Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

Abstract

Gastrointestinal (GI) side-effects of chemotherapy are a debilitating and often overlooked clinical hurdle in cancer management. Chemotherapy-induced constipation (CIC) and Diarrhea (CID) present a constant challenge in the efficient and tolerable treatment of cancer and are amongst the primary contributors to dose reductions, delays and cessation of treatment. Although prevalence of CIC is hard to estimate, it is believed to affect approximately 16% of cancer patients, whilst incidence of CID has been estimated to be as high as 80%. Despite this, the underlying mechanisms of both CID and CIC remain unclear, but are believed to result from a combination of intersecting mechanisms including inflammation, secretory dysfunctions, GI dysmotility and alterations in GI innervation. Current treatments for CIC and CID aim to reduce the severity of symptoms rather than combating the pathophysiological mechanisms of dysfunction, and often result in worsening of already chronic GI symptoms or trigger the onset of a plethora of other side-effects including respiratory depression, uneven heartbeat, seizures, and neurotoxicity. Emerging treatments including those targeting the enteric nervous system present promising avenues to alleviate CID and CIC. Identification of potential targets for novel therapies to alleviate chemotherapy-induced toxicity is essential to improve clinical outcomes and quality of life amongst cancer sufferers.

Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea

“…Diarrhea is a common side effect of cancer chemotherapy, which can be severe and dose limiting (1)(2)(3)(4). Although many chemotherapeutic agents induce diarrhea by direct injury to the intestinal epithelium and underlying tissues with resultant mucositis, some agents may induce significant fluid secretion and would therefore be potentially amenable to therapeutics targeting intestinal ion transport mechanisms (5,6). Small-molecule ErbB tyrosine kinase inhibitors (TKIs) are used for the treatment of a variety of cancers that overexpress ErbB receptors, including breast cancer, non-small cell lung cancer, and head and neck cancers.…”

Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron

“…Cancer chemotherapy is associated with the development of numerous and feared adverse effects that may compromise treatment . Adverse effects in the gastrointestinal tract include nausea and emesis, and diarrhea or constipation, depending on the particular drug . Cisplatin is a highly emetogenic antitumoral drug, often used as reference in experimental studies searching for new antiemetics .…”

“…1 Adverse effects in the gastrointestinal tract include nausea and emesis, and diarrhea or constipation, depending on the particular drug. [1][2][3][4][5] Cisplatin is a highly emetogenic antitumoral drug, often used as reference in experimental studies searching for new antiemetics. 6,7 Although other mechanisms may be involved, serotonin released from the enterochromaffin cells and acting upon vagal afferents through 5-HT 3 receptors is one of the main components underlying nausea and emesis induced by cisplatin [8][9][10][11] and is probably also involved in the effect of other antitumoral drugs.…”

BuPiHeWei Decoction Ameliorates 5-Fu-Induced Intestinal Mucosal Injury in the Rats by Regulating the TLR-4/NF-κB Signaling Pathway

“…In severe cases, bacterial translocation might occur to cause life-threatening bacteremia. Despite the continuous development and application of mucosal protective agents and microecologics, the incidence of adverse reactions after chemotherapy, including diarrhea, abdominal pain, and constipation, is still more than 80% [1]. 5-Fu and irinotecan are considered as having obvious gastrointestinal toxicity caused by chemotherapy, which is closely associated with intestinal mucosal microinflammation [2].…”