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Management of acute chemotherapy-related diarrhea

Management of acute chemotherapy-related diarrhea
Author:
Carole Macaron, MD
Section Editor:
Reed E Drews, MD
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Jan 2024.
This topic last updated: Dec 14, 2022.

INTRODUCTION — Most chemotherapeutic agents target rapidly dividing cells, and effects on these cells within the gastrointestinal tract can lead to a variety of symptoms. Diarrhea caused by chemotherapy, referred to here as chemotherapy-related diarrhea (CRD), is a serious and potentially life-threatening complication of a wide variety of chemotherapy drugs and hospital admission is frequently needed for adequate supportive care. CRD may also result in treatment delays and diminished compliance, which may compromise long-term outcomes.

This topic will review the management of CRD. The pathogenesis of CRD, predictive markers for fluoropyrimidine- and irinotecan-related diarrhea, and management of diarrhea in patients receiving immune checkpoint inhibitors are discussed in detail separately. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Diarrhea' and "Immune checkpoint inhibitor colitis".)

AGENTS MOST COMMONLY ASSOCIATED WITH DIARRHEA

Conventional cytotoxic agents – CRD is a common problem in cancer patients receiving systemic antineoplastic therapy, and is most often described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is often the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with irinotecan. The frequency of severe (grade 3 or 4 (table 1)) diarrhea with these agents ranges from 5 to 44 percent, and rates vary according to the dose, the specific agents administered, and the schedule of administration. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Fluorouracil' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Irinotecan'.)

Molecularly targeted agents – In addition to conventional cytotoxic drugs, such as fluoropyrimidines and irinotecan, several molecularly targeted agents are also associated with high rates of CRD:

For many tyrosine kinase inhibitors (TKIs), such as afatinib, ceritinib, erlotinib, lapatinib, sorafenib, and sunitinib, and phosphatidylinositol 3-kinase (PI3K) inhibitors (eg, alpelisib), diarrhea is second only to rash as the most common toxicity. Diarrhea develops in one-half or more of treated patients, although the incidence of severe (grade 3 or 4) diarrhea is lower than with conventional cytotoxic agents. Diarrhea is especially common with ceritinib, neratinib, and afatinib, occurring in 75 to 95 percent of treated patients, but severe in only 2 to 16 percent. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Small molecule EGFR inhibitors' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Small molecule inhibitors of VEGFR' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Lapatinib, pertuzumab, neratinib, and tucatinib' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'ALK inhibitors'.)

Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) rarely cause severe diarrhea when used as monotherapy but can increase the incidence of severe diarrhea when combined with cytotoxic chemotherapy. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Anti-EGFR monoclonal antibodies'.)

-The antiangiogenic agent aflibercept, which is a recombinant fusion protein of the vascular endothelial growth factor (VEGF) binding portions of the VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1 (IgG1), increased severe diarrhea by 10 percent when added to FOLFIRI (irinotecan plus leucovorin and short-term infusional FU) chemotherapy [1]. When added to FOLFOX (oxaliplatin plus leucovorin and short-term infusional FU) chemotherapy, aflibercept increased the incidence of severe diarrhea by 8 percent [2].

Checkpoint inhibitor immunotherapy with the cytotoxic T lymphocyte associated antigen 4 (CTLA4) inhibitor ipilimumab and programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab, causes an immune-mediated colitis that is severe in up to 9 percent of treated patients. The anti-programmed cell death ligand 1 (PD-L1) antibodies atezolizumab and durvalumab can also cause diarrhea, but severe diarrhea is rare [3,4]. (See "Immune checkpoint inhibitor colitis".)

OVERVIEW OF MECHANISMS — In general, most cases of CRD occur through three different pathophysiologic mechanisms: increased secretion of electrolytes, caused by luminal secretagogues or reduced absorptive capacity (due to surgery or epithelial damage caused by the chemotherapy drugs themselves), called secretory diarrhea; increased intraluminal osmotic substances, leading to osmotic diarrhea; or altered gastrointestinal motility. In general, secretory diarrhea characteristically continues despite fasting, is associated with stool volumes >1 L/day, and occurs day and night, in contrast to osmotic diarrhea, in which these characteristics are uncommon. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Pathogenesis/mechanisms'.)

Briefly:

Both fluorouracil (FU) and irinotecan can cause damage to the intestinal mucosa, leading to loss of epithelium and secretory diarrhea [5].

Approximately 10 percent of patients being treated with FU have decreased expression of the enzyme lactase in their intestinal brush border, leading to lactose intolerance and causing osmotic diarrhea [6,7].

Early onset diarrhea with irinotecan (ie, during or within several hours of drug infusion) is cholinergically mediated (ie, related to increased motility) [8]. By contrast, late irinotecan-associated diarrhea is not cholinergically mediated but, instead, appears to be multifactorial, with contributions from dysmotility and secretory factors, as well as a direct toxic effect on the intestinal mucosa. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Risk with conventional cytotoxic agents'.)

The diarrhea caused by tyrosine kinase inhibitors (TKIs) occurs through multiple mechanisms. Increased chloride secretion caused by dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway, colonic crypt damage, gut dysmotility, and alteration in gut microbiota have been proposed.

By contrast, the diarrhea caused by checkpoint inhibitor immunotherapy with the cytotoxic T lymphocyte associated antigen 4 (CTLA4) inhibitor ipilimumab and programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab is immune mediated. This subject is discussed in detail separately. (See "Immune checkpoint inhibitor colitis".)

OVERVIEW OF CLINICAL MANIFESTATIONS — CRD typically begins with an increasing frequency of bowel movements and/or a loosening of stool consistency. Excessive gas and/or intestinal cramping commonly accompanies CRD. As the CRD progresses, it can become severe, with frequent watery stools. CRD can be debilitating and, in some cases, life-threatening. Findings in such patients include volume depletion, acute kidney injury, and electrolyte disorders such as hypokalemia, metabolic acidosis, and depending on water intake, hyponatremia (increased water intake that cannot be excreted because of the hypovolemic stimulus to the release of antidiuretic hormone) or hypernatremia (insufficient water intake to replace losses). Infection, including life-threatening sepsis, can result due to breach of the intestinal mucosa, which is worsened in the setting of chemotherapy-induced immunosuppression. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Clinical manifestations'.)

Given the risk for dehydration and infection, severe CRD frequently requires hospital admission for adequate supportive care [9-12]. Other sequelae of CRD include increased cost of care, reduced quality of life, treatment delays, and diminished compliance with treatment regimens, which may compromise long-term outcomes if the chemotherapy is being administered with curative intent [10].

CLINICAL ASSESSMENT — The severity of CRD is often described using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grades; the latest version (v5.0) is outlined in the table (table 1). Severity is determined by the number of stools per day or an increase in ostomy output compared with baseline, the need for hospitalization, and the effect on activities of self-care. It is critical to ascertain the patient's baseline bowel pattern when grading the severity of CRD. Although adequate for study purposes, these criteria have been criticized because they do not take into account the volume or the duration of diarrhea [13]. Other validated CRD measurement scales have been developed but are not in general use [14].

Evaluation — A general approach to evaluation and management of CRD is outlined in the algorithm (algorithm 1), which is based on several published guidelines [13,15,16].

History and physical examination — Evaluation of the patient with CRD begins with a history to determine the severity according to the NCI CTCAE grades (table 1). The volume and duration of diarrhea should also be determined, and the history should include questions concerning foods or drugs that might play a contributory role (which are usually avoided in patients with CRD) (table 2) [13]. A recent initiation of proton pump inhibitors, nonsteroidal anti-inflammatory agents, antibiotics, or laxatives and/or a stool softener (eg, to prevent opioid-induced constipation) can all cause or contribute to diarrhea.

Because mucosal injury caused by chemotherapy may lead to a temporary lactase deficiency, the ingestion of milk-containing foods may be an important trigger for diarrhea and should be specifically queried. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management".)

It should also be appreciated that other factors can contribute to diarrhea in cancer patients treated with chemotherapy, and the history should be geared to exploring the possibility of intestinal infection (eg, Clostridioides [formerly Clostridium] difficile, especially in a patient with prior C. difficile infection), abdominopelvic radiation therapy, prior intestinal resection, malabsorption, intake of excess laxatives or artificial sweeteners, and stool impaction. Patients who have anorexia, abdominal bloating or pain, and frequent soft or loose stool, as opposed to watery diarrhea, may have overflow diarrhea (ie, passage of stool around impacted stool). The presence of fever, dizziness, or abdominal pain should raise concern for a possible complication, such as sepsis or bowel obstruction. (See 'Differential diagnosis' below.)

Patients who have an ileostomy are at increased risk for severe diarrhea and dehydration from copious watery ileostomy output. Average output for the ileostomy patient ranges from 500 to 1300 mL a day. Ileostomy effluent contains significant amounts of sodium and potassium. This daily fluid loss places the ileostomy patient at greater risk for dehydration and electrolyte disorders, especially during episodes of increased output. Patients who have an ileostomy are frequently on a baseline regimen of loperamide to maintain thick ileostomy output and should be carefully queried about loperamide use and oral fluid intake. (See "Ileostomy or colostomy care and complications", section on 'Ileostomy patients'.)

A careful physical examination should be performed to assess for signs of volume depletion (eg, reduced skin turgor, hypotension, which may be primarily orthostatic, and low jugular venous pressure) (see "Etiology, clinical manifestations, and diagnosis of volume depletion in adults") and infection.

Investigations — Laboratory testing should address both the complications and causes of CRD. These include a complete blood count and a standard chemistry screen including magnesium. For patients with severe (grade 3 or 4) diarrhea, persistent mild to moderate (grade 1 or 2) diarrhea, or diarrhea accompanied by neutropenia, fever, or blood in the stools, cultures of blood and stool, and diagnostic testing for toxin-producing strains of C. difficile are indicated. (See 'Infectious causes' below.)

Radiographic imaging is not typically needed in most patients with acute CRD. However, for patients who have fever, peritoneal signs, or bloody diarrhea, abdominal imaging (most typically computed tomography [CT]) can be important to identify potential complications, such as bowel perforation, abscess, or neutropenic enterocolitis, or to rule out causes of diarrhea not associated with chemotherapy (eg, bowel ischemia). Surgical consultation may also be needed in these cases. Abdominal radiographs, which can document the extent of stool, are useful in cases of suspected overflow diarrhea.

Endoscopy is not indicated in the vast majority of cases but should be considered for refractory cases and for patients who develop chronic diarrhea (ie, diarrhea that persists throughout the entire chemotherapy cycle) or bloody diarrhea. (See 'Lymphocytic colitis' below and 'Management of refractory patients' below.)

Differential diagnosis — Patients who develop diarrhea during chemotherapy may also suffer from organic causes of diarrhea, which may or may not be related to the chemotherapy and should not be overlooked. These include small intestinal bacterial overgrowth (SIBO), fat or bile acid malabsorption, intake of excess quantities of sorbitol or lactose intolerance, inflammatory and infectious causes, and stool impaction.

Small intestinal bacterial overgrowth as a cause of fat and carbohydrate malabsorption — Although difficult to diagnose with certainty, SIBO has been reported in immunosuppressed patients after bowel resection surgery and following pelvic radiation therapy [17-19]. SIBO causes fat malabsorption through bacterial deconjugation of bile acids and carbohydrate malabsorption secondary to luminal degradation of carbohydrates by the gut bacteria. Patients often report abdominal discomfort, flatulence, and foul-smelling, oily, and difficult to flush stools. Deficiencies in lipid-soluble vitamins and in vitamin B12 (consumed by the gut bacteria), as well as elevated folate levels (synthesized by the gut microbiota), are indirect biochemical indices of SIBO [20]. The diagnosis of SIBO most often relies on the use of noninvasive carbohydrate breath tests, which have a sensitivity of only approximately 60 percent [20]. Jejunal aspirate cultures are considered the reference standard, although they are difficult to perform. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis".)

Treatment consists of an antibiotic course, which will cure the diarrhea. (See "Small intestinal bacterial overgrowth: Management".)

Fat malabsorption due to other causes — Fat malabsorption occurs for reasons other than SIBO in patients undergoing treatment for cancer. Pancreatic exocrine insufficiency is reported in the setting of conditioning regimens preceding hematopoietic cell transplantation [21] and following pancreaticoduodenectomy. (See "Surgical resection of lesions of the head of the pancreas", section on 'Pancreatic enzyme supplementation'.)

Obstruction of lymphatic vessels secondary to tumor infiltration, radiation therapy-induced intestinal lymphangiectasia, and multiple small bowel resections (>100 cm of small bowel resected) may also result in malabsorption of free fatty acids, leading to diarrhea [15].

Bile acid malabsorption or bile acid diarrhea (excessive secretion of bile acids) may result from chemotherapy-induced epithelial damage of the terminal ileum. Among 506 patients with a history of prior cancer treatment including radiation, surgery, or chemotherapy who were evaluated in a gastroenterology clinic at the Royal Marsden Hospital because of chronic loose or watery stool, bile acid malabsorption or bile acid diarrhea was newly diagnosed in over 40 percent [22]. Patients who had pelvic chemoradiation were more likely to have bile acid malabsorption than those who had pelvic radiation alone, possibly due to radiation sensitization of the terminal ileum. Right hemicolectomy was associated with bile acid malabsorption due to resection of the terminal ileum. Bile acid malabsorption/bile acid diarrhea was also frequently associated with pancreatoduodenectomy.

A referral to gastroenterology should be considered for patients with CRD that persists throughout the chemotherapy cycle (eg, those with chronic loose stool) to evaluate the possibility of bile acid malabsorption. An empiric trial of a bile-acid binding resin (eg, cholestyramine) is another option. (See "Approach to the adult with chronic diarrhea in resource-abundant settings".)

Infectious causes — Among the infectious agents that may cause acute diarrhea in adults are Salmonella species, Shigella species, Campylobacter, Escherichia coli, and C. difficile. A routine stool culture will identify Salmonella, Campylobacter, and Shigella, the three most common causes of bacterial diarrhea in the United States. A stool culture that is positive for one of these pathogens in a patient with acute diarrheal symptoms can be interpreted as a true positive.

Clostridioides difficile-associated colitis — Clostridioides difficile colitis is a common problem in patients with cancer, mostly due to the high rate of oral antibiotic use and hospitalization. However, several reports have described this complication in patients without any prior antibiotic use following chemotherapy [23-25]. The proposed mechanism is chemotherapy-induced intestinal damage that facilitates the proliferation of C. difficile.

A frequent occurrence of C. difficile-related diarrheal episodes has been reported in patients treated with paclitaxel-containing regimens, especially with the use of "dose-dense" regimens [26]. The spectrum of illness varies from mild to fulminant; management is discussed in detail separately. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridioides difficile infection in adults: Treatment and prevention".)

Bloody diarrhea — For patients with bloody diarrhea, two potential pathogens, enterohemorrhagic E. coli (E. coli O157:H7 [EHEC]) and Entamoeba, warrant additional testing. EHEC can be isolated on special plates, or identified with antigen testing or polymerase chain reaction of stool. In addition to culture, we check bloody stools for Shiga toxin, and fecal leukocytes or lactoferrin, if available; if the fecal leukocyte/lactoferrin test is negative, we test for amebiasis.

Neutropenic enterocolitis — Neutropenic enterocolitis (a form of necrotizing enterocolitis or typhlitis) is one of the most common gastrointestinal complications in leukemic patients who are undergoing induction therapy, and can occur in other malignancies and following stem cell-supported high-dose chemotherapy [27,28].

The pathogenesis, risk factors, diagnosis, and management of patients with neutropenic enterocolitis are discussed separately. (See "Neutropenic enterocolitis (typhlitis)".)

Ischemic colitis — A small number of cases of ischemic colitis have been reported with docetaxel-containing regimens in patients with metastatic breast cancer, including 3 of 14 patients in a phase I study of docetaxel and vinorelbine [29,30]. The typical onset is 4 to 10 days following administration. Patients with acute colonic ischemia usually present with rapid onset of mild abdominal pain and tenderness over the affected bowel, commonly on the left side of the abdomen. Mild to moderate amounts of rectal bleeding or bloody diarrhea typically develop within 24 hours of the onset of abdominal pain. (See "Overview of intestinal ischemia in adults".)

Stool impaction — Patients who have anorexia, abdominal bloating or pain, and frequent soft or loose stool, as opposed to watery diarrhea, may have overflow diarrhea (ie, passage of stool around an impaction) [15]. A digital rectal examination will usually discover the impaction.

Lymphocytic colitis — Patients receiving treatment with aflibercept may develop lymphocytic colitis (microscopic colitis), for which specific treatment with budesonide may be beneficial [31]. These cases will typically present with diarrhea that persists throughout the entire chemotherapy cycle (ie, chronic rather than acute diarrhea). Patients with chronic diarrhea during chemotherapy should be referred to gastroenterology for a workup to include colonoscopy. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)

MANAGEMENT — Treatment for CRD includes nonpharmacologic and pharmacologic interventions to slow the diarrhea, and careful serial evaluation to assess response to therapy and to rule out significant volume depletion or other risk factors that would require targeted intervention or hospitalization.

Management according to the severity of diarrhea and other exacerbating factors — Initial management depends on the severity of diarrhea and whether or not additional "risk factors" are present. In keeping with consensus-based guidelines from an academic panel convened to address management of CRD in 2004 [13], we recommend classifying patients with CRD as "uncomplicated" or "complicated." An algorithmic approach to evaluation and management of CRD according to severity and exacerbating factors is provided (algorithm 1), and the specific treatment strategies are discussed in more detail in the sections below.

Uncomplicated, mild to moderate chemotherapy-related diarrhea — Patients with mild to moderate (grade 1 or 2 (table 1)) diarrhea and no moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), decreased performance status, fever, frank bleeding, or suspected dehydration are classified as "uncomplicated." These patients can initially be managed conservatively at home with oral hydration, dietary modification, and antidiarrheal therapy (typically loperamide 4 mg to start, and then 2 mg every four hours or after each loose stool). (See 'General measures' below and 'Loperamide and diphenoxylate-atropine' below.)

If symptoms persist after 12 to 24 hours (but are not worse or associated with worrisome signs and/or symptoms), the loperamide dose can be increased to 2 mg every two hours. If mild to moderate diarrhea persists 12 to 24 hours later despite the higher dose of loperamide, patients should be evaluated in the office; be assessed for hydration status, neutropenia, and electrolyte abnormalities; and have stool sent for culture and diagnostic testing for toxin-producing strains of C. difficile. In the absence of an added risk factor for complicated diarrhea (moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), decreased performance status, fever, hypotension, neutropenia, frank bleeding), chest pain, or prior admission for CRD, outpatient octreotide is a reasonable next step. (See 'Patients refractory to loperamide' below.)

Persistent mild to moderate diarrhea despite the higher dose of loperamide and the addition of octreotide, any progression to severe (grade 3 or 4 (table 1)) diarrhea, or the development of an added risk factor for complicated diarrhea should prompt admission to the hospital and further evaluation and treatment.

Complicated chemotherapy-related diarrhea — Patients who present with grade 3 or 4 diarrhea (table 1) and those with grade 1 or 2 diarrhea associated with moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), declining performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration are classified as "complicated." Year 2014 guidelines for CRD from a multidisciplinary British group include recognition of these complicating symptoms, but they also include chest pain and a previous admission for CRD as signs of potentially severe diarrhea necessitating aggressive management [15].

Most of these patients warrant admission for intravenous fluids, octreotide, monitoring of cardiovascular status, serial assessment of electrolytes, and antibiotics, if needed. However, selected patients who have grade 3 diarrhea that has not yet been treated adequately with loperamide, who are well hydrated, and who have no worrisome signs or symptoms may be managed at home initially [15]. (See 'Loperamide and diphenoxylate-atropine' below.)

If not already done, cultures of stool and diagnostic testing for toxin-producing strains of C. difficile should be performed. For patients with bloody diarrhea, at least two potential pathogens, enterohemorrhagic E. coli (EHEC) and Entamoeba histolytica, warrant additional testing. In addition to culture, bloody stools should be checked for Shiga toxin, and fecal leukocytes or lactoferrin, if available; if the fecal leukocyte/lactoferrin test is negative, we test for intestinal amebiasis. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Bloody diarrhea' and "Intestinal Entamoeba histolytica amebiasis", section on 'Diagnosis'.)

Patients with fever, peritoneal signs, or bloody diarrhea should have an urgent CT scan of the abdomen and pelvis, and a surgical consultation [15]. If the patient is neutropenic, avoidance of surgery is prudent, if possible. (See 'Investigations' above.)

Blood cultures are recommended for neutropenic patients with CRD or for those with fever or bloody diarrhea.

For patients who develop severe symptoms (diarrhea, mucositis, myelosuppression) during a first chemotherapy cycle containing a fluoropyrimidine, in whom deficiency of one of the fluoropyrimidine metabolizing enzymes (ie, dihydropyrimidine dehydrogenase [DPD] or thymidylate synthetase) is suspected, or who have had an unintentional overdose of fluorouracil [FU] or capecitabine, the need for uridine triacetate should be addressed. In order to be effective, uridine triacetate must be started within 96 hours of the last exposure. (See 'Uridine triacetate' below.)

General measures — Initial nonpharmacologic measures include avoidance of foods that might aggravate the diarrhea (table 2) and aggressive oral rehydration with fluids that contain water, salt, and sugar (since glucose promotes intestinal sodium absorption), such as broth or Gatorade [32]. These principles are similar to those used for initial treatment of infectious diarrhea. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Fluid repletion' and "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Dietary guidance'.)

Because of potential mucosal damage and loss of absorptive surfaces, patients should ingest easy-to-digest food until the CRD resolves. Patients should be advised to follow a "BRAT" diet (ie, bananas, rice, applesauce, and toast) [16]. Fresh fruits and vegetables should be avoided, as they will worsen diarrhea, except for bananas, which can be binding. High-osmolar dietary supplements should be avoided [13]. Patients with CRD may be temporarily lactose intolerant [6,7] and should, thus, follow a lactose-free diet (table 4) until the CRD resolves. Particularly if diarrhea is severe, a clear liquid diet can provide bowel rest and may decrease the volume of diarrhea.

Alcohol should be avoided, as it is dehydrating. Caffeine should be avoided, as it stimulates gastrointestinal (GI) tract motility.

Patients should be instructed to stop other medications and supplements that could cause diarrhea, such as stool softeners, laxatives, milk thistle, aloe, saw palmetto, Siberian ginseng, plantago seeds, coenzyme Q10, high doses of vitamin C, and green tea [16]. Lactose is often used as an excipient in pharmaceutical drugs. For most drugs, the amount of lactose is insufficient to induce symptoms in persons with lactose intolerance, although highly sensitive individuals may be affected, especially if they ingest multiple medications that contain lactose [33,34].

Withholding chemotherapy — The management of oral antineoplastic therapy in patients who develop diarrhea varies according to the specific drug, and the United States prescribing information generally includes recommendations for dose modification for individual drugs. In general:

Anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs; afatinib, erlotinib, gefitinib) – For grade 2 diarrhea, continue the drug. If the patient does not respond to loperamide by 48 hours, temporarily discontinue the drug until diarrhea returns to grade 1, after which the drug can be resumed with a dose reduction (afatinib and erlotinib). For grade 3 or 4 diarrhea, withhold the TKI until diarrhea reaches grade 1, then resume, usually with a dose reduction. If the diarrhea does not resolve to grade 1 within 14 days, the drug should be permanently discontinued.

For lapatinib, the United States prescribing information recommends that the drug be interrupted in patients with grade 3 diarrhea, or grade 1 or 2 diarrhea with complicating features (moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration), and resumed with a dose reduction after recovery to grade 1. Discontinue the drug permanently for grade 4 diarrhea.

For the anaplastic lymphoma kinase (ALK) inhibitor ceritinib, the United States prescribing information recommends withholding the drug for severe or intolerable diarrhea, despite optimal antidiarrheal therapy, and resuming once resolved with a dose reduction.

The United States prescribing information for capecitabine recommends that the drug be temporarily interrupted for grade 2 or worse diarrhea until resolved to grade 0 or 1.

While the United States prescribing information does not explicitly make this statement, we also discontinue infusional FU for grade 2 or worse diarrhea until resolved to grade 0 or 1.

Pharmacologic management

Loperamide and diphenoxylate-atropine — We recommend loperamide rather than diphenoxylate-atropine for initial therapy of CRD. For mild to moderate (grade 1 or 2) uncomplicated CRD, we suggest an initial dose of 4 mg, followed by 2 mg every four hours or 2 mg after each loose stool (maximum daily dose 16 mg per day). For patients with severe (grade 3 or 4) diarrhea; mild to moderate diarrhea that is complicated by moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration; or mild to moderate uncomplicated diarrhea that persists after 24 hours of loperamide, we suggest high-dose loperamide (4 mg initially, followed by 2 mg every two hours; maximum daily dose 16 mg).

The mainstays of pharmacologic therapy for CRD are opioids. Loperamide (Imodium) and diphenoxylate-atropine (Lomotil) are the most commonly used, and both are US Food and Drug Administration (FDA)-approved for this indication. Both have a rapid onset of action.

Loperamide is a synthetic opioid that binds to mu opiate receptors in the intestinal wall and inhibits peristalsis by inhibiting the release of acetylcholine through activation of the mu opioid receptors [35]. This slows GI transit time, allowing more time for absorption of water in the intestine [36-38]. Inhibition of acetylcholine release also leads to antisecretory activity because muscarinic acetylcholine receptors exist on secretory epithelial cells in the intestinal wall [39]. As a result of all of these actions, loperamide reduces fluid and electrolyte loss, decreases fecal volume, and increases stool consistency.

Loperamide is rapidly absorbed from the GI tract and extensively metabolized by the liver. The amount of loperamide entering the systemic circulation is minimal (systemic bioavailability is only 0.3 percent), and the blood brain barrier prevents any absorbed loperamide from entering the central nervous system [15]. As such, it has a much wider margin between central and peripheral opioid action than do other centrally acting opioids, such as fentanyl, codeine, and even diphenoxylate [36]. The main adverse effect is constipation.

Diphenoxylate is a synthetic opioid chemically related to meperidine; it inhibits excessive GI motility and GI propulsion; commercial preparations contain a subtherapeutic amount of atropine to discourage abuse. Excess doses of diphenoxylate-atropine can result in symptoms of excess cholinergic and central narcotic effects, including drowsiness, flushing, dry mouth, tachycardia, dilated pupils, rash, and nausea [40].

Both loperamide and diphenoxylate-atropine are effective at controlling acute and chronic diarrhea of various causes. There are no randomized trials directly comparing loperamide with diphenoxylate in patients with CRD. However, efficacy data from double-blind crossover studies comparing these agents in a variety of settings of non-chemotherapy-related acute and chronic diarrhea suggest that loperamide is the more effective agent, providing more rapid control of diarrhea and prolonging the time to first recurrence of diarrhea [41-48]; furthermore, it has a more favorable side effect profile, especially lacking central narcotic activity [49]. Loperamide is the preferred approach in several published guidelines for treatment of CRD [13,15,50,51].

The standard dose of loperamide for CRD is an initial 4 mg dose, followed by 2 mg every four hours or after every loose stool, maximum 16 mg daily. Four randomized placebo-controlled trials established the efficacy of this dose of loperamide in a variety of settings of both acute and chronic diarrhea [52-55]. This dose has been used empirically for patients with CRD and has been shown to be effective [56-59]. However, this regimen is only moderately effective for severe (grade 3 or 4) CRD [59,60]. In one study among patients with grade 1 to 4 diarrhea due to FU-based chemotherapy, loperamide at 4 mg for the first dose, followed by 4 mg every eight hours (16 mg per 24 hours) for up to 48 hours, led to resolution of grade 1 or 2 diarrhea in 84 percent of patients but was effective in only 52 percent of patients with grade 3 or 4 diarrhea (table 1) [59].

More aggressive regimens may be recommended for severe or complicated diarrhea (eg, 4 mg initially, then 2 mg every two hours or 4 mg every four hours until diarrhea free for 12 hours). However, doses higher than 16 mg daily should be avoided due to the risk of cardiac arrhythmias [61-63].

Octreotide — We recommend initiating octreotide for any patient with CRD that is refractory to loperamide. We suggest initiating therapy at 100 or 150 mcg subcutaneously three times daily (or 50 to 150 mcg/hour intravenously). The octreotide dose should be rapidly escalated to 500 mcg subcutaneously/intravenously three times a day if lower doses are not effective.

Octreotide, a synthetic somatostatin analog, is effective for the control of diarrhea associated with a number of conditions, including carcinoid syndrome, vasoactive intestinal polypeptide (VIP)- and gastrin-secreting tumors, and short bowel syndrome. (See "Treatment of the carcinoid syndrome", section on 'Somatostatin-analog therapy' and "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Somatostatin analogs' and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Somatostatin analogs' and "Management of short bowel syndrome in adults", section on 'Pharmacologic therapy to reduce fluid loss'.)

Octreotide diminishes diarrhea via several mechanisms. It acts directly on epithelial cells to reduce the secretion of a number of pancreatic and GI hormones, such as VIP, serotonin, gastrin, secretin, and pancreatic polypeptide [64]. In both animal models and clinical studies, it prolongs intestinal transit time, promotes intestinal absorption, and decreases secretion of fluids and electrolytes [65-67]. Absorption after subcutaneous injection is rapid and complete, but the duration of effect is 6 to 12 hours, necessitating multiple daily doses or infusional intravenous therapy [56]. A long-acting depot suspension that is released slowly is available for intramuscular use (Sandostatin long-acting release [LAR]); it is designed to be injected every four weeks. Peak serum levels after intramuscular injection occur after one hour, they slowly decline over three to five days, then slowly increase again and reach a plateau over two to three weeks. Octreotide is approved by the FDA for the treatment of diarrhea related to VIP-secreting tumors and symptoms due to carcinoid syndrome. (See "Clinical features of carcinoid syndrome" and "VIPoma: Clinical manifestations, diagnosis, and management".)

Patients refractory to loperamide — We recommend that patients who have persistent diarrhea despite 24 to 48 hours of loperamide use be treated with octreotide [13]. It is unlikely that higher doses of loperamide will be beneficial [13]. There are no published data on the use of diphenoxylate-atropine in the setting of diarrhea refractory to loperamide, but as diphenoxylate-atropine is another opioid, it is unlikely that it will be effective for patients with severe diarrhea despite aggressive loperamide use. We suggest an initial octreotide dose of 100 to 150 mcg subcutaneously three times daily, with escalation to 500 mcg three times daily and, rarely, higher (up to 2000 mcg three times daily), as needed for refractory cases.

Benefit from octreotide has been shown in patients with CRD from fluoropyrimidines, irinotecan, and FU-based chemoradiotherapy who are failing to respond to loperamide or diphenoxylate-atropine [56,57,68-71]. In one trial of 32 patients with grade 2 or 3 CRD (from a variety of agents, including FU, irinotecan, cyclophosphamide, methotrexate, and cisplatin) who were refractory to loperamide and treated with octreotide (100 mcg three times daily for three days, then 50 mcg three times daily for three days), complete resolution of diarrhea was obtained in 30 (94 percent) [71]. Resolution occurred within 24 hours in five, within 48 hours in 14, and within 72 hours in 11. Nineteen patients were successfully treated as outpatients. No adverse effects related to octreotide were observed in this trial, although others report local pain at the injection site, flatulence, nausea, fatigue, weakness, and constipation [72].

The optimal dose has not been established. Most guidelines suggest initiating therapy with 100 or 150 mcg three times daily based on efficacy as demonstrated in the studies cited above [13,15,50,51,73].

However, at least some data suggest that a dose-response relationship with escalating doses provides better control of diarrhea [56,68,70,74]. As examples:

The safety of octreotide at subcutaneous doses of 50 to 2500 mcg three times daily for five days was evaluated in a dose-escalation study conducted in patients with grade 2 or worse diarrhea associated with FU therapy [68]. The maximally tolerated dose was 2000 mcg three times daily. There was a significant correlation between dose and complete resolution of diarrhea, and a significantly greater chance of completing therapy as the dose of octreotide increased.

The only prospective comparison of octreotide 100 and 500 mcg, both administered subcutaneously three times a day in 59 patients with grade 3 or 4 diarrhea due to FU, found complete resolution of diarrhea within five days in a significantly higher percentage of patients treated initially at the higher dose (90 versus 61 percent) [74].

These data support upward titration of the octreotide dose up to 2000 mcg three times daily. The side effects of octreotide are generally mild, including bloating, cramping, flatulence, and fat malabsorption. Hypersensitivity-like reactions and hypoglycemia can occur at higher doses (2500 mcg three times daily) [68]. Octreotide should be discontinued when diarrhea has resolved to prevent ileus from developing [70].

Versus loperamide as initial therapy — At least two randomized trials in patients with CRD showed that octreotide was more effective than standard-dose loperamide for initial treatment of grade 2 or 3 diarrhea (90 versus 15 percent resolution of diarrhea by day 3 in one trial [60] and 80 versus 30 percent resolution by day four in the second [75]). However, loperamide dosing was relatively low by modern standards in both trials (4 mg initially, then 2 mg every six hours in one [60] and 4 mg three times daily in the second [75]). Given the high cost of octreotide and the general effectiveness of loperamide when administered at therapeutic doses, octreotide is generally reserved as a second-line therapy for patients who do not respond to high-dose loperamide. (See 'Loperamide and diphenoxylate-atropine' above.)

Octreotide long-acting release — Subcutaneous octreotide effectively relieves CRD but requires three-times-daily injections. As noted above, octreotide is available as a depot formulation for intramuscular use. One small case series of 11 patients failing conventional antidiarrhea therapy (loperamide and diphenoxylate-atropine) suggests efficacy at resolving severe (grade 3 or 4) CRD for a single dose of octreotide LAR (starting dose 30 mg) [76]. Only one of four patients receiving a 20 mg dose had resolution of diarrhea, while the remaining three and all of those initially treated with a 30 mg initial dose had resolution of diarrhea [77,78].

Given that subcutaneous octreotide dosing for outpatients is inconvenient, and many patients will not be able to administer the injections or have insurance coverage for outpatient injections, administration of a single dose of octreotide LAR (30 mg) may be a reasonable option for patients with loperamide-refractory CRD who are being managed as outpatients. However, a study of octreotide LAR as secondary prophylaxis of CRD found that when the next cycle of chemotherapy was administered at a 25 percent lower dose and was given with octreotide LAR 30 mg, 8 of 29 patients developed grade 2 or worse diarrhea in that cycle. The authors hypothesized that the pharmacokinetic profile of octreotide LAR, which results in lower drug concentrations for the first 10 days after injection, may have contributed to the lack of efficacy.

Other antidiarrheal agents — Other antidiarrheal agents have been evaluated in patients with CRD.

Anticholinergic drugs are not commonly used because of side effects. However, they can be helpful when diarrhea is associated with significant cramping.

Deodorized tincture of opium (DTO) is a widely used antidiarrheal agent, despite the absence of literature reports supporting efficacy for treatment of chemotherapy-induced diarrhea. DTO contains the equivalent of 10 mg/mL morphine. The recommended dose is 10 to 15 drops in water every three to four hours [60].

Outside of the United States, an alternative is paregoric, camphorated tincture of opium, a less concentrated preparation that contains the equivalent of 0.4 mg/mL morphine. The recommended dose is 5 mL (one teaspoonful) in water every three to four hours. This preparation has been discontinued in the United States.

Racecadotril is an enkephalinase inhibitor that blocks epithelial cyclic adenosine monophosphate (AMP)-mediated secretion. It has moderate activity in patients with irinotecan-induced diarrhea [79].

Budesonide is an orally administered, topically active synthetic steroid with low systemic activity due to extensive first-pass metabolism in the liver. It has proven efficacy in patients suffering from diarrhea caused by inflammatory bowel disease and collagenous colitis. At least one report suggests possible efficacy for oral budesonide in patients with diarrhea caused by irinotecan or FU [80]. In a phase I study involving 14 patients with loperamide-refractory grade 3 or 4 diarrhea, severity was reduced by at least two grades in 86 percent of the irinotecan-treated patients and 57 percent of those receiving FU.

One setting in which budesonide may be beneficial is in patients receiving aflibercept, which has been associated with microscopic (lymphocytic) colitis [31]. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)

Oral antibiotics — There is no consensus on the appropriate role for oral antibiotics in patients with CRD. The 2004 guidelines from Benson and colleagues recommend starting oral antibiotics for mild to moderate, uncomplicated diarrhea that persisted after 12 to 24 hours of initial loperamide therapy; these guidelines were published around the time that deaths were reported in patients with CRD from irinotecan in conjunction with bolus FU and leucovorin (the IFL regimen), many of which occurred in the setting of neutropenia. As noted above, this regimen has fallen out of favor. More recent British guidelines do not include this recommendation [15]. We would start antibiotics only for patients with fever, hypotension, peritoneal signs, neutropenia, or bloody diarrhea and would use intravenous antibiotics in these settings.

Uridine triacetate — For patients who have received a fluoropyrimidine, who develop severe diarrhea after the initial dose, in conjunction with severe myelosuppression, mucositis, cardiotoxicity, or neurotoxicity, or after an unintentional overdose, and who are identified within 96 hours of the last chemotherapy dose, we recommend uridine triacetate. For individuals with ongoing severe fluoropyrimidine-related toxicity (diarrhea, myelosuppression, mucositis, cardiotoxicity, or neurotoxicity) who are identified later than 96 hours after the last chemotherapy dose, we also suggest initiation of uridine triacetate. Following recovery of unusually severe toxicity after the first dose of a fluoropyrimidine, testing for specific high-risk mutations/polymorphisms in FU-metabolizing enzymes should be undertaken prior to retreatment with a fluoropyrimidine. (See 'Pharmacogenetic and pharmacokinetic testing' below.)

Uridine triacetate (originally called vistonuridine) is an orally administered prodrug of uridine, a specific pharmacologic antidote to fluoropyrimidines, including FU and capecitabine. It is a safe, effective, and potentially life-saving treatment for overdoses of these agents. Uridine triacetate was studied in 173 adult and pediatric patients who were treated in two separate trials and had either received an overdose of FU or capecitabine (n = 147) or had early onset, unusually severe, or rapid-onset life-threatening toxicities within 96 hours after receiving FU (n = 26, the fraction who had DPD deficiency as the cause for severe early toxicity could not be determined) [81]. Overall, 137 of 142 assessable overdose patients (five were lost to follow-up) treated with uridine triacetate (96 percent) survived to 30 days, had rapid reversal of acute neurotoxicity or cardiotoxicity (affecting 12 patients), and had either prevention of or recovery from severe mucositis or leucopenia. Of the 141 uridine triacetate patients with a diagnosis of cancer, 53 were able to resume chemotherapy within 30 days. Among the 26 patients treated for early onset toxicity following fluoropyrimidine therapy, 21 survived to 30 days (81 percent); all five deaths were in patients who initiated uridine triacetate beyond 96 hours after the last dose of the fluoropyrimidine. These results compared favorably with a historical cohort of 25 patients, derived from published case reports, who had experienced FU overdose and for whom the report contained information about the total dose of FU administered, the time and rate of administration, and the patient outcomes. Overall, 21 died (84 percent). Adverse events attributable to uridine triacetate were mild and infrequent, and included diarrhea, nausea, and vomiting.

The dismal outcome for supportive care alone in these patients is underscored by an analysis of FU toxicity cases from the FDA Adverse Event Reporting System (FAERS) [82]. Of the reports of fatalities in patients who experienced early onset, severe, or life-threatening toxicity after FU (n = 58) or capecitabine (n = 145) despite intensive supportive care, all had a uniformly fatal outcome.

There are less data on the use of uridine triacetate in patients who develop severe fluoropyrimidine toxicity because of deficiency in DPD or thymidylate synthetase (table 5) [83]. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Predictive markers'.)

However, the drug has been shown to prevent fatalities in mice that are treated with FU after receiving an inhibitor of DPD [84]. Thus, DPD enzyme-deficient patients who develop early, severe toxicity after receiving the first dose of a fluoropyrimidine should also benefit from treatment with uridine triacetate, if the deficiency is identified soon enough after the drug is administered. Uridine triacetate should not be administered for nonemergency toxicities as it may interfere with the efficacy of fluoropyrimidine treatment. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Management of DPD-deficient patients'.)

Uridine triacetate has received orphan drug designation for treatment of capecitabine or FU overexposure from the European Medicines Agency (EMA). In the United States, uridine triacetate is approved for emergency use following a FU or capecitabine overdose, regardless of the presence of symptoms, for patients who exhibit early onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (eg, GI toxicity and/or neutropenia) within 96 hours following the end of FU or capecitabine administration [85]. There are reports, however, of patients with severe toxicity from FU or capecitabine responding to uridine triacetate administered beyond 96 hours after the last fluoropyrimidine dose [81,86-88]. In our view, uridine triacetate should be given to any patient with severe toxicity from fluoropyrimidine chemotherapy and suspected DPD or thymidylate synthetase enzyme deficiency regardless of the duration of time since the last dose of chemotherapy. The recommended dose and schedule for uridine triacetate in adults is 10 g orally every six hours for 20 doses. The recommended dose and schedule for pediatric patients is 6.2 g/m2 of body surface area, orally, every six hours for 20 doses.

Following recovery of unusually severe toxicity after the first dose of a fluoropyrimidine, testing for specific high-risk mutations/polymorphisms in the genes for DPD (DPYD) and thymidylate synthetase (TYMS) should be undertaken prior to retreatment with a fluoropyrimidine. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Testing for DPYD and TYMS variants'.)

Management of refractory patients — For diarrhea that has not resolved after loperamide and higher dose octreotide, gastroenterology should be consulted for upper endoscopy to include duodenal biopsy and aspirate [15]. Ulcers and erosions may indicate viral infection, such as cytomegalovirus (CMV), and should be biopsied. Duodenal aspirate can assess for small bowel bacterial overgrowth and parasitic infection [15]. For non-neutropenic patients with no signs of typhlitis, flexible sigmoidoscopy should be performed to assess for ulcerations indicative of CMV or plaques associated with C. difficile. Colonoscopy and flexible sigmoidoscopy are contraindicated in patients suspected of having neutropenic enterocolitis. (See 'Neutropenic enterocolitis' above.)

CMV is one of the most common causes of GI tract infection in patients treated with chemotherapy [15]. The esophagus and colon are the most common sites of infection within the GI tract. Clinical manifestations include diarrhea (up to 80 percent), bleeding, fever, and abdominal pain. Serology, viral cultures, and polymerase chain reaction (PCR) techniques may not be positive for three to four weeks after the start of symptoms [15]. Patients with severe ulcerations and immunosuppressed patients suspected of having CMV infection should be treated empirically with ganciclovir.

Restarting chemotherapy — For most chemotherapy agents, treatment is routinely withheld for grade 2 or worse diarrhea and is only restarted after toxicity resolves. For many drugs with a high risk of CRD (eg, alpelisib, afatinib, ceritinib), the United States Prescribing Information provides specific recommendations for dose reduction in subsequent cycles of therapy in individuals who have severe treatment-related toxicity, including diarrhea.

Guidelines about CRD published in response to septic deaths that occurred with weekly irinotecan chemotherapy concluded that patients must be free from diarrhea for at least 48 hours and not require antidiarrheals above baseline before retreatment with irinotecan [13]. This is a critical principle that, in our opinion, applies to treatment of patients with CRD due to any cytotoxic chemotherapy. Patients should be educated about the importance of not resuming chemotherapy until they have completely recovered from the CRD caused by the prior dose. The need for dose reduction should be addressed for any patient who develops grade 2 or worse diarrhea, particularly complicated diarrhea, during a prior cycle of therapy.

PREVENTION

Patient education — Patients must be educated about the risk of severe diarrhea with certain chemotherapy regimens (particularly those containing irinotecan and fluorouracil [FU]) and neratinib and about its management. Patients should be instructed to use loperamide as directed by the oncologist's office and to not be limited by the package instructions. Loperamide is not absorbed but is excreted in stool, and the risk of overdose in the setting of CRD is unlikely [15]. Patients should be instructed and encouraged to call with any concerns, including diarrhea that does not respond to six to eight loperamide tablets in a 24 hour period, abdominal cramping, and fever. The potential need for in-person assessment, intravenous fluids, and antibiotics should be explained.

Pharmacogenetic and pharmacokinetic testing — Strategies to reduce CRD include initial dosing of irinotecan based on uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) genotype (individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia and diarrhea following treatment), pharmacogenetic testing for mutations and polymorphisms in the fluoropyrimidine-metabolizing enzymes dihydropyrimidine dehydrogenase (DPD) and thymidylate synthetase, and pharmacokinetically guided dosing of FU. However, none of these approaches has been widely adopted. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan' and "Dosing of anticancer agents in adults", section on 'Fluoropyrimidines, dihydropyrimidine dehydrogenase, and thymidylate synthase variants' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Testing for DPYD and TYMS variants' and "Dosing of anticancer agents in adults", section on 'Therapeutic drug monitoring'.)

However, one exception is that patients who have a history of unconjugated hyperbilirubinemia without an identifiable cause, such as hemolysis, typically have Gilbert syndrome. Patients with Gilbert syndrome have a defect in the promoter of the gene that encodes UGT1A1, which is responsible for the conjugation of bilirubin with glucuronic acid. The UGT1A1 protein also conjugates SN-38, the active metabolite of irinotecan [89], to glucuronic acid. Gilbert syndrome manifests clinically in homozygous carriers of this mutation, but heterozygotes will also have elevated bilirubin levels. We recommend an initial dose reduction (eg, 25 percent) of irinotecan for patients who have known or suspected Gilbert syndrome based on a history of elevated unconjugated bilirubin without another cause. (See "Gilbert syndrome".)

Is there a role for prophylaxis? — Prophylactic antidiarrheal treatment is recommended during the first two cycles of neratinib, to reduce the incidence and severity of treatment-related diarrhea. Prophylactic antidiarrhea treatment is not a standard approach for any other chemotherapy regimen.

Neratinib — Neratinib is an orally active, irreversible tyrosine kinase inhibitor of several epidermal growth factor receptors, including HER1, HER2, and HER4; it is approved for extended adjuvant therapy in early stage HER2-positive breast cancer, and in combination with capecitabine for advanced HER2-positive breast cancer. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Dual anti-HER2 therapy in high-risk disease'.)

Treatment-related diarrhea occurs in almost all treated patients, and it is severe (grade 3 or 4) in approximately 40 percent. Antidiarrheal prophylaxis has been shown to reduce both the incidence and severity of neratinib-induced diarrhea [90,91]. The United States Prescribing Information for neratinib recommends prophylactic loperamide (4 mg three times a day during the first two weeks of therapy initiated with the first dose, then 4 mg twice daily during weeks three to eight until day 56, and thereafter, titration of the dose to maintain one to two bowel movements per day [91]). Neratinib dose modifications for grade 2 to 4 diarrhea despite the use of loperamide are also included in the prescribing information.

Other regimens — A variety of approaches have been explored for primary antidiarrheal therapy prophylaxis in patients treated with a variety of other high-risk regimens, mostly bolus FU plus leucovorin and irinotecan-containing. There is insufficient evidence to support a recommendation for any of these treatments, and for most patients we suggest not pursuing any of these approaches. One scenario where long-acting octreotide (octreotide LAR) might be considered is for secondary prophylaxis in patients who have experienced severe CRD during a prior cycle of chemotherapy, in order to maintain dose intensity.

Octreotide – In contrast to its therapeutic benefit, the role of prophylactic octreotide is unproven [77,78,92,93]. In the only randomized study to compare octreotide long-acting release (LAR) with a no-treatment control arm in 139 patients receiving chemotherapy for colorectal cancer with FU, capecitabine, and/or irinotecan, octreotide LAR did not prevent or reduce the severity of CRD [93].

However, one scenario where octreotide LAR might be considered is for secondary prophylaxis in patients who have experienced severe CRD during a prior cycle of chemotherapy, in order to maintain dose intensity. The benefit of this approach was suggested in a study, which closed early due to poor accrual of patients who experienced grade 2 or higher diarrhea with an initial cycle of chemotherapy; treatment was continued with a 25 percent reduction in the chemotherapy dose plus the addition of octreotide 30 mg LAR intramuscular injection monthly [78]. Patients who did not experience grade 2 or higher diarrhea with the second cycle could resume full-dose chemotherapy with continuation of the octreotide. Ten of the 29 patients assigned to this approach were able to resume full-dose chemotherapy without severe diarrhea. No patient experienced adverse events related to octreotide that were greater than grade 1. This approach should only be considered if diarrhea is the only dose-limiting toxicity, and only if maintaining dose intensity is clinically important. (See 'Octreotide' above.)

Activated charcoal – Activated charcoal may have a role in preventing irinotecan-induced diarrhea [94]. In one study, 28 patients received activated charcoal during the first treatment cycle but not the second. The incidence of grade 3 or 4 diarrhea increased from 7 to 25 percent between cycles 1 and 2, and more patients required 10 or more tablets of loperamide without prophylaxis.

Oral alkalinization – A complicated regimen of oral alkalinization of the intestinal lumen in conjunction with control of defecation may have been beneficial in a Japanese case-control study of patients undergoing irinotecan and cisplatin chemotherapy [95].

Probiotics – An interesting but investigational strategy is oral administration of "probiotics," microorganisms such as the Lactobacillus species. Based on the success of this approach in children afflicted by diarrheal illnesses, as well as for antibiotic-induced diarrhea, a trial was conducted in 150 patients receiving two different FU-based chemotherapy regimens, in which the random assignment was to receive or not receive Lactobacillus rhamnosus GG and/or fiber supplementation [96]. Patients who received Lactobacillus supplements had significantly less grade 3 and 4 diarrhea (22 versus 37 percent) and required fewer hospitalizations and dose reductions due to bowel toxicity. However, this group also had a trend toward a higher number of neutropenic complications. Fiber intake did not alter chemotherapy toxicity. Interpretation of this trial is limited by the lack of stratification for method of chemotherapy administration. A randomized, placebo-controlled trial of probiotics for patients treated with irinotecan was closed early for poor accrual. Among the 46 patients enrolled, those on probiotics had less diarrhea and less severe diarrhea, but the results are not statistically significant [97]. Further studies are needed to assess the overall benefit of such interventions.

Racecadotril – A randomized phase II trial demonstrated no benefit for the enkephalinase inhibitor racecadotril to prevent or diminish the severity of delayed diarrhea in patients treated with irinotecan [98].

Lafutidine – Lafutidine is a histamine antagonist that has been shown to reduce FU-induced mucosal injury [99]. Twenty-two patients with resected stage II or III gastric cancer were randomly assigned to adjuvant S1 chemotherapy or S1 plus lafutidine. The addition of lafutidine to chemotherapy significantly reduced the overall incidence of diarrhea from 83 to 10 percent (p = 0.002) [100]. Larger studies are needed to confirm these findings.

Calcium aluminosilicate clay – Calcium aluminosilicate clay, a cation exchange absorbent, did not prevent severe irinotecan-induced diarrhea in a randomized trial of 100 patients [101].

BudesonideBudesonide is an orally administered, topically active synthetic steroid with proven efficacy in patients suffering from diarrhea caused by inflammatory bowel disease and collagenous colitis. A prospective, double-blind, placebo-controlled, randomized phase III study in 56 patients receiving irinotecan failed to show a significant protective benefit, although there were some trends toward fewer diarrhea episodes (0.7 versus 2.2), a shorter duration of diarrhea (1.8 versus 4.2 days), and less frequent use of loperamide (42 versus 56 percent) with budesonide. Larger studies are needed.

PaliferminPalifermin, a keratinocyte growth factor, administered intravenously for three days before and after chemotherapy was found to reduce severe diarrhea from 26 to 8 percent (p = 0.01) in 155 patients with acute myelogenous leukemia undergoing induction chemotherapy [102].

Glutamine – Whether glutamine is beneficial to prevent CRD is unclear; studies have had mixed results [103-107]. In three studies, glutamine (oral in two, parenteral in one) did not reduce the incidence of severe diarrhea in patients undergoing chemoradiation for rectal cancer [103], in patients receiving leucovorin-modulated FU chemotherapy for colorectal cancer [107], or in breast cancer patients treated with doxifluridine [105]. On the other hand, modest benefit was suggested in a small (n = 70), randomized, placebo-controlled trial in which oral glutamine (18 g/day) administered prophylactically to patients treated with leucovorin-modulated FU decreased the duration of diarrhea but had no significant impact on severity; treated patients also took fewer loperamide tablets after one cycle of chemotherapy (0.4 versus 2.6) [104].

SUMMARY AND RECOMMENDATIONS

Highest-risk agents – Chemotherapy-related diarrhea (CRD) is a common problem in cancer patients and is most often described with fluoropyrimidines; irinotecan; and several molecularly targeted agents, especially sorafenib, sunitinib, afatinib, ceritinib lapatinib, and aflibercept. In addition, immune checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab) cause an immune-mediated colitis. (See "Immune checkpoint inhibitor colitis".)

Clinical manifestations

CRD typically begins with an increasing frequency of bowel movements and/or a loosening of stool consistency, commonly accompanied by excessive gas and/or intestinal cramping. As the CRD progresses, it can become severe, with frequent watery stools.

CRD can be debilitating and, in some cases, life-threatening; hospital admission is frequently needed for adequate supportive care. Other sequelae include reduced quality of life, treatment delay, and diminished compliance with treatment regimens, which may compromise long-term outcomes if the chemotherapy is being administered with curative intent. (See 'Introduction' above.)

Assessment

Patients with CRD should be assessed for number of stools and stool composition (and if relevant, the volume and consistency of ostomy output) (table 1), as well as for symptoms or signs that suggest "complicated" diarrhea, such as cramping, grade 2 or worse (table 3) nausea or vomiting, decreased performance status, fever, dizziness, hypotension, neutropenia, bleeding, dehydration, chest pain, and prior admission for CRD. (See 'History and physical examination' above.)

Patients who develop diarrhea during chemotherapy may also suffer from organic causes, which may or may not be related to the chemotherapy and should not be overlooked. These include small intestinal bacterial overgrowth, fat or bile acid malabsorption, intake of excess quantities of sorbitol or lactose intolerance, inflammatory and infectious causes, stool impaction, and collagenous colitis. (See 'Differential diagnosis' above.)

Management

Site and urgency of care – Evaluation and management depends on severity and whether exacerbating factors are present (algorithm 1). Most patients with severe (grade 3 or 4) diarrhea, as well as those with grade 1 or 2 complicated diarrhea, require admission for intravenous fluids, monitoring of cardiovascular status, and serial assessment of electrolytes. However, patients with grade 3 diarrhea that has not yet been treated adequately with loperamide and who are well hydrated may be managed at home with serial assessment for response to therapy and development of complications that might indicate the need for hospitalization or targeted therapy. (See 'Management according to the severity of diarrhea and other exacerbating factors' above.)

Investigations

-Laboratory testing should address both the complications and causes of CRD. These include a complete blood count and a standard chemistry screen including magnesium. For patients with severe (grade 3 or 4) diarrhea, persistent mild to moderate (grade 1 or 2) diarrhea, or diarrhea accompanied by neutropenia, fever, or blood in the stools, cultures of blood and stool, and diagnostic testing for toxin-producing strains of C. difficile are indicated

-Patients with fever, peritoneal signs, or bloody diarrhea should also have an urgent CT scan of the abdomen and pelvis, and surgical consultation.

-Endoscopy is not indicated in the vast majority of cases but should be considered for refractory cases and for patients who develop chronic diarrhea (ie, diarrhea that persists throughout the entire chemotherapy cycle) or bloody diarrhea. (See 'Lymphocytic colitis' above and 'Management of refractory patients' above.)

Nonpharmacologic measures – Initial nonpharmacologic measures include avoidance of foods that might aggravate the diarrhea (table 2); aggressive oral rehydration with fluids that contain water, salt, and sugar, such as broth or Gatorade; and either a clear liquid diet or a BRAT (bananas, rice, applesauce, and toast) diet. Patients should be instructed to avoid alcohol, caffeine, and lactose-containing foods (table 4), and to stop other medications and supplements that could cause diarrhea, such as stool softeners, laxatives, milk thistle, aloe, saw palmetto, Siberian ginseng, plantago seeds, coenzyme Q10, high doses of vitamin C, and green tea. (See 'General measures' above.)

Pharmacologic therapy

-We recommend loperamide rather than diphenoxylate-atropine for initial therapy of CRD (Grade 1A). For mild to moderate (grade 1 or 2) uncomplicated CRD, we suggest an initial dose of 4 mg, followed by 2 mg every four hours or 2 mg after each loose stool (no more than 16 mg per day) (Grade 2C).

-For patients with severe (grade 3 or 4) diarrhea, mild to moderate diarrhea that is complicated by moderate to severe abdominal cramping, grade 2 or worse nausea/vomiting (table 3), decreased performance status, fever, sepsis, neutropenia, frank bleeding, dehydration, or mild to moderate uncomplicated diarrhea that persists after 24 hours of loperamide, we suggest high-dose loperamide (4 mg initially, followed by 2 mg every two hours, no more than 16 mg daily) (Grade 2C). (See 'Loperamide and diphenoxylate-atropine' above.)

-We recommend octreotide for any patient with CRD that is refractory to loperamide (Grade 1B). We suggest initiating therapy at 100 or 150 mcg subcutaneously three times daily (or 50 to 150 mcg/hour intravenously). The octreotide dose should be rapidly escalated to 500 mcg subcutaneously three times a day (rarely up to 2000 mcg three times a day) if lower doses are not effective. (See 'Patients refractory to loperamide' above.)

-For fluoropyrimidine-treated patients who develop severe diarrhea after the initial dose, in conjunction with severe myelosuppression, mucositis, cardiotoxicity, or neurotoxicity, or after an unintentional overdose, who are identified within 96 hours of the last chemotherapy dose, we recommend uridine triacetate (Grade 1A). For individuals with ongoing severe fluoropyrimidine-related toxicity (diarrhea, myelosuppression, mucositis, cardiotoxicity, or neurotoxicity) who are identified later than 96 hours after the last chemotherapy dose, we also suggest initiation of uridine triacetate (Grade 2C). (See 'Uridine triacetate' above.)

-There is no consensus on the appropriate role for oral antibiotics in patients with CRD. We would start intravenous antibiotics for patients with fever, neutropenia, hypotension, peritoneal signs, or bloody diarrhea. (See 'Oral antibiotics' above.)

-For refractory cases, empiric anti-cytomegalovirus therapy may be needed for selected patients who have severe ulceration in the upper or lower gastrointestinal tract. (See 'Management of refractory patients' above.)

Rechallenge – Patients who experience CRD should not be retreated with the same chemotherapy regimen until they are diarrhea-free without the use of antidiarrheal agents for 48 hours. The need for dose reduction should be addressed in any patient who develops grade 2 or worse diarrhea, particularly complicated diarrhea, during a prior cycle of therapy. (See 'Restarting chemotherapy' above.)

Prophylaxis

For patients receiving neratinib, we recommend daily prophylactic loperamide, at least for the first eight weeks of therapy (Grade 1B). (See 'Neratinib' above.)

A variety of approaches have been explored for primary antidiarrheal therapy prophylaxis in patients treated with a variety of other high-risk regimens, mostly bolus FU plus leucovorin and irinotecan-containing, but there is insufficient evidence to support a recommendation for any of these treatments, and for most patients we suggest not pursuing any of these approaches (Grade 2C).

One scenario where long-acting octreotide (octreotide LAR) might be considered is for secondary prophylaxis in patients who have experienced severe CRD as the only dose-limiting toxicity during a prior cycle of chemotherapy, if maintaining dose intensity is critical. (See 'Is there a role for prophylaxis?' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Smitha S Krishnamurthi, MD, who contributed to earlier versions of this topic review.

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Topic 98342 Version 22.0

References

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