The reported prevalence and severity of diarrhea vary greatly. Some chemotherapeutic regimens are associated with diarrhea rates as high as 50% to 80%, particularly those containing fluoropyrimidines or irinotecan.[1,2] Diarrhea is also commonly observed in patients diagnosed with carcinoid tumors, receiving radiation therapy to abdominal/pelvic fields, or undergoing bone marrow transplantation or surgical intervention of the gastrointestinal tract. In a large heterogeneous sample of cancer patients in various stages of treatment, the prevalence of moderate-to-severe diarrhea was 14%. Diarrhea occurs in approximately 7% to 10% of cancer patients upon admission to hospice. Among children with cancer during the last month of life, 19% experienced diarrhea.
The consequences of diarrhea can be significant and life-threatening. According to the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events, more than half of patients receiving chemotherapy for colorectal cancer experienced diarrhea of grade 3 or grade 4, requiring treatment changes or the reduction, delay, or discontinuation of therapy (see Table 1).[7,8] A review of several clinical trials of irinotecan plus high-dose fluorouracil and leucovorin in colorectal cancer revealed early death rates of 2.2% to 4.8%, primarily due to gastrointestinal toxicity. With the advent of more aggressive anticancer therapies, the potential physical and psychosocial consequences of diarrhea and its indirect effect on cancer treatment outcome are likely to expand.Table 1. National Cancer Institute's Common Terminology Criteria for Adverse Events: Diarrheaa,b
|1||Increase of <4 stools/day over baseline; mild increase in ostomy output compared to baseline|
|2||Increase of 4–6 stools/day over baseline; moderate increase in ostomy output compared to baseline|
|3||Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADLc|
|4||Life-threatening consequences; urgent intervention indicated|
|ADL = activities of daily living.|
|aAdapted from National Cancer Institute.|
|bDefinition: A disorder characterized by frequent and watery bowel movements.|
|cSelf-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.|
Etiology of Diarrhea
In patients being treated for cancer, diarrhea is most commonly induced by therapy. Conventional methods of diarrhea-causing treatment include surgery, chemotherapy, radiation therapy, and bone marrow transplantation. Other causes of acute diarrhea include antibiotic therapy, stress and anxiety associated with cancer diagnosis and treatment, and infection. Typical infections are of viral, bacterial, protozoan, parasitic, or fungal etiology; they may also be caused by pseudomembranous colitis, a cause of diarrhea that often does not respond to treatment. Clostridium difficile is a common cause of pseudomembranous colitis. Other causes of diarrhea in patients with cancer include the underlying cancer, responses to diet, or concomitant diseases (see Table 2). Common causes of diarrhea in patients receiving palliative care are difficulty adjusting the laxative regimen and impaction leading to leakage of stool around the fecal obstruction.
Another strategy for categorizing the causes of diarrhea is by putative underlying mechanisms. These include exudative (i.e., excess blood or mucous enters the gastrointestinal tract), malabsorptive, dysmotile, osmotic, and secretory (due to increased secretion of electrolytes and fluid—probably the mechanism underlying chemotherapy-induced diarrhea) factors or combinations of these factors.
Surgery, a primary treatment modality for many cancers, can affect the body by mechanical, functional, and physiological alterations. Postsurgical complications of gastrointestinal surgery affecting normal bowel function that may contribute to diarrhea include increased transit time, gastroparesis, fat malabsorption, lactose intolerance, fluid and electrolyte imbalance, and dumping syndrome.[14,15]
Certain chemotherapeutic agents can alter normal absorption and secretion functions of the small bowel, resulting in treatment-related diarrhea. Examples of chemotherapy agents with diarrhea-related potential are listed in Table 2. Patients receiving concomitant abdominal or pelvic radiation therapy or recovering from recent gastrointestinal surgery will often experience more severe diarrhea.
Radiation therapy to abdominal, pelvic, lumbar, or para-aortic fields can result in changes to normal bowel function. Factors contributing to the occurrence and severity of intestinal complications depend on total dose, fractionation, volume of bowel irradiated, and concomitant chemotherapy. Common side effects of intestinal enteritis include diarrhea, malabsorption, gas, bloating, and cramping. Acute intestinal side effects occur at approximately 10 Gy and may last up to 8 to 12 weeks posttherapy. Chronic radiation enteritis may present months to years after completion of therapy and necessitates dietary modification and pharmacological management and, in some instances, surgical intervention. (Refer to the Radiation Enteritis section of this summary for more information.)
Graft-versus-host disease (GVHD) is a major complication of allogeneic transplantation, and the intestinal tract, skin, and liver are commonly affected. Symptoms of gastrointestinal GVHD include nausea and vomiting, severe abdominal pain and cramping, and watery, green diarrhea. The volume of accompanying GVHD-associated diarrhea may reach up to 10 L per day and is an indicator of the degree and extent of mucosal damage. Acute GVHD is usually manifested within 100 days posttransplant, although it can occur as early as 7 to 10 days posttransplant. It may resolve or develop into a chronic form requiring long-term treatment and dietary management.Table 2. Possible Contributions to Diarrhea in Cancer
|Cancer-related [5,18]||Carcinoid syndrome|
|Medullary carcinoma of the thyroid|
|Pancreatic cancer, particularly islet cell tumors (Zollinger-Ellison syndrome)|
|Surgery- or procedure-related ||Celiac plexus block|
|Gastrectomy, pancreaticoduodenectomy (Whipple procedure)|
|Intestinal resection (malabsorption due to short bowel syndrome)|
|Chemotherapy-related [19-21]||Capecitabine, cisplatin, cytosine arabinoside, cyclophosphamide, daunorubicin, docetaxel, doxorubicin, 5-fluorouracil, interferon, irinotecan, leucovorin, methotrexate, oxaliplatin, paclitaxel, topotecan, lapatinib|
|Radiation therapy–related (refer to the Radiation Enteritis section of this summary for more information) [22,23]||Irradiation to the abdomen, para-aortics, lumbar, and pelvis|
|Bone marrow transplantation–related ||Conditioning chemotherapy, total-body irradiation, graft-versus-host disease after allogeneic bone marrow or peripheral blood stem cell transplants|
|Drug adverse effects [5,18]||Antibiotics, magnesium-containing antacids, antihypertensives, colchicine, digoxin, iron, lactulose, laxatives, methyldopa, metoclopramide, misoprostol, potassium supplements, propranolol, theophylline|
|Concurrent disease [5,18]||Diabetes, hyperthyroidism, inflammatory bowel disease (Crohn disease, diverticulitis, gastroenteritis, HIV/AIDS, ulcerative colitis), obstruction (tumor-related)|
|Infection ||Clostridium difficile, Clostridium perfringens, Bacillus cereus, Giardia lamblia, Cryptosporidium, Salmonella, Shigella, Campylobacter, Rotavirus|
|Fecal impaction [5,18]||Constipation leading to obstruction|
|Diet [5,18]||Alcohol, milk, and dairy products (particularly in patients with lactose intolerance)|
|Caffeine-containing products (coffee, tea, chocolate); specific fruit juices (prune juice, unfiltered apple juice, sauerkraut juice)|
|High-fiber foods (raw fruits and vegetables, nuts, seeds, whole-grain products, dried legumes); high-fat foods (deep-fried foods, high fat–containing foods)|
|Lactulose intolerance or food allergies|
|Sorbitol-containing foods (candy and chewing gum); hot and spicy foods; gas-forming foods and beverages (cruciferous vegetables, dried legumes, melons, carbonated beverages)|
|Psychological factors ||Stress|
Because of the potentially life-threatening nature of diarrhea, rapid, yet thorough, assessment is imperative. Few standardized assessment tools are available, and studies suggest that, as a result, standardized assessment is rare in the clinical setting. For a complete assessment, one author suggests obtaining background information from the patient that includes the type and extent of the patient’s cancer, anticancer treatment, comorbid factors, coexisting symptoms, patient and provider perceptions, as well as a thorough description of the diarrhea. Stringent monitoring conducted at least weekly is indicated during therapy using chemotherapeutic agents known to cause diarrhea. The NCI’s Common Terminology Criteria for Adverse Events (Table 1) evaluate diarrhea by number of stools per day, incontinence, and increase in ostomy output compared to baseline.
The history also should include questions regarding the frequency of bowel movements during the past 24 hours, the character of the fecal material, and the time course of the development of diarrhea. One author has developed a visual tool to assist patients and families in characterizing the consistency of the stool. Six diagrams illustrate fecal material consistency ranging from well-formed, formed, and semiformed to loose, very loose, and liquid. Patients should be questioned regarding related symptoms that might indicate hemodynamic compromise or the underlying etiology. Specifically, questions should include information about dizziness, orthostatic symptoms, lethargy, cramping, abdominal pain, nausea, vomiting, fever, and rectal bleeding. These symptoms should be classified as complicated or uncomplicated, with therapy based on these classifications. Uncomplicated symptoms include grade 1 or 2 diarrhea with no other signs or symptoms. Management is conservative. Complicated symptoms include grade 1 or 2 diarrhea with any one of the following risk factors: moderate to severe cramping, grade 2 or higher nausea/vomiting (see Table 3), decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration. Grade 3 or 4 diarrhea is also classified as complicated. Thorough evaluation and close monitoring is warranted. The time course of diarrhea and concomitant symptom development are key to determining underlying etiology. Medication and dietary intake, as well as a history of recent travel, may provide additional clues regarding etiology. Weight loss and reduced urine output provide additional data regarding the severity of the effects of diarrhea.Table 3. National Cancer Institute’s Common Terminology Criteria for Adverse Events: Nausea and Vomitinga
|Nauseab||1||Loss of appetite without alteration in eating habits|
|2||Oral intake decreased without significant weight loss, dehydration, or malnutrition|
|3||Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated|
|4||Grade not available|
|5||Grade not available|
|Vomitingc||1||1–2 episodes (separated by 5 min) in 24 h|
|2||3–5 episodes (separated by 5 min) in 24 h|
|3||≥6 episodes (separated by 5 min) in 24 h; tube feeding, TPN, or hospitalization indicated|
|4||Life-threatening consequences; urgent intervention indicated|
|TPN = total parenteral nutrition.|
|aAdapted from National Cancer Institute.|
|bDefinition: A disorder characterized by a queasy sensation and/or the urge to vomit.|
|cDefinition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.|
The goal of physical examination is to identify potential causes of diarrhea and its complications as quickly as possible to reduce morbidity. The physical examination should include vital signs and evaluation of skin turgor and oral mucosa to assess hemodynamic status and dehydration. Abdominal examination includes evaluation for rebound tenderness, guarding, hypoactive or hyperactive bowel sounds, and stool collection. A rectal exam can rule out fecal impaction but should be performed judiciously in neutropenic or thrombocytopenic patients.
Laboratory tests may include stool cultures for bacterial, fungal, and viral pathogens. A complete chemistry panel and hematologic profile can provide information regarding the effect of diarrhea on kidney function and electrolytes as well as identify changes in white blood cell count in response to infection. Urinalysis with specific gravity can provide information regarding hydration status. Stool osmolality may also be measured.
In some cases, radiographic procedures are conducted to identify ileus, obstruction, or other abnormalities. In rare cases, endoscopy may be indicated.Management
A review of early toxic deaths in two NCI-sponsored cooperative trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the revision of previously published clinical practice guidelines for the treatment of cancer treatment–induced diarrhea, with a heightened emphasis on assessment and early aggressive interventions. The guidelines distinguish between uncomplicated and complicated diarrhea.Uncomplicated symptoms
The current treatment of cancer-related diarrhea is often empiric and nonspecific. Whenever possible, treat underlying causes such as fecal impaction or modify the stimulant laxative regimen as necessary. Medications such as bulk laxatives and promotility agents (e.g., metoclopramide) should be discontinued. Dietary modifications are commonly implemented to stop or lessen the severity of cancer treatment-related diarrhea.[7,23,24,29] One author recommends that patients should consume foods that build stool consistency, are low in fiber, contain minerals, and do not stimulate or irritate the gastrointestinal tract. In some cases, dietary modification for diarrhea management includes advising patients to eat small, frequent meals and avoid lactose-containing food (milk and dairy products), spicy foods, alcohol, caffeine-containing foods and beverages, certain fruit juices, gas-forming foods and beverages, high-fiber foods, and high-fat foods. For mild cases of diarrhea, the BRAT (bananas, rice, apples, toast) diet may reduce the frequency of stools. When experiencing diarrhea, patients should be encouraged to increase clear liquid intake to at least 3 L per day (e.g., water, sports drinks, broth, weak decaffeinated teas, caffeine-free soft drinks, clear juices, and gelatin).[12,31] (Refer to the Diarrhea subsection of the Nutritional Suggestions for Symptom Management section in the PDQ summary on Nutrition in Cancer Care for more information.)
While some case reports suggest the efficacy of glutamine in relieving diarrhea and other gastrointestinal symptoms associated with cancer therapy, one randomized controlled trial that used oral glutamine to prevent pelvic radiation-induced diarrhea was unable to demonstrate any benefit.[Level of evidence: I][33,34]
The goals of pharmacologic therapy include inhibition of intestinal motility, reduction in intestinal secretions, and promotion of absorption. Absorbents include agents that form a gelatinous mass that gives density to fecal material. Methylcellulose and pectin are most commonly used, with little data to support their efficacy. These bulk-forming agents may not be well tolerated in some patients because of the large volume required for therapeutic effect and the associated abdominal discomfort and bloating. Adsorbents such as kaolin, clays, and activated charcoals have been used extensively, but no data support their use. Furthermore, they may inhibit absorption of other oral antidiarrheals that may be administered.
Opioids bind to receptors within the gastrointestinal tract and reduce diarrhea by reducing transit time. Loperamide is the most common opioid used, due to its availability and reduced effect on cognition, although codeine and other opioids can also be effective. Common loperamide doses begin with 4 mg, followed by 2 mg after each unformed stool with a maximum of approximately 12 mg/day.[5,26] Regardless of the dose, however, loperamide may be less effective in patients with grade 3 or 4 diarrhea.[Level of evidence: I]
Mucosal prostaglandin inhibitors, also referred to as antisecretory agents, include aspirin, bismuth subsalicylate, corticosteroids, and octreotide. Aspirin may be useful for radiation-induced diarrhea. Bismuth subsalicylate is believed to have direct antimicrobial effects on Escherichia coli, hence its prophylactic use in traveler’s diarrhea. This agent is contraindicated in patients who should not be taking aspirin, and large doses can produce toxic salicylate levels. Corticosteroids reduce edema associated with obstruction and radiation colitis and can reduce hormonal influences of some endocrine tumors.
Other pharmacologic therapies for the relief of diarrhea may be specific to the underlying mechanism. Delayed diarrhea (>24 hours) occurs with irinotecan and can be severe in 25% of patients. In a small study of seven patients, six patients obtained relief with oral neomycin, 1,000 mg 3 times daily. This relief occurred without reduction in the active metabolite of irinotecan, SN-38; thus, the poorly metabolized antibiotic did not alter efficacy of the chemotherapeutic agent.[Level of evidence: II] In another small study of 37 patients with non-small cell lung cancer receiving irinotecan, investigators alkalized the feces through oral administration of sodium bicarbonate, basic water, and ursodeoxycholic acid, while speeding transit time of the drug metabolites (thought to reduce damage to the intestinal lumen by reducing stasis of the drug) through the use of magnesium oxide. The incidence of delayed diarrhea was significantly reduced in this group when compared to 32 patients receiving the same chemotherapeutic regimen without oral alkalization and controlled defecation.[Level of evidence: III]
In addition to antidiarrheal agents and immunosuppressive medications, a specialized five-phase dietary regimen should be instituted to effectively manage the diarrhea associated with GVHD. Phase 1 consists of total bowel rest until the diarrhea is reduced. Nitrogen losses associated with diarrhea can be severe and are compounded by the high-dose corticosteroids used to treat GVHD. Phase 2 reintroduces oral feedings consisting of beverages that are isotonic, low-residue, and lactose-free to compensate for the loss of intestinal enzymes secondary to alterations in the intestinal villi and mucosa. If these beverages are well tolerated, phase 3 may reintroduce solids containing minimal lactose, low fiber, low fat, low total acidity, and no gastric irritants. In phase 4, dietary restrictions are progressively reduced as foods are gradually reintroduced and tolerance is established. Phase 5 includes the resumption of the patient’s regular diet; however, most patients usually remain lactose intolerant.Probiotics
Probiotics are nutritional supplements that contain a defined amount of viable microorganisms and, upon administration, confer a benefit to the patient. The use of probiotic functional foods (beneficial live microorganisms) to modify gut microflora has been suggested in clinical conditions associated with diarrhea, gut-barrier dysfunction, and inflammatory response. There are a vast number of different strains of probiotics; however, much of the clinical research has investigated the species belonging to the family of Lactobacillus and Bifidobacterium. Probiotics have been promoted for the following:[41-46]
- Prevention of antibiotic-induced diarrhea and rotavirus.
- Treatment or prevention of inflammatory bowel disease, irritable bowel syndrome, and gastroenteritis.
- Treatment of necrotizing enterocolitis in premature infants.
The results of one study among adults with cancer have been published. In a double-blind, randomized, controlled trial, 450 adults with cancer who were receiving radiation to the pelvic region were randomly assigned to receive the blend probiotic product VSL #3 or placebo during radiation therapy. The authors reported a decrease in the incidence and severity of diarrhea. No adverse events were reported.
Clinical trials for the following patients are under way:
- Patients with familial adenomatous polyposis (NCT00319007).
- Patients undergoing donor stem cell transplantation for hematologic cancer or myelodysplastic syndrome (NCT00946283). This trial is now closed to accrual.
While the optimal dose of octreotide has not been determined, a panel of experts has recommended that complicated cases of diarrhea should be managed with intravenous (IV) fluids, octreotide at a starting dose of 100 to 150 μg subcutaneously (SC) 3 times a day or 25 to 50 μg/hour IV with a dose escalation to 500 μg 3 times a day, and administration of antibiotics. This regimen should be continued until the patient has been diarrhea free for 24 hours. Particularly when patients are receiving chemotherapy, additional evaluation should include stool workup (including blood, fecal leukocytes, C. difficile, Salmonella, E. coli, Campylobacter, and infectious colitis), complete blood count, and electrolyte profile. This workup and treatment should also be considered for patients who progress to grade 3 or 4 diarrhea while taking loperamide. The same panel suggests that severe radiation therapy–induced diarrhea may not require hospitalization (an alternative outpatient unit or intensive home care nursing may be able to provide the same level of care and monitoring) but the patient's constellation of symptoms should be considered to determine the appropriate workup and whether IV fluids or octreotide is indicated.
Octreotide, a somatostatin analog, is currently the most promising agent in the management of severe diarrhea caused by a variety of diseases and treatments. The doses used in clinical trials have varied widely. Regardless of the lack of consensus regarding optimal dose, octreotide has been shown to be effective in relieving diarrhea associated with AIDS, carcinoid syndrome, and vasoactive intestinal polypeptide tumors.[Level of evidence: II] Several open-label and randomized controlled studies of octreotide in the relief of chemotherapy-induced diarrhea have demonstrated the efficacy of this therapy.[49-51][Level of evidence: I];[52-54][Level of evidence: II] In a prospective trial of 32 patients who had chemotherapy-induced diarrhea that was refractory to loperamide, octreotide 100 µg SC 3 times a day produced complete resolution in 30 patients. Resolution occurred rapidly, with 5 patients responding within 24 hours, 14 patients responding within 48 hours, and 11 patients responding within 72 hours after beginning treatment. No adverse effects of the octreotide were noted. Octreotide has also been shown to be effective in diarrhea associated with GVHD.[56,57] An expert panel recommended using high-dose loperamide (2 mg every 2 hours) for the first day of chemotherapy-induced diarrhea that is low grade (1 and 2), followed by octreotide, 100 to 150 µg every 8 hours. If the patient presents with severe diarrhea (grade 3 or 4), octreotide, 500 to 1,500 µg SC or IV every 8 hours, should be first-line therapy. A phase III, double-blind study of depot octreotide for the prevention of diarrhea during pelvic radiation treatment did not demonstrate any benefit. In fact, some gastrointestinal symptoms such as cramping may have been worse. Parenteral hydration and electrolyte supplementation may be indicated, and in severe cases, total parenteral nutrition may be initiated. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about diarrhea that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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