Gastrointestinal Complications (PDQ®): Supportive care - Health Professional Information [NCI]

Overview

Gastrointestinal complications such as constipation, impaction, bowel obstruction, diarrhea, and radiation enteritis are common problems for patients with cancer. The growth and spread of cancer, as well as its treatment, contribute to these conditions.

Constipation is the slow movement of feces through the large intestine that results in the passage of dry, hard stool. This can result in discomfort or pain.[1] The longer the transit time of stool in the large intestine, the greater the fluid absorption and the drier and harder the stool becomes.

Perhaps the most common causes of constipation are inadequate fluid intake and pain medications. Inactivity, immobility, or physical and social impediments (particularly inconvenient bathroom availability) can contribute to constipation. Depression and anxiety caused by cancer treatment or cancer pain can also lead to constipation. Many of these contributing conditions are manageable.

Constipation may be annoying and uncomfortable, but fecal impaction can be life-threatening. Impaction is the accumulation of dry, hardened feces in the rectum or colon. The patient with a fecal impaction may present with circulatory, cardiac, or respiratory symptoms rather than with gastrointestinal symptoms.[2] If the fecal impaction is not recognized, the signs and symptoms may progress and result in death.

In contrast to constipation and impaction, an intestinal obstruction is a partial or complete occlusion of the bowel lumen by a process other than fecal impaction. Intestinal obstructions can be classified by the type of obstruction, the obstructing mechanism, and the part of the bowel involved.

Structural disorders, such as intraluminal and extraluminal bowel lesions caused by primary or metastatic tumor, postoperative adhesions, volvulus of the bowel, or incarcerated hernia, affect peristalsis and the maintenance of normal bowel function. These disorders can lead to total or partial obstruction of the bowel. Patients who have colostomies are at special risk of developing constipation. If stool is not passed on a regular basis (once a day to several times a day), further investigation is warranted. A partial or complete blockage may have occurred, particularly if no flatus has been passed.[3]

Diarrhea can occur throughout cancer care, and the effects can be physically and emotionally devastating. Although less prevalent than constipation, diarrhea remains a significant symptom burden for people with cancer. This condition can do the following:

• Alter dietary patterns.
• Trigger dehydration.
• Create electrolyte imbalance.
• Impair function.
• Cause fatigue.
• Impair skin integrity.
• Limit activity.

In some cases, diarrhea can be life-threatening. Furthermore, diarrhea can lead to increased caregiver burden.

Specific definitions of diarrhea vary widely. Acute diarrhea is generally considered to be an abnormal increase in stool liquid that lasts more than 4 days but less than 2 weeks. Another definition suggests that diarrhea is an increase in stool liquidity (>300 mL of stool) and frequency (the passage of more than three unformed stools) during a 24-hour period.[4] Diarrhea is considered chronic when it persists longer than 2 months.

Radiation enteritis is a functional disorder of the large and small bowel that occurs during or after a course of radiation therapy to the abdomen, pelvis, or rectum. One report also documented radiation-induced diarrhea in individuals with lung or head and neck cancers who were receiving radiation with or without chemotherapy.[5]

The large and small bowel are sensitive to ionizing radiation. Although the probability of tumor control increases with the radiation dose, so does the damage to normal tissues. Acute side effects to the intestines occur at approximately 10 Gy. Because curative doses for many abdominal or pelvic tumors range between 50 and 75 Gy, enteritis is likely to occur.[6]

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

References:

1. Culhane B: Constipation. In: Yasko J, ed.: Guidelines for Cancer Care: Symptom Management. Reston Publishing Company, Inc., 1983, pp 184-7.
2. Wright BA, Staats DO: The geriatric implications of fecal impaction. Nurse Pract 11 (10): 53-8, 60, 64-6, 1986.
3. Hampton BG, Bryant RA, eds.: Ostomies and Continent Diversions: Nursing Management. Mosby Year Book, Inc., 1992.
4. Tuchmann L, Engelking C: Cancer-related diarrhea. In: Gates RA, Fink RM, eds.: Oncology Nursing Secrets. 2nd ed. Hanley and Belfus, 2001, pp 310-22.
5. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015.
6. Perez CA, Brady LW, eds.: Principles and Practice of Radiation Oncology. 3rd ed. Lippincott-Raven Publishers, 1998.

Constipation

Etiology of Constipation

Common factors that contribute to the development of constipation in the general population include the following:

• Diet.
• Altered bowel habits.
• Inadequate fluid intake.
• Lack of exercise.

Constipation can be a presenting symptom of cancer, or it can occur later as a side effect of a growing tumor or treatment of the tumor. For patients with cancer, additional causative factors include the following:[1]

• The tumor itself.
• Cancer-related problems.
• Effects of drug therapy for cancer or cancer pain.
• Other concurrent processes such as organ failure, decreased mobility, and depression.

Physiological factors include the following:

• Inadequate oral intake.
• Dehydration.
• Inadequate intake of dietary fiber.
• Organ failure.

Any of these factors can occur because of the disease process, aging, debilitation, or treatment.

Causes of Constipation

*Frequently seen in oncology patients.

Medications

• Chemotherapy (e.g., any agent that can cause autonomic nervous system changes such as vinca alkaloids, oxaliplatin, taxanes, and thalidomide).*
• Opioids and sedatives.
• Anticholinergic preparations (e.g., gastrointestinal antispasmodics, antiparkinsonism agents, and antidepressants).
• Phenothiazines.
• Calcium- and aluminum-based antacids.
• Diuretics.
• Vitamin supplements (e.g., iron and calcium).
• Tranquilizers and sleeping medications.
• General anesthesia and pudendal blocks.

Diet

• Inadequate fluid intake.*

Altered bowel habits

• Repeatedly ignoring defecation reflex.
• Excessive use of laxatives and/or enemas.

Prolonged immobility* and/or inadequate exercise

• Spinal cord injury or compression, fractures, fatigue, weakness, or inactivity (including bedrest).
• Intolerance with respiratory or cardiac problems.

Bowel disorders

• Irritable colon, diverticulitis, or tumor.*

Neuromuscular disorders (disruption of innervation leads to atony of the bowel)

• Neurological lesions (cerebral tumors).
• Spinal cord injury or compression.*
• Paraplegia.
• Cerebrovascular accident with paresis.
• Weak abdominal muscles.

Metabolic disorders

• Hypothyroidism and lead poisoning.
• Uremia.*
• Dehydration.*
• Hypercalcemia.*
• Hypokalemia.
• Hyponatremia.

Depression

• Chronic illness.
• Anorexia.
• Immobility.
• Antidepressants.

Inability to increase intra-abdominal pressure

• Emphysema.
• Any neuromuscular impairment of the diaphragm or abdominal muscles.
• Massive abdominal hernias.

Atony of muscles

• Malnutrition.
• Cachexia, anemia, or carcinoma.*
• Senility.

Environmental factors

• Inability to get to the bathroom without assistance.
• Unfamiliar or hurried environment.
• Excess heat leading to dehydration.
• Change in bathroom habits (e.g., use of a bedpan).
• Lack of privacy.

Narrowing of colon lumen

• Related to scarring from radiation therapy, surgical anastomosis, or compression from growth of extrinsic tumor.

Constipation is frequently the result of autonomic neuropathy caused by vinca alkaloids, oxaliplatin, taxanes, and thalidomide. Other drugs, such as opioid analgesics or anticholinergics (antidepressants and antihistamines), may lead to constipation by causing decreased sensitivity to the defecation reflex and decreased gut motility. Since constipation is common with the use of opioids, a bowel regimen should be initiated when opioids are prescribed and continued for as long as the patient takes them. Opioids produce varying degrees of constipation, suggesting a dose-related phenomenon. One study suggests that clinicians should not base laxative prescribing on the opioid dose, but rather titrate the laxative according to bowel function. Lower doses of opioids or weaker opioids, such as codeine, are just as likely to cause constipation.[2] For more information, see the Constipation section in Cancer Pain.

Other diseases, such as diabetes (with autonomic neuropathy) and hypothyroidism, may cause constipation. Metabolic disorders, such as hypokalemia and hypercalcemia, also predispose cancer patients to developing constipation. Once these disorders are corrected, constipation will subside.[1]

Assessment of Constipation

A normal bowel pattern is having at least three stools per week and no more than three stools per day; however, these criteria may be inappropriate for patients with cancer.[1,3] Constipation is viewed as a subjective symptom involving complaints of decreased frequency with incomplete passage of dry, hard stool. A thorough history of the patient's bowel pattern, dietary changes, and medications, along with a physical examination, can identify possible causes of constipation. The evaluation also includes assessment of associated symptoms such as distention, flatus, cramping, or rectal fullness. A digital rectal examination is done to rule out fecal impaction at the level of the rectum. A test for occult blood will be helpful in determining a possible intraluminal lesion. A thorough examination of the gastrointestinal tract is necessary if cancer is suspected.[4]

The following questions may provide a useful assessment guide:

1. What is normal for the patient (frequency, amount, and timing)?
2. When was the last bowel movement? What was the amount, consistency, and color? Was blood passed with it?
3. Has the patient been having any abdominal discomfort, cramping, nausea or vomiting, pain, excessive gas, or rectal fullness?
4. Does the patient regularly use laxatives or enemas? What does the patient usually do to relieve constipation? Does it usually work?
5. What type of diet does the patient follow? How much and what type of fluids are taken on a regular basis?
6. What medications (dose and frequency) is the patient taking?
7. Is this symptom a recent change?
8. How many times a day is flatus passed?

Physical assessment will determine the presence or absence of bowel sounds, flatus, or abdominal distention. Patients with colostomies are assessed for constipation. Dietary habits, fluid intake, activity levels, and use of opioids in these patients are examined.

Management of Constipation

Comprehensive management of constipation includes prevention (if possible), elimination of causative factors, and judicious use of laxatives. Some patients can be encouraged to increase dietary fiber (fruits; green, leafy vegetables; 100% whole-grain cereals and breads; and bran) and to increase fluid intake to one-half ounce per pound of body weight daily (if not contraindicated by renal or heart disease). See Nutrition in Cancer Care for more information.

A study that involved geriatric patients compared the efficacy, cost, and ease of administration of a natural laxative mixture (raisins, currants, prunes, figs, dates, and prune concentrate) with protocols using stool softeners, lactulose, and other laxatives. Results indicated lower costs, more natural and regular bowel movements, and increased ease of administration with natural laxatives. Even though generalization from these findings was limited by small sample size, additional exploration of natural laxatives in cancer patient populations might be useful.[5] A program for prevention of constipation in cancer patients is described below.

Assessment

• Establish the patient's normal bowel pattern and habits (time of day for normal bowel movement, consistency, color, and amount).
• Explore the patient's level of understanding and compliance relating to exercise level, mobility, and diet (fluid, fruit, and fiber intake).
• Determine normal or usual use of laxatives, stimulants, or enemas.
• Determine laboratory values, specifically looking at platelet count.
• Conduct a physical assessment of the rectum (or stoma) to rule out impaction.

Commonly used interventions

• Record bowel movements daily.
• Encourage patient to increase fluid intake, with a goal of drinking eight 8-oz (240-mL) glasses of fluid daily unless contraindicated.
• Encourage regular exercise, including abdominal exercises in bed or moving from bed to chair if the patient is not ambulatory.
• Encourage adequate fiber intake. Experts recommend that:
  • Healthy adults consume 20 g to 35 g of fiber per day (average consumption is 11 g).
  • Children and adolescents up to age 18 years consume the number of grams of fiber equal to their age plus 5—for example, a 10-year-old consumes 15 g of fiber per day (10 + 5).

    While there are no specific fiber recommendations for cancer patients, they are encouraged to eat more high-fiber foods such as fruits (e.g., raisins, prunes, peaches, and apples), vegetables (e.g., squash, broccoli, carrots, and celery), and 100% whole-grain cereals, breads, and bran. Increased fiber intake must be accompanied by increased fluid intake, or constipation may result. High fiber intake is contraindicated in patients at increased risk for bowel obstruction, such as those with a history of bowel obstruction or status postcolostomy.

• Provide a warm or hot drink approximately one-half hour before time of patient's usual defecation.
• Provide privacy and quiet time at the patient's usual or planned time for defecation.
• Provide toilet or bedside commode and appropriate assistive devices; avoid bedpan use whenever possible.

Another approach, shown below in two parts, is adapted from the MD Anderson Cancer Center practice consensus algorithm for the prevention and management of opioid-induced constipation. Copyright 2008 The University of Texas MD Anderson Cancer Center

MD Anderson Cancer Center Algorithm for the Prevention of Opioid-induced Constipation

Unless there are existing alterations in bowel patterns (e.g., bowel obstruction or diarrhea), patients receiving opioids are started on a laxative bowel regimen and receive education for bowel management. Stimulant laxative plus stool softener (e.g., Senokot-S [senna 8.6 mg plus docusate 50 mg]), two tablets per day and titrate up (maximum nine tablets per day). Ensure adequate fluids, dietary fiber, and exercise, if feasible. Prune juice followed by warm beverage may be considered.

MD Anderson Cancer Center Algorithm for the Management of Opioid-induced Constipation

1. Assess potential cause of constipation (e.g., recent opioid dose increase, use of other constipating medications, or new bowel obstruction).
2. Increase Senokot-S (or senna and docusate tablets, if using separately), and add one or both of the following:
   1. Milk of magnesia oral concentrate (1170/5 mL), 10 mL by mouth 2 to 4 times per day.
   2. Polyethylene glycol (MiraLAX), 17 g in 8-oz beverage daily.
3. If no response to above, perform digital rectal examination to rule out low impaction. Continue above steps AND:
   1. If impacted, disimpact manually if stool is soft. If not, soften with mineral oil fleets enema before disimpaction. Follow up with milk of molasses enemas until clear with no formed stools.
   2. Consider use of rescue analgesics before disimpaction.
   3. If not impacted on rectal examination, patient may still have higher level impaction; if history is appropriate, consider abdominal imaging and/or administer milk of molasses enema with magnesium citrate 8 oz by mouth. Consider bowel management consult.
4. If patient is neutropenic or thrombocytopenic, arrange for bowel management consult.

• Start one of the following regimens if the patient has not had a stool in 3 days or on the first day that any patient starts taking drugs associated with constipation:
  • Stool softeners (e.g., docusate sodium, one to two capsules per day). For opioid-related constipation, stool softeners may be used in combination with a stimulant laxative. Bulk-producing agents are not recommended in a regimen used to counteract the bowel effects of opioids.
  • Two tablets of a senna preparation twice daily.
  • One bisacodyl tablet at bedtime.
  • Milk of magnesia, 30 to 45 mL, if a bowel movement is not achieved in 24 hours after other methods are instituted.
• If the amount of stool is still inadequate, increase stool softeners up to six capsules per day or a senna preparation gradually to a maximum of eight tablets (four tablets twice a day); bisacodyl may be increased gradually to three tablets.
• If the amount of stool is still inadequate, a glycerin or bisacodyl suppository or enema (phosphate/biphosphate, oil retention, or tap water) is used with caution, especially in patients with neutropenia or thrombocytopenia.

Medical management includes the administration of saline or chemical laxatives, suppositories, enemas, or agents that increase bulk.

Contraindications

Rectal agents should be avoided in cancer patients at risk of thrombocytopenia, leukopenia, and/or mucositis from cancer and its treatment. In the immunocompromised patient, manipulation of the rectum and anus should be avoided (i.e., no rectal examinations, no suppositories, and no enemas). These actions can lead to the development of anal fissures or abscesses, which are portals of entry for infection. Also, the stoma of a patient with neutropenia should not be manipulated unnecessarily.

Transanal irrigation (TAI) is a recently described therapeutic modality intended to manage chronic neurogenic and anatomic dysmotility of the colon resulting in chronic constipation or fecal incontinence.[6] Several studies have found greater efficacy with TAI than with conventional management strategies for neurogenic bowel dysfunction;[7,8,9] however, no studies have shown either safety or efficacy in people with constipation related directly to a tumor or caused by treatment for cancer or side-effect management (e.g., opioid-induced constipation). Complications, although rare in the currently indicated populations, include bowel perforation.[10,11] Colon cancer, history of any colorectal surgery, and pelvic radiation are considered relative or absolute contraindications to using TAI.[6]

At this time, for patients with cancer or a history of cancer, the evidence does not support the use of TAI for management of chronic constipation or fecal incontinence for conditions other than neurogenic dysfunction.

Medical Agents for Constipation

Bulk producers

• Bulk producers are natural or semisynthetic polysaccharide and cellulose. They work with the body's natural processes to hold water in the intestinal tract, soften the stool, and increase the frequency of stool passage. Bulk producers are not recommended for a regimen to counteract the bowel effects of opioids.
• Onset: 12 to 24 hours (may be delayed up to 72 hours).
• Caution: Patients take the bulk producer with two full 8-oz (240-mL) glasses of water and maintain adequate hydration to avoid the risk of developing a bowel obstruction. Avoid administering psyllium with salicylates, nitrofurantoin, and digitalis because psyllium decreases the actions of these drugs. Avoid use if intestinal obstruction is suspected.
• Use: Effective in managing irritable bowel syndrome.
• Drugs and dosages:
  • Methylcellulose (Cologel): 5 to 20 cc 3 times per day with water.
  • Barley malt extract (Maltsupex): Four tablets with meals and at bedtime or 2 tbsp powder or liquid 2 times per day for 3 to 4 days, then 1 to 2 tbsp at bedtime.
  • Psyllium: Varies from 1 tbsp to one packet, depending on brand, 1 to 3 times per day.

Saline laxatives

• The high osmolarity of the compounds in saline laxatives attracts water into the lumen of the intestines. The fluid accumulation alters the stool consistency, distends the bowel, and induces peristaltic movement. Cramps may occur.
• Onset: 0.5 to 3 hours.
• Caution: Repeated use can alter fluid and electrolyte balance. Avoid magnesium-containing laxatives in patients with renal dysfunction. Avoid sodium-containing laxatives in patients with edema, congestive heart failure, megacolon, or hypertension.
• Use: Mostly as a bowel preparation to clear the bowels for rectal or bowel examinations.
• Drugs and dosages:
  • Magnesium sulfate: 15 g in a glass of water.
  • Milk of magnesia: 10 to 20 cc if concentrated, 15 to 30 cc if regular.
  • Magnesium citrate: 240 cc.
  • Sodium phosphate: 4 to 8 g dissolved in water.
  • Monobasic and dibasic sodium phosphate (Fleet Phospho-soda): 20 to 40 mL mixed with 4 oz of cold water.

Stimulant laxatives

• Stimulant laxatives increase motor activity of the bowels by direct action on the intestines.
• Onset: 6 to 10 hours.
• Caution: Prolonged use of these drugs causes laxative dependency and loss of normal bowel function. Prolonged use of danthron discolors rectal mucosa and discolors alkaline urine red. Bisacodyl must be excreted in bile to be active and is not effective with biliary obstruction or diversion. Avoid bisacodyl with known or suspected ulcerative lesions of the colon. These medications may cause cramping.
• Drug interactions: Avoid taking bisacodyl within 1 hour of taking antacids, milk, or cimetidine because they cause premature dissolving of the enteric coating, which results in gastric or duodenal stimulation. There is an increased absorption of danthron when it is given with docusate.
• Use: To evacuate bowel for rectal or bowel examinations. Most of the stimulant laxatives act on the colon.
• Drugs and dosages:
  • Danthron: 37.5 to 150 mg with evening meal or 1 hour after evening meal.
  • Calcium salts of sennosides: 12 to 24 mg at bedtime; senna: Senolax, Seneson, or Black-Draught (two tablets); Senokot (two tablets or 10–15 cc at bedtime).
  • Bisacodyl: 10 to 15 mg swallowed whole, not chewed, or a 10-mg suppository.

Lubricant laxatives

• Lubricant laxatives lubricate intestinal mucosa and soften stool.
• Caution: Administer on empty stomach at bedtime. Mineral oil prevents absorption of oil-soluble vitamins and drugs. With older patients, aspiration potential suggests that mineral oil be avoided because it can cause lipid pneumonitis. It can interfere with postoperative healing of anorectal surgery. Avoid giving with docusate sodium, which causes increased systemic absorption of mineral oil.
• Use: Prophylactically to prevent straining in patients for whom straining would be dangerous.
• Drugs and dosages:
  • Mineral oil: 5 to 30 cc at bedtime.

Fecal softeners

• Fecal softeners promote water retention in the fecal mass, thus softening the stool. Stool softeners and emollient laxatives are of limited use because of colonic resorption of water from the forming stool.
• Fecal softeners are not used as the sole regimen but may be useful in combination with stimulant laxatives.
• Onset: Up to 3 days.
• Caution: May increase the systemic absorption of mineral oil when administered together.
• Use: Prophylactically to prevent straining. Most beneficial when stool is hard.
• Drugs and dosages:
  • Docusate sodium: 50 to 240 mg taken with a full glass of water.
  • Docusate calcium: 240 mg each day until bowel movement is normal.
  • Docusate potassium: 100 to 300 mg each day until bowel movement is normal; increase daily fluid intake.
  • Poloxamer 188: 188 mg (480 mg at bedtime).

Lactulose (Cholac, Cephulac)

• Lactulose is a synthetic disaccharide that passes to the colon undigested. When it is broken down in the colon, it produces lactic acid, formic acid, acetic acid, and carbon dioxide. These products increase osmotic pressure, increasing the amount of water held in the stool, which softens the stool and increases the frequency of passage.
• Onset: 24 to 48 hours.
• Caution: Excessive amounts may cause diarrhea with electrolyte losses. Avoid giving to patients with acute abdomen, fecal impaction, or obstruction.
• Dosage: 15 to 30 cc each day (contains 10–20 g of lactulose).

Polyethylene glycol and electrolytes (Golytely, Colyte)

• Five packets are mixed with 1 gallon (3.785 L) of tap water and contain the following: polyethylene glycol (227.1 g), sodium chloride (5.53 g), potassium chloride (2.82 g), sodium bicarbonate (6.36 g), and sodium sulfate (anhydrous, 21.5 g). Do not add flavorings. Serve chilled to improve palatability. Can be stored up to 48 hours in the refrigerator.
• Use: To clear bowel with minimal water and sodium loss or gain.

Opioid antagonists (naloxone, methylnaltrexone, naldemedine)

• Caution: Administer only if other drugs have failed. This drug is contraindicated in patients with bowel obstruction.
• Subcutaneous methylnaltrexone, 0.15 mg per kilogram of body weight, can be administered daily or every other day to treat opioid-induced constipation.
• Onset: In a study of patients receiving palliative care, including those with cancer and noncancer etiologies, approximately one-half of patients defecated within 4 hours of receiving the injection, with 30% of patients having a bowel movement within the first 30 minutes.
• In two studies of patients receiving palliative care—one a single-dose trial and the other a 2-week every-other-day-dose trial—there was no evidence of withdrawal or other central effects of the opioid, and pain scores remained unchanged.[12,13]
• The most common side effects are dizziness, nausea, abdominal pain, flatulence, and diarrhea.
• A study of prolonged-released naloxone in an oxycodone:naloxone ratio of 2:1 (average results of 40:20 mg, 60:30 mg, and 80:40 mg oxycodone:naloxone combination relative to placebo) demonstrated improved bowel function without reversal of analgesia.[14]
• A study of daily oral naldemedine, 0.2 mg for 2 weeks, demonstrated improved bowel function from baseline compared with placebo. There was no associated opioid withdrawal or decrease in opioid-mediated analgesia.[15]

Other drugs (lubiprostone, linaclotide, prucalopride)

• In general, Multinational Association for Supportive Care in Cancer guidelines recommend that lubiprostone, linaclotide, and prucalopride be prescribed and monitored by clinicians with experience using these specialty medications.[16] The use of these agents may be considered if patients with functional/secondary constipation do not respond to conventional first-line laxatives. Lubiprostone and prucalopride may also be considered in patients with opioid-induced constipation who do not respond to opioid antagonists.

  Lubiprostone
  

  • Caution: This drug is contraindicated in patients with bowel obstruction. Dyspnea and chest tightness may occur within 30 to 60 minutes of the first dose and resolve within a few hours. Syncope and hypotension, some requiring hospitalization, may also occur.
  • Lubiprostone is a chloride channel activator that acts to increase intestinal fluid secretion and improve fecal transit, thus bypassing the antisecretory effects of opiates.
  • Onset: 24 to 48 hours in chronic constipation.[17]
  • The most common side effects are diarrhea, nausea, headache, and abdominal pain.
  • Use: Chronic idiopathic constipation, irritable bowel syndrome (IBS) with constipation, and opioid-induced constipation.
  • Dosage: 24 mcg PO twice daily (8 mcg PO twice daily in IBS).

  Linaclotide
  

  • Caution: This drug is contraindicated in pediatric patients less than 2 years of age and in patients with mechanical gastrointestinal obstruction. It may cause severe diarrhea associated with syncope, hypertension, and electrolyte abnormalities.
  • Linaclotide is a guanylate cyclase-C agonist that causes increased chloride and bicarbonate secretion into the intestinal lumen, leading to increased intestinal fluid and GI transit.
  • Onset: N/A.
  • The most common side effects are diarrhea, headache, and abdominal pain.
  • Use: Chronic idiopathic constipation, IBS with constipation.
  • Dosage: 145 mcg PO daily (72 mcg PO daily for tolerability or 290 mcg PO daily in IBS).

  Prucalopride
  

  • Caution: This drug is contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, and severe inflammatory conditions of the GI tract.
  • Prucalopride is a selective 5-HT4 receptor agonist that causes stimulation of the peristaltic reflux and increases intestinal secretions and gastrointestinal motility.
  • Onset: N/A.
  • The most common side effects are diarrhea, nausea, headache, and abdominal pain.
  • Use: Chronic idiopathic constipation.
  • Dosage: 2 mg PO daily.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Portenoy RK: Constipation in the cancer patient: causes and management. Med Clin North Am 71 (2): 303-11, 1987.
2. Bennett M, Cresswell H: Factors influencing constipation in advanced cancer patients: a prospective study of opioid dose, dantron dose and physical functioning. Palliat Med 17 (5): 418-22, 2003.
3. McShane RE, McLane AM: Constipation. Consensual and empirical validation. Nurs Clin North Am 20 (4): 801-8, 1985.
4. Bruera E, Suarez-Almazor M, Velasco A, et al.: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 9 (8): 515-9, 1994.
5. Beverley L, Travis I: Constipation: proposed natural laxative mixtures. J Gerontol Nurs 18 (10): 5-12, 1992.
6. Emmanuel AV, Krogh K, Bazzocchi G, et al.: Consensus review of best practice of transanal irrigation in adults. Spinal Cord 51 (10): 732-8, 2013.
7. Christensen P, Bazzocchi G, Coggrave M, et al.: A randomized, controlled trial of transanal irrigation versus conservative bowel management in spinal cord-injured patients. Gastroenterology 131 (3): 738-47, 2006.
8. Krogh K, Ostergaard K, Sabroe S, et al.: Clinical aspects of bowel symptoms in Parkinson's disease. Acta Neurol Scand 117 (1): 60-4, 2008.
9. Coggrave M, Norton C, Cody JD: Management of faecal incontinence and constipation in adults with central neurological diseases. Cochrane Database Syst Rev 1: CD002115, 2014.
10. Christensen P, Krogh K, Buntzen S, et al.: Long-term outcome and safety of transanal irrigation for constipation and fecal incontinence. Dis Colon Rectum 52 (2): 286-92, 2009.
11. Memon S, Bissett IP: Rectal perforation following transanal irrigation. ANZ J Surg 86 (5): 412-3, 2016.
12. Thomas J, Karver S, Cooney GA, et al.: Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358 (22): 2332-43, 2008.
13. Portenoy RK, Thomas J, Moehl Boatwright ML, et al.: Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage 35 (5): 458-68, 2008.
14. Meissner W, Leyendecker P, Mueller-Lissner S, et al.: A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 13 (1): 56-64, 2009.
15. Katakami N, Harada T, Murata T, et al.: Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J Clin Oncol 35 (34): 3859-3866, 2017.
16. Davies A, Leach C, Caponero R, et al.: MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 28 (1): 23-33, 2020.
17. Thayalasekeran S, Ali H, Tsai HH: Novel therapies for constipation. World J Gastroenterol 19 (45): 8247-51, 2013.

Impaction

Etiology of Impaction

Five major factors that precipitate impaction include the following:

• Opioid analgesics.
• Prolonged inactivity.
• Dietary alterations.
• Psychiatric illness.
• Chronic use of drugs for constipation.[1]

Laxatives used to decrease constipation are the drugs that contribute most to the development of constipation and impaction. Repeated and escalating dosing of laxatives renders the colon less sensitive to its intrinsic reflexes stimulated by distention. For causes of constipation that may lead to impaction, see the Etiology of Constipation section.

Signs and Symptoms of Impaction

The patient may exhibit symptoms similar to constipation or present with symptoms unrelated to the gastrointestinal system. If the impaction presses on the sacral nerves, the patient may experience back pain. If the impaction presses on the ureters, bladder, or urethra, urinary symptoms, such as urinary retention or increased or decreased frequency or urgency of urination, may develop.

When abdominal distention occurs, movement of the diaphragm may be compromised, which can lead to insufficient aeration with subsequent hypoxia and/or left ventricular dysfunction. Hypoxia can, in turn, precipitate angina or tachycardia. If the vasovagal response is stimulated by the pressure of impaction, the patient may become dizzy and hypotensive.

Movement of stool around the impaction may result in diarrhea, which can be explosive. Coughing or activities that increase intra-abdominal pressure may cause leakage of stool. The leakage may be accompanied by nausea, vomiting, abdominal pain, and dehydration and is virtually diagnostic of the condition. Thus, the patient with an impaction may present in an acutely confused and disoriented state, with signs of tachycardia, diaphoresis, fever, elevated or low blood pressure, and/or abdominal fullness or rigidity.

Assessment of Impaction

Assessment includes the questions listed previously for the patient with constipation. Additional assessment includes auscultation of bowel sounds to determine if they are present, absent, hyperactive, or hypoactive. The abdomen is inspected for distention and gently palpated for any masses, rigidity, or tenderness. A rectal examination will determine the presence of stool in the rectum or sigmoid colon. An abdominal x-ray (flat and upright) will show loss of haustral markings, gas patterns reflecting gross amounts of stool, and dilatation proximal to the impaction.[2] For more information, see the Assessment of Constipation section.

If a diagnosis of fecal impaction is uncertain, a laboratory workup can rule out other problems. A complete blood cell count, appropriate blood chemistries, chest x-ray, and electrocardiogram can be performed. If the patient has become dehydrated, the blood levels of urea nitrogen, creatinine, and serum osmolality will be elevated. There may be elevated hemoglobin and hematocrit levels, indicating hemoconcentration. The white blood cell (WBC) count may be slightly higher in the presence of a fever. If the WBC count is extremely elevated and the patient has a high fever and abdominal pain, an obstruction, perforation, infection, or inflammatory process must be ruled out. With marked distention of the cecum (diameter ≥12 cm), there is a risk of bowel perforation.

Treatment of Impaction

The primary treatment of impaction is to hydrate and soften the stool so that it can be removed or passed. Enemas (oil retention, tap water, or hypertonic phosphate) lubricate the bowel and soften the stool. Caution must be exercised in that fecal impaction can irritate the bowel wall, and excess enemas may perforate the bowel. The patient may need to be digitally disimpacted if the stool is within reach. This is best done after administering an enema to lubricate the bowel.

Nonstimulating bowel softeners such as docusate can be used to help soften stool higher in the colon. Mineral or olive oil can be given to loosen the stool. Caution is used when giving docusate sodium with mineral oil because there could be an increased systemic absorption of the mineral oil leading to systemic lipid granulomas.[3] Glycerin suppositories can also be used. Any laxatives that might stimulate the bowel or cause cramping are avoided so that the bowel is not damaged further.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Cefalu CA, McKnight GT, Pike JI: Treating impaction: a practical approach to an unpleasant problem. Geriatrics 36 (5): 143-6, 1981.
2. Bruera E, Suarez-Almazor M, Velasco A, et al.: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 9 (8): 515-9, 1994.
3. Brandt LJ: Gastrointestinal Disorders of the Elderly. Raven Press, 1984.

Large or Small Bowel Obstruction

The four types of obstruction include the following:

1. Simple.
2. Closed-loop.
3. Strangulated.
4. Incarcerated.

A simple obstruction is blocked in one place; a closed-loop obstruction is blocked in two places. A closed-loop obstruction may develop when the bowel twists around on itself, isolating the looped section of the bowel and obstructing the portion above it. With a strangulated obstruction, there is decreased blood flow to the bowel that, if not relieved, will develop into an incarcerated obstruction, and the bowel will become necrotic.

The obstructing mechanism can be mechanical or nonmechanical.

Mechanical factors can be anything that causes a narrowing of the intestinal lumen such as the following:[1]

• Inflammation or trauma to the bowel.
• Neoplasms.
• Adhesions.
• Hernias.
• Volvulus.
• Compression from outside the intestinal tract.

Nonmechanical factors include those that interfere with the muscle action or innervation of the bowel such as the following:

• Paralytic ileus.
• Mesenteric embolus or thrombus.
• Hypokalemia.

Eighty percent of bowel obstructions occur in the small intestine; the other 20% occur in the colon.[2] Bowel obstructions are frequently seen in the ileum. Small bowel obstructions are caused often by adhesions or hernias, while large bowel obstructions are caused by carcinomas, volvulus, or diverticulitis. The presentation of obstruction will relate to whether the small or large intestine is involved.

Etiology of Bowel Obstruction

The most common malignancies that cause bowel obstruction are cancers of the colon, stomach, and ovary. Extra-abdominal cancers (such as lung and breast cancers and melanoma) can spread to the abdomen, causing bowel obstruction.[3] Patients who have had abdominal surgery or abdominal radiation are also at higher risk of developing bowel obstruction.[2] Bowel obstructions are most common during advanced stages of disease.

Assessment and Diagnosis of Bowel Obstruction

Examination of the patient will determine the presence or absence of abdominal pain, vomiting, and evidence of the passage of flatus or stool. A complete blood cell count, electrolyte panel, and urinalysis are obtained to evaluate fluid and electrolyte imbalance and/or sepsis. An elevated white blood cell count (15,000–20,000/mm³) suggests bowel necrosis. Flat and upright abdominal films, as well as a barium enema, may be necessary to determine the location of the obstruction. While it remains controversial, an upper gastrointestinal series is contraindicated with an acutely presenting obstruction because it can cause a partial obstruction to become complete or may further complicate a total obstruction. If the patient exhibits dehydration, oliguria, or shock, perforation of the bowel may have occurred, and immediate medical or surgical intervention is indicated.

Treatment of Acute Bowel Obstruction

Careful serial examinations are necessary to manage patients with progressive abdominal symptoms that may be due to acute bowel obstruction. The principles of supportive care in this setting include volume resuscitation, correction of electrolyte imbalances, and transfusion support (if necessary). These measures may precede or accompany decompression efforts.

When bowel obstruction is partial, decompression of the distended bowel may be attempted with nasogastric or intestinal tubes. Although use of these tubes may reduce edema, relieve fluid and gas accumulation, or decrease the need for multiple stage procedures,[4] surgery may be necessary within 24 hours if there is complete, acute obstruction. The use of self-expandable stents to decompress complete, acute malignant bowel obstruction has been noted to decrease the frequency of unnecessary surgery by permitting staging of the disease, increasing the rate of primary anastomosis relative to colostomy, and decreasing morbidity in patients with left-sided colon and rectal malignancies. Further study is warranted, including cost analysis.[5]

Management of Chronic, Malignant Bowel Obstruction

Patients with advanced cancer may have chronic, progressive bowel obstruction that is inoperable.[6,7] The most frequent causes of inoperability are extensive tumor and multiple partial obstructions.[8,9][Level of evidence: II][10] A retrospective review evaluated surgical palliation of malignant bowel obstruction secondary to peritoneal carcinomatosis in 63 patients with nongynecological cancers. The ability to tolerate solid food at hospital discharge was the criterion for successful palliation. Multiple logistic regression analysis identified the absence of ascites and obstruction not involving the small bowel as predictors of successful surgical palliation in this population. Successful palliation was achieved in 45% of patients and was maintained in 76% of this group at a median follow-up of 78 days, for an overall success rate of 35%. The postoperative mortality rate was 15%, and postoperative complications occurred in 44% of patients.[11]

For some patients with malignant obstructions of the gastrointestinal tract, the use of expandable metal stents may provide palliation of obstructive symptoms. Esophageal, biliary, gastroduodenal, and colorectal stents are available.[5,12,13,14,15,16,17] Stents may be placed under endoscopic guidance, with or without fluoroscopy, or by an interventional radiologist using fluoroscopy. Morbidity with stent placement may be lower than with surgery. Adequate imaging of the stricture itself and the gastrointestinal tract distal to the stricture is recommended to assess stricture length, detect multifocal disease, and determine the appropriateness of stenting.[18,19][Level of evidence: II][20].

When neither surgery nor stenting is possible, the accumulation of the unabsorbed secretions produce nausea, vomiting, pain, and colicky activity as a result of the partial or complete occlusion of the lumen. In this case, a gastrostomy tube is commonly used to provide decompression of air and fluid that may accumulate and cause visceral distention and pain. The gastrostomy tube is placed into the stomach and is attached to a drainage bag that can be easily concealed under clothing. When the valve between the gastrostomy tube and the bag is open, the patient may be able to eat or drink by mouth without creating discomfort since the food is drained directly into the bag. Dietary discretion is advised to minimize the risk of tube obstruction by solid food. If the obstruction improves, the valve can be closed and the patient may once again benefit from enteral nutrition.

Sometimes, decompression is difficult even with a gastrostomy tube in place. Accumulation of fluid may cause this problem since several liters of gastrointestinal secretions may be produced per day. To relieve continuous abdominal pain, opioid analgesics via continuous subcutaneous or intravenous infusion may be necessary. Effective antispasmodics in this situation include anticholinergics (such as hyoscine butylbromide) [21] and possibly corticosteroids as well as centrally acting agents. If the bowel obstruction is thought to be functional (rather than mechanical) in origin, metoclopramide is the drug of choice because of its prokinetic effects on the bowel. For complete bowel obstruction thought to be irreversible, a trial of an antispasmodic such as hyoscyamine may decrease bowel contractions and therefore yield pain relief. Another option for management of refractory pain and/or nausea is the synthetic somatostatin analogue octreotide. This agent inhibits the release of several gastrointestinal hormones and reduces gastrointestinal secretions.[22,23][Level of evidence: I][24]

Octreotide is usually given subcutaneously at 50 to 200 µg 3 times per day and may reduce the nausea, vomiting, and abdominal pain of malignant bowel obstruction. For select patients, the addition of an anticholinergic such as scopolamine may be helpful in reducing the associated painful colic of malignant bowel obstruction when octreotide alone is ineffective. When either scopolamine or octreotide is used alone, each is ineffective.[12,25,26,27] Corticosteroids are widely used to treat bowel obstruction, but empirical support is limited.[28] They may be useful as adjuvant antiemetics and analgesics in this setting, given as dexamethasone at a starting dose of 6 to 10 mg subcutaneously or intravenously 3 to 4 times per day.[12,25]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Givens BA, Simmons SJ: Gastroenterology in Clinical Nursing. 4th ed. C.V. Mosby Co, 1984.
2. Bouchier IA: Gastroenterology. 3rd ed. Balliere Tindall, 1982.
3. Ripamonti C, De Conno F, Ventafridda V, et al.: Management of bowel obstruction in advanced and terminal cancer patients. Ann Oncol 4 (1): 15-21, 1993.
4. Horiuchi A, Maeyama H, Ochi Y, et al.: Usefulness of Dennis Colorectal Tube in endoscopic decompression of acute, malignant colonic obstruction. Gastrointest Endosc 54 (2): 229-32, 2001.
5. Martinez-Santos C, Lobato RF, Fradejas JM, et al.: Self-expandable stent before elective surgery vs. emergency surgery for the treatment of malignant colorectal obstructions: comparison of primary anastomosis and morbidity rates. Dis Colon Rectum 45 (3): 401-6, 2002.
6. Ripamonti C, Bruera E: Palliative management of malignant bowel obstruction. Int J Gynecol Cancer 12 (2): 135-43, 2002 Mar-Apr.
7. Potluri V, Zhukovsky DS: Recent advances in malignant bowel obstruction: an interface of old and new. Curr Pain Headache Rep 7 (4): 270-8, 2003.
8. Jung GS, Song HY, Kang SG, et al.: Malignant gastroduodenal obstructions: treatment by means of a covered expandable metallic stent-initial experience. Radiology 216 (3): 758-63, 2000.
9. Camúñez F, Echenagusia A, Simó G, et al.: Malignant colorectal obstruction treated by means of self-expanding metallic stents: effectiveness before surgery and in palliation. Radiology 216 (2): 492-7, 2000.
10. Coco C, Cogliandolo S, Riccioni ME, et al.: Use of a self-expanding stent in the palliation of rectal cancer recurrences. A report of three cases. Surg Endosc 14 (8): 708-11, 2000.
11. Blair SL, Chu DZ, Schwarz RE: Outcome of palliative operations for malignant bowel obstruction in patients with peritoneal carcinomatosis from nongynecological cancer. Ann Surg Oncol 8 (8): 632-7, 2001.
12. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
13. Law WL, Chu KW, Ho JW, et al.: Self-expanding metallic stent in the treatment of colonic obstruction caused by advanced malignancies. Dis Colon Rectum 43 (11): 1522-7, 2000.
14. Repici A, Reggio D, De Angelis C, et al.: Covered metal stents for management of inoperable malignant colorectal strictures. Gastrointest Endosc 52 (6): 735-40, 2000.
15. Harris GJ, Senagore AJ, Lavery IC, et al.: The management of neoplastic colorectal obstruction with colonic endolumenal stenting devices. Am J Surg 181 (6): 499-506, 2001.
16. Aviv RI, Shyamalan G, Watkinson A, et al.: Radiological palliation of malignant colonic obstruction. Clin Radiol 57 (5): 347-51, 2002.
17. Dauphine CE, Tan P, Beart RW, et al.: Placement of self-expanding metal stents for acute malignant large-bowel obstruction: a collective review. Ann Surg Oncol 9 (6): 574-9, 2002.
18. Lopera JE, Alvarez O, Castaño R, et al.: Initial experience with Song's covered duodenal stent in the treatment of malignant gastroduodenal obstruction. J Vasc Interv Radiol 12 (11): 1297-303, 2001.
19. Razzaq R, Laasch HU, England R, et al.: Expandable metal stents for the palliation of malignant gastroduodenal obstruction. Cardiovasc Intervent Radiol 24 (5): 313-8, 2001 Sep-Oct.
20. Baron TH, Rey JF, Spinelli P: Expandable metal stent placement for malignant colorectal obstruction. Endoscopy 34 (10): 823-30, 2002.
21. De Conno F, Caraceni A, Zecca E, et al.: Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 6 (8): 484-6, 1991.
22. Ripamonti C, Mercadante S, Groff L, et al.: Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial. J Pain Symptom Manage 19 (1): 23-34, 2000.
23. Mystakidou K, Tsilika E, Kalaidopoulou O, et al.: Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double- blind, controlled clinical trial. Anticancer Res 22 (2B): 1187-92, 2002 Mar-Apr.
24. Fallon MT: The physiology of somatostatin and its synthetic analogue, octreotide. European Journal of Palliative Care 1 (1): 20-2, 1994.
25. Mercadante S: Assessment and management of mechanical bowel obstruction. In: Portenoy RK, Bruera E, eds.: Topics in Palliative Care. Volume 1. Oxford University Press, 1997, pp. 113-30.
26. Fainsinger RL: Integrating medical and surgical treatments in gastrointestinal, genitourinary, and biliary obstruction in patients with cancer. Hematol Oncol Clin North Am 10 (1): 173-88, 1996.
27. Ripamonti C, Panzeri C, Groff L, et al.: The role of somatostatin and octreotide in bowel obstruction: pre-clinical and clinical results. Tumori 87 (1): 1-9, 2001 Jan-Feb.
28. Feuer DJ, Broadley KE: Systematic review and meta-analysis of corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancers. Systematic Review Steering Committee. Ann Oncol 10 (9): 1035-41, 1999.

Diarrhea

The reported prevalence and severity of diarrhea in patients with cancer vary greatly. Some chemotherapeutic regimens, particularly those containing fluoropyrimidines or irinotecan, are associated with diarrhea rates as high as 50% to 80%.[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.[3] In a large heterogeneous sample of cancer patients in various stages of treatment, the prevalence of moderate-to-severe diarrhea was 14%.[4] Diarrhea occurs in approximately 7% to 10% of cancer patients upon admission to hospice.[5] Among children with cancer during the last month of life, 19% experienced diarrhea.[6]

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.[9] 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.[10]

Table 1. National Cancer Institute's Common Terminology Criteria for Adverse Events: Diarrhea^a,b

Grade	Description
ADL = activities of daily living.
a Adapted from National Cancer Institute.[8]
b Definition: A disorder characterized by an increase in frequency and/or loose or watery bowel movements.
c Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
d Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being bedridden.
1	Increase of <4 stools/day over baseline; mild increase in ostomy output compared with baseline
2	Increase of 4–6 stools/day over baseline; moderate increase in ostomy output compared with baseline; limiting instrumental ADLc
3	Increase of ≥7 stools/day over baseline; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care ADLd
4	Life-threatening consequences; urgent intervention indicated
5	Death

Etiology of Diarrhea

In patients being treated for cancer, diarrhea is most commonly induced by therapy.[11] Conventional methods of diarrhea-causing treatment include the following:

• Surgery.
• Chemotherapy.
• Immunotherapy.
• Radiation therapy.
• Bone marrow transplantation.

Other causes of acute diarrhea include the following:[12]

• Antibiotic therapy.
• Stress and anxiety associated with cancer diagnosis and treatment.
• 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.[3]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 mechanisms 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.[13]

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 the following:[14,15]

• Increased transit time.
• Gastroparesis.
• Fat malabsorption.
• Lactose intolerance.
• Fluid and electrolyte imbalance.
• Dumping syndrome.

Certain chemotherapeutic agents can alter normal absorption and secretion functions of the small bowel, resulting in treatment-related diarrhea.[7] 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 the following:

• Total dose.
• Fractionation.
• Volume of bowel irradiated.
• Concomitant chemotherapy.

Common side effects of intestinal enteritis include the following:

• Diarrhea.
• Malabsorption.
• Gas.
• Bloating.
• 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 therapy ends and necessitates dietary modification, pharmacological management, and, in some instances, surgical intervention. For more information, see the Radiation Enteritis section.

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.[16] 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.[17] 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 Contributors to Diarrhea in Cancer Patients

Cancer[5,18]	Carcinoid syndrome
	Colon cancer
	Lymphoma
	Medullary carcinoma of the thyroid
	Pancreatic cancer, particularly islet cell tumors (Zollinger-Ellison syndrome)
	Pheochromocytoma
Surgery or procedure[14]	Celiac plexus block
	Cholecystectomy, esophagogastrectomy
	Gastrectomy, pancreaticoduodenectomy (Whipple procedure)
	Intestinal resection (malabsorption due to short bowel syndrome)
	Vagotomy
Chemotherapy[19,20,21];[22][Level of evidence: IV]	Capecitabine, cisplatin, cytosine arabinoside, cyclophosphamide, daunorubicin, docetaxel, doxorubicin, 5-fluorouracil, interferon, irinotecan, leucovorin, methotrexate, oxaliplatin, paclitaxel, topotecan, lapatinib, pertuzumab
Radiation therapy (For more information, see the Radiation Enteritissection.)[23,24,25]	Irradiation to the abdomen, para-aortics, lumbar, and pelvis or radiation for lung and head and neck cancers
Bone marrow transplantation[26]	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, 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[27]	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[18]	Stress

Assessment of Diarrhea

Rapid yet thorough assessment of diarrhea is imperative because of its potentially life-threatening nature. Few standardized assessment tools are available, and as a result, standardized assessment is rare in the clinical setting.[3] 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, and a thorough description of the diarrhea. Stringent monitoring conducted at least weekly is indicated during therapy using chemotherapeutic agents known to cause diarrhea.[9] The NCI's Common Terminology Criteria for Adverse Events (see Table 1) evaluate diarrhea by the following:[8]

• Number of stools per day.
• Incontinence.
• Increase in ostomy output compared with baseline.
• Interference with activities of daily living.

The history also includes 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.[28] One author has developed a visual tool to assist patients and families in characterizing the consistency of the stool.[29] Six diagrams illustrate fecal material consistency ranging from well-formed, formed, and semiformed to loose, very loose, and liquid.

Patients are questioned regarding related symptoms that might indicate hemodynamic compromise or the underlying etiology. Specific questions include information about the following:

• Dizziness.
• Orthostatic symptoms.
• Lethargy.
• Cramping.
• Abdominal pain.
• Nausea.
• Vomiting.
• Fever.
• Rectal bleeding.

These symptoms are classified as complicated or uncomplicated, with therapy based on these classifications.[30]

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.
• Dehydration.

Grade 3 or 4 diarrhea is also classified as complicated. Thorough evaluation and close monitoring is warranted.[30]

The time course of diarrhea and concomitant symptom development are key to determining underlying etiology.[28] 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 Vomiting^a

Adverse Event	Grade	Description
IV = intravenous; TPN = total parenteral nutrition.
a Adapted from National Cancer Institute.[8]
b Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
c Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
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 assigned
	5	Grade not assigned
Vomitingc	1	Intervention not indicated
	2	Outpatient IV hydration; medical intervention indicated
	3	Tube feeding, TPN, or hospitalization indicated
	4	Life-threatening consequences; urgent intervention indicated
	5	Death

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 includes 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 is performed judiciously in neutropenic or thrombocytopenic patients.[5]

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.[5]

In some cases, radiographic procedures are conducted to identify ileus, obstruction, or other abnormalities. In rare cases, endoscopy may be indicated.

Management of Diarrhea

A review was conducted of early toxic deaths in two NCI-sponsored cooperative trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer. It led to the revision of 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.[30]

Uncomplicated symptoms

The 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) are discontinued. Dietary modifications are commonly implemented to stop or lessen the severity of cancer treatment-related diarrhea.[7,24,26,31] In some cases, dietary changes include advising patients to eat small, frequent meals and avoid the following:[32]

• 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.
• High-fat foods.

For mild cases of diarrhea, the BRAT (bananas, rice, applesauce, toast) diet may reduce the frequency of stools. When experiencing diarrhea, patients are encouraged to increase their intake of clear liquids to at least 3 L per day (e.g., water, sports drinks, broth, weak decaffeinated teas, caffeine-free soft drinks, clear juices, and gelatin).[12,33] For more information, see the Behavioral strategies for symptom management section in Nutrition in Cancer Care.

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 did not show any benefit.[34][Level of evidence: I][35,36]

The goals of pharmacological 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, but little data support their efficacy. Some patients may not tolerate these bulk-forming agents 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.[18] Common loperamide doses begin with 4 mg, followed by 2 mg after each unformed stool, with a maximum of approximately 12 mg/day.[5,28] Regardless of the dose, however, loperamide may be less effective in patients with grade 3 or 4 diarrhea.[37][Level of evidence: I]

Mucosal prostaglandin inhibitors, also referred to as antisecretory agents, include the following:

• Aspirin, which may be useful for radiation-induced diarrhea.
• Bismuth subsalicylate, which 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 take aspirin, and large doses can produce toxic salicylate levels.
• Corticosteroids, which reduce edema associated with obstruction and radiation colitis and can reduce the hormonal influences of some endocrine tumors.
• Octreotide.

Other pharmacological 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.[38] 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.[39][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 with 32 patients receiving the same chemotherapeutic regimen without oral alkalization and controlled defecation.[40][Level of evidence: III]

In addition to antidiarrheal agents and immunosuppressive medications, a specialized, five-phase dietary regimen may be instituted to effectively manage diarrhea associated with GVHD.[26]

1. 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.
2. 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.
3. If the beverages in phase 2 are well tolerated, phase 3 may reintroduce solids containing minimal lactose, low fiber, low fat, low total acidity, and no gastric irritants.
4. In phase 4, dietary restrictions are progressively reduced as foods are gradually reintroduced and tolerance is established.
5. Phase 5 includes 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.[41] 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.[42] 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:[43,44,45,46,47,48]

• 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.

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.[49]

Complicated symptoms

While the optimal dose of octreotide has not been determined, a panel of experts has recommended that complicated cases of diarrhea 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 continues until the patient has been diarrhea free for 24 hours.[30] Particularly when patients are receiving chemotherapy, additional evaluation includes stool workup (including blood, fecal leukocytes, C. difficile, Salmonella, E. coli, Campylobacter, and infectious colitis), complete blood count, and electrolyte profile.[30] This workup and treatment is also 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. The patient's symptoms will determine the appropriate workup and whether IV fluids or octreotide is indicated.

Octreotide, a somatostatin analogue, 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.[50][Level of evidence: II][18]

Several open-label and randomized controlled studies of octreotide for chemotherapy-induced diarrhea have demonstrated the efficacy of this therapy.[51,52,53][Level of evidence: I];[54,55,56][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 after beginning treatment, 14 patients responding within 48 hours, and 11 patients responding within 72 hours. No adverse effects were noted.[57] Octreotide has also been shown to be effective for treating diarrhea associated with GVHD.[58,59]

An expert panel recommended using high-dose loperamide (2 mg q2h) for the first day of chemotherapy-induced, low-grade diarrhea (grade 1 or 2), followed by octreotide (100 µg–150 µg q8h).[28] If the patient presents with severe diarrhea (grade 3 or 4), octreotide (500 μg–1,500 µg SC or IV q8h) may be given as 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.[60] 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. For more information, see Nutrition in Cancer Care.

Unique scenarios

Irinotecan

Irinotecan is notorious for causing diarrhea. Irinotecan is associated with both acute diarrhea (occurring immediately after drug administration) and delayed diarrhea (occurring more than 24 hours after drug administration). Acute diarrhea is related to acute cholinergic excess and responds well to atropine. Delayed diarrhea, however, is typically managed with antidiarrheals and other supportive measures, as outlined above.[61]

Immune checkpoint inhibitors

Immune-mediated colitis is a potential side effect of immune checkpoint inhibitors (ICIs). CTLA-4 inhibitors typically cause diarrhea and colitis more frequently than do PD-1 and PD-L1 inhibitors, with the highest rates of colitis seen in patients receiving a combination of ICIs.[62] The onset of these events can be unpredictable but typically occurs within the first ten doses of an ICI and may occur after cessation of an ICI.[63] Symptoms are treated according to the grade of diarrhea/colitis. Patients with mild diarrhea/colitis may be managed symptomatically with fluids and antidiarrheals. More severe diarrhea/colitis may necessitate treatment with systemic steroids and even permanent discontinuation of ICI therapy. Detailed management of ICI-induced diarrhea is further outlined in National Comprehensive Cancer Network guidelines for the management of immunotherapy-related toxicities.[64]

Phosphatidylinositol 3-kinase (PI3K) inhibitors

The U.S. Food and Drug Administration has approved four PI3K inhibitors, two of which (idelalisib and duvelisib) carry a boxed warning for gastrointestinal complications, including diarrhea.[65,66] Given the severity of diarrhea that may be seen with idelalisib, an expert panel convened to develop management strategies for idelalisib-associated diarrhea.[67] Panelists commented that it is not clear whether diarrhea is a class effect of PI3K inhibitors. The authors noted that for idelalisib, two types of diarrhea may be seen. The first type appears to be self-limiting, occurring within the first 8 weeks of treatment; the second type tends to respond poorly to antidiarrheal therapy and occurs later, approximately 7 months after the start of treatment. In the second type of diarrhea, the histological appearance of the colon is consistent with lymphocytic colitis. Therefore, the panel recommended considering treatment with steroids or budesonide.[67]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

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3. Rutledge DN, Engelking C: Cancer-related diarrhea: selected findings of a national survey of oncology nurse experiences. Oncol Nurs Forum 25 (5): 861-73, 1998.
4. Cleeland CS, Mendoza TR, Wang XS, et al.: Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer 89 (7): 1634-46, 2000.
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7. Arbuckle RB, Huber SL, Zacker C: The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist 5 (3): 250-9, 2000.
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9. Rothenberg ML, Meropol NJ, Poplin EA, et al.: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19 (18): 3801-7, 2001.
10. Arnold RJ, Gabrail N, Raut M, et al.: Clinical implications of chemotherapy-induced diarrhea in patients with cancer. J Support Oncol 3 (3): 227-32, 2005 May-Jun.
11. Cartoni C, Dragoni F, Micozzi A, et al.: Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol 19 (3): 756-61, 2001.
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14. Yahanda AM: Hepatobiliary cancers. In: Berger DH, Feig BW, Fuhrman GM, eds.: The M.D. Anderson Surgical Oncology Handbook. Little, Brown, 1995, pp 194-224.
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16. McDonald GB, Shulman HM, Sullivan KM, et al.: Intestinal and hepatic complications of human bone marrow transplantation. Part I. Gastroenterology 90 (2): 460-77, 1986.
17. Herrmann VM, Petruska PJ: Nutrition support in bone marrow transplant recipients. Nutr Clin Pract 8 (1): 19-27, 1993.
18. Mercadante S: Diarrhea in terminally ill patients: pathophysiology and treatment. J Pain Symptom Manage 10 (4): 298-309, 1995.
19. Gupta E, Lestingi TM, Mick R, et al.: Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54 (14): 3723-5, 1994.
20. Wadler S, Benson AB, Engelking C, et al.: Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 16 (9): 3169-78, 1998.
21. Crown JP, Burris HA, Boyle F, et al.: Pooled analysis of diarrhea events in patients with cancer treated with lapatinib. Breast Cancer Res Treat 112 (2): 317-25, 2008.
22. Swain SM, Schneeweiss A, Gianni L, et al.: Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol 28 (4): 761-768, 2017.
23. Makrauer FL, Oates E, Becker J, et al.: Does local irradiation affect gastric emptying in humans? Am J Med Sci 317 (1): 33-7, 1999.
24. Donaldson SS: Nutritional consequences of radiotherapy. Cancer Res 37 (7 Pt 2): 2407-13, 1977.
25. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015.
26. Charuhas PM: Medical nutrition therapy in bone marrow transplantation. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000, pp 90-8.
27. DuPont HL: Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 92 (11): 1962-75, 1997.
28. Kornblau S, Benson AB, Catalano R, et al.: Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage 19 (2): 118-29, 2000.
29. Mertz HR, Beck CK, Dixon W, et al.: Validation of a new measure of diarrhea. Dig Dis Sci 40 (9): 1873-82, 1995.
30. Benson AB, Ajani JA, Catalano RB, et al.: Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22 (14): 2918-26, 2004.
31. Polisena CG: Nutrition concerns with the radiation therapy patient. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000, pp 70-8.
32. McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000.
33. Hogan CM: The nurse's role in diarrhea management. Oncol Nurs Forum 25 (5): 879-86, 1998.
34. Kozelsky TF, Meyers GE, Sloan JA, et al.: Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol 21 (9): 1669-74, 2003.
35. Savy GK: Glutamine supplementation. Heal the gut, help the patient. J Infus Nurs 25 (1): 65-9, 2002 Jan-Feb.
36. Ziegler TR, Bye RL, Persinger RL, et al.: Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 315 (1): 4-10, 1998.
37. Cascinu S, Bichisao E, Amadori D, et al.: High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients. Support Care Cancer 8 (1): 65-7, 2000.
38. Creemers GJ, Lund B, Verweij J: Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev 20 (1): 73-96, 1994.
39. Kehrer DF, Sparreboom A, Verweij J, et al.: Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7 (5): 1136-41, 2001.
40. Takeda Y, Kobayashi K, Akiyama Y, et al.: Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer 92 (2): 269-75, 2001.
41. de Vrese M, Schrezenmeir J: Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol 111: 1-66, 2008.
42. Isolauri E: Probiotics in human disease. Am J Clin Nutr 73 (6): 1142S-1146S, 2001.
43. Johnston BC, Supina AL, Ospina M, et al.: Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev (2): CD004827, 2007.
44. Pillai A, Nelson R: Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev (1): CD004611, 2008.
45. Huertas-Ceballos A, Logan S, Bennett C, et al.: Dietary interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database Syst Rev (1): CD003019, 2008.
46. Alfaleh K, Bassler D: Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev (1): CD005496, 2008.
47. Karimi O, Peña AS: Indications and challenges of probiotics, prebiotics, and synbiotics in the management of arthralgias and spondyloarthropathies in inflammatory bowel disease. J Clin Gastroenterol 42 (Suppl 3 Pt 1): S136-41, 2008.
48. Butterworth AD, Thomas AG, Akobeng AK: Probiotics for induction of remission in Crohn's disease. Cochrane Database Syst Rev (3): CD006634, 2008.
49. Delia P, Sansotta G, Donato V, et al.: Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 13 (6): 912-5, 2007.
50. Cello JP, Grendell JH, Basuk P, et al.: Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial. Ann Intern Med 115 (9): 705-10, 1991.
51. Cascinu S, Fedeli A, Fedeli SL, et al.: Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial. J Clin Oncol 11 (1): 148-51, 1993.
52. Cascinu S, Fedeli A, Fedeli SL, et al.: Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin. Oncology 51 (1): 70-3, 1994 Jan-Feb.
53. Gebbia V, Carreca I, Testa A, et al.: Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy. Anticancer Drugs 4 (4): 443-5, 1993.
54. Petrelli NJ, Rodriguez-Bigas M, Rustum Y, et al.: Bowel rest, intravenous hydration, and continuous high-dose infusion of octreotide acetate for the treatment of chemotherapy-induced diarrhea in patients with colorectal carcinoma. Cancer 72 (5): 1543-6, 1993.
55. Wadler S, Haynes H, Wiernik PH: Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea. J Clin Oncol 13 (1): 222-6, 1995.
56. Cascinu S, Fedeli A, Fedeli SL, et al.: Control of chemotherapy-induced diarrhoea with octreotide in patients receiving 5-fluorouracil. Eur J Cancer 28 (2-3): 482-3, 1992.
57. Zidan J, Haim N, Beny A, et al.: Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 12 (2): 227-9, 2001.
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59. Morton AJ, Durrant ST: Efficacy of octreotide in controlling refractory diarrhea following bone marrow transplantation. Clin Transplant 9 (3 Pt 1): 205-8, 1995.
60. Martenson JA, Halyard MY, Sloan JA, et al.: Phase III, double-blind study of depot octreotide versus placebo in the prevention of acute diarrhea in patients receiving pelvic radiation therapy: results of North Central Cancer Treatment Group N00CA. J Clin Oncol 26 (32): 5248-53, 2008.
61. Stein A, Voigt W, Jordan K: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2 (1): 51-63, 2010.
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Radiation Enteritis

Etiology of Radiation Enteritis

Almost all patients undergoing radiation to the abdomen, pelvis, or rectum will show signs of acute enteritis. Injuries clinically evident during the first course of radiation and up to 8 weeks later are considered acute.[1] Chronic radiation enteritis may present months to years after the completion of therapy, or it may begin as acute enteritis and persist after the cessation of treatment. Only 5% to 15% of people treated with radiation to the abdomen will develop chronic problems.[2]

Factors that influence the occurrence and severity of radiation enteritis include the following:

• Dose and fractionation.
• Tumor size and extent.
• Volume of normal bowel treated.
• Concomitant chemotherapy.
• Radiation intracavitary implants.
• Individual patient variables (e.g., previous abdominal or pelvic surgery, hypertension, diabetes mellitus, pelvic inflammatory disease, inadequate nutrition).[3,4]

In general, the higher the daily and total dose delivered to the normal bowel and the greater the volume of normal bowel treated, the greater the risk of radiation enteritis. In addition, the individual patient variables listed above can decrease vascular flow to the bowel wall and impair bowel motility, increasing the chance of radiation injury.

Acute Radiation Enteritis

Diagnosis

Radiation therapy exerts a cytotoxic effect mainly on rapidly proliferating epithelial cells, like those lining the large and small bowel. Crypt cell wall necrosis can be observed 12 to 24 hours after a daily dose of 1.5 to 3 Gy. Progressive loss of cells, villous atrophy, and cystic crypt dilation occur in the ensuing days and weeks. Patients suffering from acute enteritis may complain of nausea, vomiting, abdominal cramping, tenesmus, and watery diarrhea. With diarrhea, the digestive and absorptive functions of the gastrointestinal tract are altered or lost, resulting in malabsorption of fat, lactose, bile salts, and vitamin B₁₂. Symptoms of proctitis—including mucoid rectal discharge, rectal pain, and rectal bleeding (if mucosal ulceration is present)—may result from radiation damage to the anus or rectum.

One study of radiation for lung and head and neck cancers, with or without accompanying chemotherapy, noted significant diarrhea despite no direct radiation to the large or small intestine. Higher rates were noted for chemoradiation (42%) than for radiation alone (29%). Additionally, this radiation-induced diarrhea was associated with worse health outcomes and increased resource utilization. Individuals with moderate or worse diarrhea were more likely to have gastrostomy tube placement, weight loss, unplanned office visits, more inpatient days, and longer radiation breaks. This early report requires additional validation studies to fully evaluate the prevalence and impact of this phenomenon.[5]

Acute enteritis symptoms usually resolve 2 to 3 weeks after the completion of treatment, and the mucosa may appear nearly normal.[6]

Assessment

Patient examination and assessment of radiation enteritis includes the following:[7]

1. The usual pattern of elimination.
2. The pattern of diarrhea, including the following:
   1. Onset.
   2. Duration.
   3. Frequency, amount, and character of stools.
   4. Presence of other symptoms such as flatus, cramping, nausea, abdominal distension, tenesmus, bleeding, and rectal excoriation.
3. The nutritional status of the patient, including the following:
   1. Height and weight.
   2. Usual eating habits, any change in eating habits, and amount of residue in diet.
   3. Signs of dehydration such as poor skin turgor, serum electrolyte imbalance, increased weakness, or fatigue.
4. Present level of stress, coping patterns, and impact of signs and symptoms of enteritis on usual lifestyle patterns.

Medical management

Medical management includes treating diarrhea, dehydration, malabsorption, and abdominal or rectal discomfort. Symptoms usually resolve with medications, dietary changes, and rest. If symptoms become severe despite these measures, a treatment break may be warranted.

Medications may include the following:

• Kaopectate, an antidiarrheal agent. Dose: 30 to 60 cc by mouth after each loose bowel movement.
• Lomotil (diphenoxylate hydrochloride with atropine sulfate). Usual dose: One or two tablets by mouth every 4 hours as needed. Dose can be adjusted to individual patients and patterns of diarrhea. For example, one patient may achieve control of diarrhea with one tablet 3 times a day, while another patient may require two tablets every 4 hours. Patients are not to take more than eight tablets of Lomotil within a 24-hour period.
• Paregoric, an antidiarrheal agent. Usual dose: 1 teaspoon by mouth 4 times a day as needed for diarrhea. Paregoric may also be alternated with Lomotil.
• Cholestyramine, a bile salt sequestering agent. Dose: One package by mouth after each meal and at bedtime.
• Donnatal, an anticholinergic antispasmodic agent to alleviate bowel cramping. Dose: One or two tablets every 4 hours as needed.
• Imodium (loperamide hydrochloride), a synthetic antidiarrheal agent. Recommended initial dose: Two capsules (4 mg) by mouth every 4 hours, followed by one capsule (2 mg) by mouth after each unformed stool. Daily total dose should not exceed 16 mg (eight capsules).

In addition to these medications, opioids may offer relief from abdominal pain. If proctitis is present, a steroid foam given rectally may offer relief from symptoms. Finally, if patients with pancreatic cancer have diarrhea during radiation therapy, they will be evaluated for oral pancreatic enzyme replacement, as deficiencies in these enzymes alone can cause diarrhea.

The role of nutrition

Damage to the intestinal villi from radiation therapy results in a reduction or loss of enzymes, one of the most important of these being lactase. Lactase is essential in the digestion of milk and milk products. Although there is no evidence that a lactose-restricted diet will prevent radiation enteritis, a diet that is lactose free, low fat, and low residue can be an effective modality in symptom management.[8][Level of evidence: I]

Foods to avoid

• Milk and milk products. Exceptions are buttermilk and yogurt, which are often tolerated because lactose is altered by the presence of Lactobacillus. Processed cheese may also be tolerated because the lactose is removed with the whey when it is separated from the cheese curd. Milkshake supplements such as Ensure are lactose free and may be used.
• Whole-bran bread and cereal.
• Nuts, seeds, and coconuts.
• Fried, greasy, or fatty foods.
• Fresh and dried fruit and some fruit juices such as prune juice.
• Raw vegetables.
• Rich pastries.
• Popcorn, potato chips, and pretzels.
• Strong spices and herbs.
• Chocolate, coffee, tea, and soft drinks with caffeine.
• Alcohol and tobacco.

Foods to encourage

• Fish, poultry, and meat that are cooked, broiled, or roasted.
• Bananas, applesauce, peeled apples, and apple and grape juices.
• White bread and toast.
• Macaroni and noodles.
• Baked, boiled, or mashed potatoes.
• Cooked vegetables that are mild, such as asparagus tips, green and waxed beans, carrots, spinach, and squash.
• Mild processed cheese, eggs, smooth peanut butter, buttermilk, and yogurt.

Helpful hints

• Ingest food at room temperature.[7]
• Drink 3,000 cc of fluid per day. Allow carbonated beverages to lose carbonation before being ingested.
• Add nutmeg to food, which will help decrease mobility of the gastrointestinal tract.
• Start a low-residue diet on day 1 of radiation therapy treatment.[Level of evidence: IV]

Chronic Radiation Enteritis

Diagnosis

Only 5% to 15% of patients who receive abdominal or pelvic irradiation develop chronic radiation enteritis. Signs and symptoms include the following:

• Colicky abdominal pain.
• Bloody diarrhea.
• Tenesmus.
• Steatorrhea.
• Weight loss.
• Nausea and vomiting.

Less common are bowel obstruction, fistulas, bowel perforation, and massive rectal bleeding.[9]

The initial signs and symptoms occur 6 to 18 months after radiation therapy. Radiological findings include submucosal thickening, single or multiple stenoses, adhesions, and sinus or fistula formation.[10] Microscopic findings include villi that are fibrotic or may be lost altogether. Ulceration is common, varying from simple loss of epithelial layers to ulcers that may penetrate to different depths of the intestinal wall, even to the serosa. Lymphatic tissue is often atrophic or absent. The submucosa is severely diseased. Arterioles and small arteries show profound changes, with hyalinization of the entire wall thickness. The muscularis is often distorted or focally replaced by fibrosis.

The diagnosis of chronic radiation enteritis may be difficult to make. Clinically and radiologically recurrent tumor needs to be ruled out. Because of the possible latency of the illness, it is essential to obtain a detailed history of the patient's radiation therapy course. It is often advisable to include the radiation therapy physician in the continued management of the patient's care.

Treatment

Medical management of the patient's symptoms (which are similar to symptoms of acute radiation enteritis) is indicated, with surgical management reserved for severe damage.[8][Level of evidence: I] Fewer than 2% of the 5% to 15% of patients who received abdominal or pelvic radiation will require surgical intervention.[11]

The timing and choice of surgical techniques remain somewhat controversial. A lower operative mortality (21% vs. 10%) and incidence of anatomic dehiscence (36% vs. 6%) have been reported with intestinal bypass compared with resection.[12][Level of evidence: II][13] Those who favor resection point out that the removal of diseased bowel decreases the mortality rate for resection and is comparable to the bypass procedure.[12] All agree that simple lysis of adhesions is inadequate and that fistulas require bypass.

Surgery is undertaken only after careful assessment of the patient's clinical condition and extent of radiation damage because wound healing is often delayed, necessitating prolonged parenteral feeding after surgery. Even after apparently successful operations, symptoms may persist in a significant share of patients.[14]

Prevention

Treatment techniques that can minimize the risk of severe radiation enteritis include the following:

1. Radiation therapy techniques, including the following:
   1. Use of a three- or four-field technique (as opposed to a two-field technique) to minimize the amount of small bowel exposed to treatment.
   2. Treatment of the patient in a physical position that will aid in removing as much small bowel from the treatment field as possible (e.g., treating a patient with a full bladder each day to aid in pushing the small bowel up and out of the pelvis when pelvic radiation is given).
   3. Daily treatment of all fields, resulting in a lower integral dose and more homogenous dose distribution.
   4. Use of computerized radiation dosimetry to best design the treatment plan and use of high-energy treatment machines such as linear accelerators that deliver a high dose-to-tumor volume while sparing normal structures.[15]
2. Surgery. Placing clips in high-risk areas to better define the location or former location of the tumor and aid in radiation treatment planning.
3. Modification of treatment sequencing. An area for exploration is the sequencing of radiation, chemotherapy, and surgery and its influence on the severity of enteritis.

References:

1. O'Brien PH, Jenrette JM, Garvin AJ: Radiation enteritis. Am Surg 53 (9): 501-4, 1987.
2. Yeoh EK, Horowitz M: Radiation enteritis. Surg Gynecol Obstet 165 (4): 373-9, 1987.
3. Gallagher MJ, Brereton HD, Rostock RA, et al.: A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 12 (9): 1565-73, 1986.
4. Haddad GK, Grodsinsky C, Allen H: The spectrum of radiation enteritis. Surgical considerations. Dis Colon Rectum 26 (9): 590-4, 1983.
5. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015.
6. Alimentary tract. In: Fajardo LF: Pathology of Radiation Injury. Masson Publishers, 1982, pp 47-76.
7. Yasko JM: Care of the Client Receiving External Radiation Therapy. Reston Publishing Company, Inc., 1982.
8. Stryker JA, Bartholomew M: Failure of lactose-restricted diets to prevent radiation-induced diarrhea in patients undergoing whole pelvis irradiation. Int J Radiat Oncol Biol Phys 12 (5): 789-92, 1986.
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14. Wellwood JM, Jackson BT: The intestinal complications of radiotherapy. Br J Surg 60 (10): 814-8, 1973.
15. Minsky BD, Cohen AM: Minimizing the toxicity of pelvic radiation therapy in rectal cancer. Oncology (Huntingt) 2 (8): 21-5, 28-9, 1988.

Changes to This Summary (08 / 02 / 2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Constipation

Added text about three drugs used to treat constipation: lubiprostone, linaclotide, and prucalopride (cited Davies et al. as reference 16 and Thayalasekeran et al. as reference 17).

Diarrhea

Updated National Comprehensive Cancer Network as reference 64.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of gastrointestinal complications, including constipation, impaction, bowel obstruction, diarrhea, and radiation enteritis. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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• be cited with text, or
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Gastrointestinal Complications are:

• Alison Palumbo, PharmD, MPH, BCOP (Oregon Health and Science University Hospital)
• Maria Petzel, RD, CSO, LD, CNSC, FAND (University of TX MD Anderson Cancer Center)
• Megan Reimann, PharmD, BCOP (Total CME)

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The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Gastrointestinal Complications. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/constipation/GI-complications-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389211]

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Last Revised: 2022-08-02