorouracil- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n = 68) and 78.9% in the control group (n = 71). Treatment with octreotide LAR did not prevent or reduce the severity of CID. Treatment choices for diarrhea management included loperamide in the majority of patients. No benefit from octreotide LAR was identified in terms of need for diarrhea treatment, opioids, or intravenous hydration or in the rate of hospitalization or quality of life. This study could not prove the efficacy of octreotide LAR in the prevention of CID.

Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation.

Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.

Chemotherapy-induced mucosal barrier dysfunction

Gut toxicity, or mucositis, is a major dose-limiting side effect of chemotherapy that until recently received very little attention. Despite significant research, the mechanisms that underpin chemotherapy-induced gut toxicity (CIGT) remain unclear. Recently however, there has been renewed interest in the role tight junctions play in the pathogenesis of CIGT and associated diarrhea. Thus, this review will cover the role of tight junctions in maintaining gastrointestinal homeostasis and touch on recently proposed mechanisms of how tight junctions may contribute to the development of chemotherapy-induced diarrhea. There is a wealth of anecdotal evidence regarding the role of tight junctions in the pathogenesis of gut toxicity. However, few studies have quantified or assessed the molecular changes in tight junctions in response to chemotherapy. This review will highlight the major findings of these studies and discuss the potential mechanisms by which tight junction disruption and mucosal barrier dysfunction may contribute to diarrhea. The significant clinical and economic impact associated with CIGT and diarrhea has only recently been appreciated. This has prompted significant research efforts in an attempt to reveal the pathophysiology of this debilitating complication. Renewed interest has been shown regarding the role of tight junctions in not only maintaining gastrointestinal health, but also contributing to mucosal barrier injury and diarrhea development. More detailed research into the effect chemotherapy has on the molecular characteristics of tight junctions will lead to a better understanding of the pathophysiology of CIGT and may uncover the therapeutic potential of tight junctions in treating diarrhea.