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Enterotoxicity of chemotherapeutic agents

Smitha S Krishnamurthi, MD
Section Editor
Reed E Drews, MD
Deputy Editor
Diane MF Savarese, MD


Gastrointestinal (GI) toxicity due to chemotherapeutic drugs is a common problem in cancer patients. The specific chemotherapy-related GI complications that are reviewed here include diarrhea, constipation, and intestinal perforation. Evaluation and management of patients with acute chemotherapy-related diarrhea is discussed separately, as is diarrhea related to immunotherapy with checkpoint inhibitors, chemotherapy-induced oral toxicity (mucositis), and chemotherapy-induced nausea and vomiting. (See "Management of acute chemotherapy-related diarrhea" and "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Diarrhea/colitis' and "Oral toxicity associated with chemotherapy" and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".)


Chemotherapy-related diarrhea (CRD) is most commonly described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with irinotecan. However, in addition to conventional cytotoxic drugs, several molecularly targeted agents (including tyrosine kinase inhibitors [TKIs] and monoclonal antibodies directed against the epidermal growth factor receptor [EGFR]) are also associated with CRD. (See 'Specific drugs' below.)

Pathogenesis/mechanisms — CRD generally occurs through three major mechanisms: increased secretion of electrolytes caused by luminal secretagogues or reduced absorptive capacity (due to surgery or epithelial damage), called secretory diarrhea; increased intraluminal osmotic substances leading to osmotic diarrhea; or altered gastrointestinal (GI) motility. Direct ischemic mucosal damage is reported in patients treated with agents targeting the vascular endothelial growth factor (VEGF), while an immune-mediated colitis is thought responsible for diarrhea with immune checkpoint inhibitors.

Secretory diarrhea — Both FU and irinotecan cause acute damage to the intestinal mucosa, leading to loss of epithelium [1,2]. FU induces mitotic arrest of crypt cells, leading to an increase in the ratio of immature secretory crypt cells to mature villous enterocytes [1,3]. The increased volume of fluid that leaves the small bowel exceeds the absorptive capacity of the colon, leading to clinically significant diarrhea. Irinotecan produces mucosal changes associated with apoptosis, such as epithelial vacuolization and goblet cell hyperplasia, suggestive of mucin hypersecretion [2]. These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa [4].

Up to 50 percent of patients treated with TKIs experience diarrhea [5]. It is thought that the diarrhea occurs through multiple mechanisms. Increased chloride secretion caused by dysregulation of the EGFR signaling pathway, [6,7] colonic crypt damage, gut dysmotility, and alteration in gut microbiota have been proposed. Monoclonal antibodies that release cancer-induced suppression of the immune system, such as ipilimumab, a human antibody to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), cause autoimmune colitis. Diffuse, segmental, or patchy colitis is seen on colonoscopy. Histologically, nonspecific acute and chronic inflammatory infiltrate, cryptitis, and crypt abscesses are noted [8]. Colonic perforation (less than 1 percent) and death in 5 percent of patients have been reported. Rituximab, an anti-CD20 monoclonal antibody used to treat B-cell lymphoma, can cause new-onset ulcerative colitis or exacerbation of preexisting colitis [9].


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