Journal of Pain and Symptom Management
Volume 36, Issue 4 , Pages 413-423, October 2008

Evaluation and Management of Treatment-Related Diarrhea in Patients with Advanced Cancer: A Review

  • Nathan I. Cherny, MBBS, FRACP, FRCP

      Affiliations

    • Corresponding Author InformationAddress correspondence to: Nathan I. Cherny, MBBS, FRAC, FRCP, Cancer Pain and Palliative Medicine Service, Department of Oncology, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 91031, Israel.

Cancer Pain and Palliative Medicine Service, Department of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel

Accepted 31 October 2007. published online 15 April 2008.

Article Outline

Abstract 

Diarrhea is a common and significant problem among patients with advanced cancer. Treatment-induced diarrhea can be severe and be associated with life-threatening dehydration and electrolyte abnormalities. The causes of diarrhea among patients with advanced cancer are diverse and some causes of diarrhea require specific therapies. Thus, careful evaluation of the underlying cause is necessary. Palliative care clinicians, particularly those dealing with patients receiving ongoing disease-modifying therapies, must be familiar with the common causes of diarrhea among cancer patients and the strategies to evaluate and manage these common and distressing symptoms. This article addresses four major issues: 1) a review of the causes of treatment-related diarrhea, focusing on diarrhea caused by chemotherapy, targeted therapies, and radiotherapy; 2) differential diagnosis and an approach to evaluation; 3) general management considerations; and 4) cause-specific issues in management.

Key Words: Diarrhea, adverse effects, diagnosis, assessment, management, palliative care, advanced cancer

 

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Introduction 

Diarrhea is a common and significant problem among patients with advanced cancer. It is defined as the frequent passage of loose stools with urgency.1 Objectively defined, it is the passage of more than three unformed stools in 24 hours. Severe diarrhea can be debilitating and, at times, even life threatening. It contributes to dehydration, electrolyte imbalance, malnutrition, declining immune function, and pressure ulcer formation.

Increasingly, diarrhea caused by disease-modifying therapies presents a clinical challenge. Treatment-induced diarrhea can be severe and associated with life-threatening dehydration and electrolyte abnormalities.2 Given the diverse causes of diarrhea among patients with advanced cancer and the availability of specific therapies, careful evaluation of the underlying cause is necessary. Palliative care clinicians, particularly those dealing with patients receiving ongoing disease-modifying therapies, must be familiar with the common causes of treatment-induced diarrhea and the strategies to evaluate and manage this common and distressing disorder.

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Causes of Treatment-Related Diarrhea 

Chemotherapy-Induced Diarrhea 

The chemotherapy agents commonly causing diarrhea include 5-fluorouracil (5-FU), irinotecan (CPT-11), and capecitabine.2 Diarrhea is usually a dose-related adverse effect and may be associated with other features of toxicity. Chemotherapy-induced diarrhea appears to be a multifactorial process, whereby acute damage to the intestinal mucosa (including loss of intestinal epithelium, superficial necrosis, and inflammation of the bowel wall) causes an imbalance between absorption and secretion in the small bowel.

5-Fluorouracil 

Mechanism. 5-FU causes mitotic arrest of intestinal epithelial crypt cells, resulting in an increase in the ratio of immature secretory crypt cells to mature villous enterocytes. This results in abnormal absorption and secretion of fluids and electrolytes.3 Opportunistic infections, causing local inflammation and factors released by necrosis secondary to chemotherapy, directly stimulate intestinal secretion of fluids and electrolytes. The diarrhea associated with 5-FU therapy may be watery or bloody. Disruption of the integrity of the gut lining may permit access of enteric organisms into the blood stream, with the potential for overwhelming sepsis, particularly if the granulocyte nadir coincides with diarrhea. Severity is variable but it may be severe and at times life threatening. Pathologic changes range in severity from a mild colitis to severe necrotizing enterocolitis with pneumocystic colitis.

Risk factors. Diarrhea is most commonly observed when 5-FU is coadministered with leucovorin (LV). It is slightly more common with bolus rather than infusional administration of 5-FU/LV, in particular with high-dose LV (500mg/m2),4, 5 but it occurs with all administration schedules.6 In the initial reports of weekly 5-FU/LV, diarrhea was seen in up to 50% of patients, with one-half of these requiring hospitalization for intravenous (IV) fluids4, 5 and, in one study, a 5% mortality rate.5 Other risk factors have been identified, including unresected primary tumor, previous episodes of chemotherapy-induced diarrhea,3 and female gender.7, 8

Dihydropyrimidine dehydrogenase (DPD) deficiency. 5-FU is normally metabolized to inactive dihydro-5-FU after an IV dose; 80% of the drug is metabolized to the inactive dihydro-5-FU by DPD in the liver. Administration of 5-FU to patients with DPD deficiency can lead to life-threatening complications, including severe diarrhea, mucositis, and pancytopenia.9, 10, 11 DPD deficiency is relatively common among Caucasians (3%–5%).11 Although the diagnosis can be made by radioimmunometric assay for the DPD enzyme, this test is not a readily available, and consequently, most cases are diagnosed retroactively after severe complications. More recently, a simple breath test has been developed12, 13 and this may provide an effective screening tool.11 Some authorities have suggested that information about DPD deficiency and its consequences be incorporated in discussions of the risks of 5-FU therapy and that patients should be offered the possibility of testing for the presence of a DPD deficiency before initiation of treatment.14

Irinotecan 

Irinotecan can cause acute diarrhea (immediately after drug administration) or a delayed diarrhea. Immediate-onset diarrhea is caused by acute cholinergic properties and it is often accompanied by other symptoms of cholinergic excess, including abdominal cramping, rhinitis, lacrimation, and salivation. The mean duration of symptoms is 30 minutes and it usually responds rapidly to atropine.15

The delayed-onset diarrhea usually occurs at least 24 hours after drug administration and can be potentially life threatening, especially in combination chemotherapy regimens with bolus IV fluorouracil and LV.15 The late diarrhea associated with irinotecan is unpredictable, noncumulative, and occurs at all dose levels. It is more common with high doses every three weeks than with lower weekly dosing.15, 16 The median time to onset is six to fourteen days. The mechanism of irinotecan-induced delayed diarrhea is not known, but it is believed to result from the deconjugation of CPT's metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide, by intestinal bacteria, thus enabling a direct effect of the active agent on colonic epithelium.17, 18 It is suggested that the active agent binds to topoisomerase I and induces apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. Additionally, both irinotecan and SN-38 may also stimulate the production of proinflammatory cytokines and prostaglandins, thus contributing to an inflammatory/secretory diarrhea.19

Genetic factors may influence the glucuronidation of SN-38, the active metabolite of irinotecan, and thus increase this risk of diarrhea. Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified; among these is a mutation in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7, or 8, instead of 6 thymine-adenine repeats. The homozygous presence of the UGT1A1*28 polymorphism, leading to less efficient glucuronidation of SN-38, has been identified as a potential risk factor for the occurrence of delayed-type diarrhea and Grade 3–4 neutropenia.20, 21 In one study, heterozygote had a twofold elevation of risk of severe diarrhea.22

Capecitabine 

Capecitabine, a precursor of 5-FU, is an oral fluoropyrimidine cytotoxic agent developed with the aim of providing a more effective, less toxic alternative to 5-FU, with the added advantage of oral administration. Capecitabine is converted to 5-FU in three sequential enzymatic reactions; the final one converting 5'-dFUR to 5-FU being completed by thymidine phosphorylase within tumor cells. The relative concentration of 5-FU generated in tumors is 8–14 times higher than the plasma concentrations. Administered at usual doses (2,000mg/m2 per day for 14 of every 21 days), the prevalence of diarrhea is 30%–40% and in 10%–20%, it is severe.23, 24

Docetaxel 

The taxane, docetaxel, commonly causes a relatively mild diarrhea. Data from Phase II and III studies indicated a prevalence of 25%–24%.25 In most cases, the diarrhea is mild; however, cases of severe enteritis and colitis have been reported.26

Neutropenic enterocolitis. Neutropenic enterocolitis (also called necrotizing enterocolitis or typhlitis) is an acute life-threatening complication of chemotherapy that is most commonly observed with high-dose treatments in the setting of myeloablative therapies.27 It is, however, also observed with nonmyeloablative therapies,26, 28 particularly with taxanes.26, 27, 29

Clinical presentation. Neutropenic enterocolitis usually occurs when the absolute neutrophil count falls below 500/μL. Patients present with fever, abdominal pain, nausea, vomiting, diarrhea, and not uncommonly, sepsis. Abdominal pain may be diffuse or localized to the right lower quadrant. Sometimes pain is absent, particularly in the patient who has received steroid therapy.

Pathogenesis. The pathogenesis of neutropenic enterocolitis is multifactorial: mucosal injury by cytotoxic drugs or other means, profound neutropenia, and impaired host defense to invasion by microorganisms.27, 30 The microbial infection leads to necrosis of various layers of the bowel wall. Anatomically, the cecum is almost always affected, and the process often extends into the ascending colon and terminal ileum. The predilection for the cecum is possibly related to its distensibility and its relatively diminished vascularization. Various bacterial and/or fungal organisms, including gram-negative rods, gram-positive cocci, anaerobes (e.g., Clostridium septicum), and Candida sp., are often seen infiltrating the bowel wall. Polymicrobial infection is frequent. Bacteremia or fungemia is also common, usually with enteric organisms, such as Pseudomonas, or yeasts, such as Candida.

Diagnostic investigations. The diagnosis is based on signs and symptoms in the appropriate clinical setting as well as imaging studies. Plain abdominal radiographs may demonstrate dilated loops of bowel, thickening of the bowel wall, “thumbprinting” resulting from bowel wall edema, or indications of a right lower quadrant mass or phlegmon. Free intraperitoneal air indicates perforation of the bowel wall. Pneumatosis intestinalis is often seen.

Computed tomography (CT) scanning is the preferred imaging modality. CT scanning techniques can evaluate the entire abdomen for pathology, especially in patients with distended loops of bowel and ileus, for whom ultrasound would not be possible. Scans commonly demonstrate concentric thickening of the bowel wall, a fluid-filled cecum, pericolic fluid collections or abscesses, pneumatosis intestinalis, and free air if an underlying perforation exists.

Abdominal ultrasonography can identify thickening of the bowel wall that produces a target or halo sign. Indeed, bowel wall thickening of greater than 5mm and greater than 10mm was associated with mortality of 29% and 60%, respectively.31 Ultrasound is useful as a follow-up tool to assess the gradual decrease in bowel wall thickening during resolution.

Targeted Therapy-Associated Diarrhea 

Erlotinib and Gefitinib 

Diarrhea is a common adverse effect of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors, erlotinib32 or gefitinib.33 It occurs in 40%–60% of patients, but it is rarely severe. When these agents are coadministered with 5-FU, irinotecan, and/or capecitabine, the toxicity may exacerbate.

Sorafenib 

Sorafenib is an inhibitor of multiple tyrosine kinases in the vascular EGF pathway. At the recommended dose of 400mg twice daily, it causes diarrhea in 30%–45% of patients treated; in 5%, diarrhea is severe.34, 35 For mild or moderate diarrhea, loperamide is usually effective. For more severe toxicity, stopping the drug until symptoms resolve (usually one to three days) and restarting therapy at 400mg per day usually controls the diarrhea.

Sunitinib 

Sunitinib is a multitargeted tyrosine-kinase inhibitor that is used in the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors (GISTs) after disease progression on, or intolerance to, imatinib. At the usual dose of 50mg/day, diarrhea is seen in 40% of patients, which is severe in approximately 5%.36

Imatinib 

Imatinib, an inhibitor of the Bcr-Abl protein tyrosine kinase used in chronic myelogenous leukemia and GIST, causes diarrhea in about 30%–50% of the patients, which is severe in 1%–5%.37, 38 Diarrhea is dose related and can be easily controlled with antidiarrheal medications. It is hypothesized that diarrhea may be related to C-Kit inhibition in the interstitial cells of Cajal, which have a pacemaker function in the intestine.37

Bortezomib 

Diarrhea is commonly seen with the use of bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma and mantle cell lymphoma. In the pivotal studies with this agent, diarrhea occurred in 51% of patients, with 8% of the events being severe.39

Radiotherapy-Induced Diarrhea 

Radiation injury to the lower intestine is usually encountered following treatment of cancers of the anus, rectum, cervix, uterus, prostate, urinary bladder, or testes, and as part of total body irradiation. Radiotherapy of the abdomen or pelvis damages intestinal mucosa, causing prostaglandin release and bile salt malabsorption. These two factors increase intestinal peristalsis, causing diarrhea.

Acute radiation enteritis/proctitis occurs within six weeks of therapy. Symptoms include diarrhea, cramping, rectal urgency or tenesmus, and, uncommonly, bleeding. These symptoms usually resolve without specific therapy within two to six months.40, 41

Chronic radiation enteritis is less common. It most commonly presents as the delayed development of diarrhea, nausea, weight loss or abdominal pain, or any combination of these symptoms. It is usually associated with radiation doses greater than 45Gy and it appears after a latency of months to years after the initial exposure.41, 42 The underlying pathology is a progressive radiation-induced endarteritis that causes intestinal ischemia. The ischemia may result in fibrosis, stricturing, ulceration, and occasionally fistula formation. The physiologic consequences of these changes include altered intestinal transit, reduced bile acid absorption, increased intestinal permeability, bacterial overgrowth, and lactose malabsorption.41

Other Causes of Treatment-Related Diarrhea 

Medications 

Excessive doses of laxatives or magnesium-containing antacids commonly result in diarrhea.

Clostridium Difficile Diarrhea 

Clostridium difficile diarrhea occurs when the normal intestinal flora is altered, allowing C. difficile to flourish in the intestinal tract and produce a toxin that causes a watery diarrhea.43 It can be triggered by repeated enemas, prolonged nasogastric tube insertion, gastrointestinal (GI) tract surgery, and the use of antibiotics, especially penicillin (ampicillin), clindamycin, and cephalosporins. Occasionally, however, it has been reported after chemotherapy in the absence of antibiotic therapy.44, 45 The most common confirmatory study is an enzyme immunoassay for C. difficile toxins A and B. The test is easy to perform, and results are available in two to four hours. Specificity of the assay is high (93%–100%), but sensitivity ranges from 63% to 99%.46

Enteral Feeding 

Tube feedings, either by nasogastric tube, gastrostomy, or jejunostomy, may be associated with the development of diarrhea.47, 48 This is a common problem, occurring in 10%–60% of patients.49 Many potential factors may contribute to the problem and indeed it is often multifactorial.50 The composition of formula may affect the incidence of diarrhea. Both formula osmolality and rate of delivery may be associated with diarrhea.51 The use of fiber-containing formulas to control diarrhea related to tube feeding is controversial and evidence of efficacy is mixed.52, 53

Contamination of the enteral formula is often a contributing or causative factor.54, 55 Recommendations to reduce the risk of contamination include hand washing before handling the feeding system, the use of clean equipment to prepare and mix feedings, jevity bag and tubing change at least once a day, limitation of “hanging time” of individual bags to under six hours, and refrigerated storage of prepared bags until use.

Patients selected for tube feeding are often hypoalbuminemic. Some data suggest that hypoalbuminemia predisposes patients to diarrhea by decreasing osmotic pressure and causing edema in the intestinal mucosa.56

Celiac Plexus Block 

Celiac plexus block is commonly associated with a self-limiting acute diarrhea. Occasionally, diarrhea may be persistent.57 This diarrhea may be amenable to treatment with atropine.58

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Differential Diagnosis of Diarrhea in Patients with Advanced Cancer 

There are other common causes of diarrhea in patients with advanced cancer and these often need to be considered in the differential diagnosis. Occasionally, fecal impaction or partial bowel obstruction can manifest as alternating constipation and diarrhea. Fecal impaction results in bacterial degradation of stools above the level of impaction, resulting in fluid stool leaking past the impacted mass, sometimes with incontinence. In some instances, diarrhea may be caused by comorbidities such as inflammatory bowel disease (IBD) and thyroxicosis.

Cancers can cause malabsorption syndromes by a number of mechanisms. Each of these is characterized by increased fecal fat. Pancreatic cancer may be associated with obstruction of the pancreatic duct, pancreatic exocrine failure, or biliary obstruction.59 In some cases, patients who have undergone either Whipple's procedure or a gastrectomy with a roux-en-y may develop bacterial overgrowth within the efferent loop, which may result in a malabsorption syndrome.60 Resection of more than 100cm of ileum can hinder the reabsorption of bile acids, causing a watery diarrhea.61 Ileal resection also causes a disaccharidase deficiency, resulting in carbohydrate malabsorption and an osmotic diarrhea.

Colectomy reduces the water absorbing capacity that occurs in the colon, which cannot be fully compensated by the small bowel and also can result in diarrhea. Changes in intestinal anatomy may cause bacterial overgrowth, resulting in diarrhea.

A number of pancreatic islet cell tumors may be associated with severe secretory diarrhea with hypokalemia.62 Vasoactive intestinal protein-secreting tumors may cause severe life-threatening watery diarrhea. Similar problems may be seen in some patients with carcinoid syndrome. Less severe diarrhea may be observed with gastrinomas causing a Zollinger Ellison Syndrome. Finally, diarrhea is also sometimes observed with medullary carcinoma of the thyroid63 and GIST.64

Assessment 

The U.S. National Cancer Institute's grading for the severity of diarrhea is presented in Table 1. In the setting of chemotherapy-induced diarrhea, it is an important consideration in treatment selection (see below).

Table 1. U.S. National Cancer Institute Common Toxicity Criteria for Grading of Diarrhea
Toxicity01234
Patients without a colostomyNoneIncrease of <4 stools/d over pretreatmentIncrease of 4–6 stools/d or nocturnal stoolsIncrease of ≥7 stools/d>10 stools/d
NoneNoneModerate cramping, not interfering with normal activitySevere cramping and incontinence, interfering with daily activitiesGrossly bloody diarrhea and need for parenteral support
Patients with a colostomyNoneMild increase in loose, watery colostomy output compared with pretreatmentModerate increase in loose, watery colostomy output compared with pretreatment, but not interfering with normal activitySevere increase in loose, watery colostomy output compared with pretreatment, interfering with normal activityPhysiological consequences requiring intensive care; hemodynamic

Adapted from Ref. 80.

The assessment of a patient with possible treatment-induced diarrhea should include a detailed medical history, dietary history, medication review, description of stools, and a physical examination focused on the identification of dehydration, and abnormalities of the abdominal and rectal areas. When appropriate, abdominal radiographs can be ordered to evaluate for abdominal obstruction or fecal impaction. Biochemical parameters should be checked for evidence of dehydration, hypokalemia, or renal impairment. If enteric infections are suspected, stool samples should be sent for fecal leukocytes, C. difficile toxins A and B, and culture for organisms including C. difficile, Salmonella, Escherichia coli, Campylobacter, and infectious colitis. As described above, when neutropenic enterocolitis is suspected, CT imaging of the abdomen should be undertaken and additional prognostic information may be obtained by ultrasound evaluation of bowel wall thickness.

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General Principles in the Management of Diarrhea 

Patients must be rehydrated either orally, or when appropriate, by parenteral infusion. In cases of large volume diarrhea, there is the potential for very rapid dehydration with risk of prerenal impairment or even, in extreme cases, shock. Patients may suffer electrolyte imbalance, particularly hypokalemia. Because a transient lactase deficiency with lactose malabsorption can occur with any form of mucosal injury to the GI tract, milk products should be avoided. Special attention should be given to patients who are incontinent of stool due to the risk of pressure ulcer formation. Skin barriers should be used to prevent skin irritation caused by fecal material.

Antidiarrheal Medications 

Opioids 

Loperamide is generally the opioid of choice because it has local activity in the gut and is absorbed only minimally (this accounts for the lack of systemic effects).65 It reduces stool weight, frequency of bowel movements, urgency, and fecal incontinence in acute and chronic diarrhea. Loperamide can be started at an initial dose of 4mg followed by 2mg every two to four hours or after every unformed stool.66 Other opioids, such as tincture of opium, morphine, or codeine, can be used.

“Tincture of opium” is a widely used antidiarrheal agent. It is often recommended as an alternative to loperamide. Deodorized tincture of opium contains the equivalent of 10mg/mL morphine and the recommended dose is 10–15 drops in water every three to four hours.67 It is important not to confuse this with paregoric, which is a camphorated (alcohol-based) tincture. The latter is a less-concentrated preparation that contains the equivalent of 0.4mg/mL morphine. The recommended dose is one teaspoon (5mL) in water every three to four hours.67

Somatostatin Analogs 

In cases of severe or persistent diarrhea, the somatostatin analog octreotide should be considered. Octreotide has multiple antidiarrheal actions, including suppression of release of insulin, glucagon, vasoactive intestinal peptide, and gastric acid; reduction in motility; and increased absorption of water, electrolytes, and nutrients from the GI tract.68 The usual starting dose for octreotide is 100–150μg SC/IV three times daily. Because there is a dose-response relationship with regard to the antidiarrheal effect, the dose can be titrated up to 500μg subcutaneous (SC)/IV three times daily or by continual IV infusion 25–50μg/h.69 Recently, a microencapsulated, long-acting formulation of octreotide has been developed for once monthly intramuscular dosing. This formulation has demonstrated efficacy in resolving severe diarrhea and preventing further episodes of diarrhea in patients receiving ongoing therapy.70

Other Agents 

Budesonide is an orally administered, topically active steroid with high activity in IBD, a 90% first pass effect in the liver and, therefore, low systemic availability. It is commonly used in the management of diarrhea in patients with low-to-medium grade IBD. One small study has demonstrated efficacy of oral budesonide in the management of chemotherapy-induced diarrhea that was refractory to loperamide.71

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Specific Management Guidelines 

Acute Chemotherapy-Induced or Radiotherapy-Induced Diarrhea 

Standard guidelines for management of acute treatment-induced diarrhea were published in 2004.69 Patients are classified as uncomplicated or complicated on the basis of clinical features and this classification guides treatment approach.

“Uncomplicated” Diarrhea 

Step 1: Patients with Grade 1 or 2 diarrhea and no other complicating signs or symptoms may be classified as “uncomplicated” and managed conservatively with oral hydration and loperamide. Initial management of mild-to-moderate diarrhea should include dietary modifications (e.g., eliminating all lactose-containing products and high-osmolar dietary supplements). The patient should be instructed to record the number of stools and report other serious symptoms (e.g., fever or dizziness on standing). Loperamide should be started at an initial dose of 4mg followed by 2mg every four hours or after every unformed stool (not to exceed 16mg/d). If diarrhea resolves with loperamide, the patients should be instructed to continue dietary modifications and to gradually add solid foods to their diet. In the case of chemotherapy-induced diarrhea, patients may discontinue loperamide when they have been diarrhea-free for at least 12 hours.

Step 2: If mild-to-moderate diarrhea persists for more than 24 hours, the dose of loperamide should be increased to 2mg every two hours, and oral antibiotics may be started as prophylaxis for infection.

Step 3: If mild-to-moderate chemotherapy-induced diarrhea has not resolved after 24 hours on high-dose loperamide (48 hours total treatment with loperamide), the patient should be seen in the physician's office or outpatient center for further evaluation, including complete stool and blood work-up. Stool work-up should include evaluation for pathogens. Fluids and electrolytes should be replaced as needed. Loperamide should be discontinued and the patient should be started on a second-line antidiarrheal agent, such as octreotide (100 μg to 150 μg starting dose, with dose escalation as needed) or other second-line agents (e.g., oral budesonide or tincture of opium).

“Complicated” Chemotherapy-Induced Diarrhea 

Patients with mild-to-moderate diarrhea complicated by moderate-to-severe cramping, nausea, and vomiting; diminished performance status, fever, sepsis, neutropenia, bleeding, or dehydration; and patients with severe diarrhea, are classified as “complicated.” These patients should be evaluated further, monitored closely and treated aggressively.

Aggressive management of complicated cases usually necessitates hospital admission and involves IV fluids; octreotide at a starting dose of 100–150μg three times daily (25–50μg/h) if the patient is severely dehydrated, with dose escalation up to 500μg three times daily until diarrhea is controlled, and administration of antibiotics (e.g., fluoroquinolone). These patients should be evaluated with complete blood count, electrolyte profile, and a stool work-up evaluating for blood, fecal leukocytes, C. difficile, Salmonella, E. coli, Campylobacter, and infectious colitis.

Chronic Radiation Therapy-Induced Diarrhea 

Opioid antidiarrheal agents are recommended, but are relatively contraindicated in patients with obstructive symptoms. Antibiotics may reduce diarrhea in patients in whom there is evidence of bacterial overgrowth on breath testing.72 Most recently, there is accumulating anecdotal evidence that hyperbaric oxygen therapy may help relieve symptoms of chronic radiation enteritis.73, 74, 75

Management of Neutropenic Enterocolitis 

Management of neutropenic enterocolitis is challenging and the risk of mortality is high. There are roles for both medical and surgical interventions.

The initial treatment for neutropenic colitis is medical, with the administration of broad-spectrum antibiotics, granulocyte colony-stimulating factors, nasogastric decompression, IV fluids, bowel rest, and serial abdominal examinations.27, 30, 76 In most patients, these measures are sufficient, and symptoms resolve after correction of the neutropenia. The administered antibiotics should have a broad spectrum of activity to cover enteric gram-negative organisms, gram-positive organisms, and anaerobes. Causative microorganisms include Pseudomonas, Staphylococcus aureus, E. coli, and Group A Streptococcus.76 In cases that do not respond to antibacterial agents, amphotericin should be considered, because fungemia is common.27, 77 Blood transfusions may be necessary because the diarrhea is often bloody. Anticholinergic, antidiarrheal, and opioid agents should be avoided because they may aggravate ileus.

The indications for, and timing of, surgical intervention are controversial. The mortality of patients who fail to respond to medical interventions is high and many patients may not be salvageable. Nonetheless, in selected patients, surgery may be helpful to avoid progressive bowel necrosis, perforation, and to help control sepsis. Commonly cited indications for surgery include: 1) persistent GI bleeding after correction of thrombocytopenia and coagulopathy; 2) evidence of intraperitoneal perforation; 3) abscess formation 4) clinical deterioration despite aggressive supportive measures; and 5) to rule out other intra-abdominal processes such as bowel obstruction or acute appendicitis.27, 30, 76, 78, 79

If exploratory surgery is performed, resection of grossly involved bowel is necessary. All necrotic material must be resected, usually by a right hemicolectomy, ileostomy, and mucous fistula. Failure to remove the necrotic focus in these severely immunocompromised patients is potentially fatal.78, 79 Primary anastomosis is not generally recommended in such severely immunocompromised patients because of the increased incidence of anastomotic leak.78, 79 Because anastomotic leak in this setting is almost always fatal, primary anastomosis should be considered only for uncomplicated cases in patients with no systemic sepsis or organ failure.

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Conclusions 

Diarrhea may pose a major management issue for cancer and palliative care clinicians. There is a clinical imperative for clinicians to be familiar with the common causes of treatment-induced diarrhea, its evaluation, and management strategies. Treatment-induced diarrhea remains a fertile domain for ongoing clinical and basic investigation. Better understanding of the mechanisms of these diverse syndromes may help facilitate new approaches to prophylaxis and risk reduction, and the development of more effective approaches to acute and long-term management.

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PII: S0885-3924(08)00111-5

doi:10.1016/j.jpainsymman.2007.10.007

Journal of Pain and Symptom Management
Volume 36, Issue 4 , Pages 413-423, October 2008

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