Thursday, July 3, 2014

Gastrointestinal Complications (PDQ®) - National Cancer Institute

The reported prevalence and severity of diarrhea
vary greatly. Some chemotherapeutic regimens are associated with
diarrhea rates as high as 50% to 80%, particularly those containing
fluoropyrimidines or irinotecan.[1,2]
Diarrhea is also commonly observed in patients diagnosed with carcinoid
tumors, receiving radiation therapy to abdominal/pelvic fields, or
undergoing bone marrow transplantation or surgical intervention of the
gastrointestinal tract.[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]
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: Diarrheaa,b
Grade Description 
1Increase of <4 stools/day over baseline; mild increase in ostomy output compared with baseline
2Increase of 4–6 stools/day over baseline; moderate increase in ostomy output compared with baseline
of ≥7 stools/day over baseline; incontinence; hospitalization
indicated; severe increase in ostomy output compared with baseline;
limiting self-care ADLc
4Life-threatening consequences; urgent intervention indicated
ADL = activities of daily living.
aAdapted from National Cancer Institute.[8]
bDefinition: A disorder characterized by frequent and watery bowel movements.
cSelf-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
Etiology of Diarrhea
In patients being treated for cancer, diarrhea is most commonly induced by therapy.[11] Conventional methods of diarrhea-causing treatment include the following:
  • Surgery.
  • Chemotherapy.
  • 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.
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.
strategy for categorizing the causes of diarrhea is by putative
underlying mechanisms. These include exudative (i.e., excess blood or
mucous enters the gastrointestinal tract), malabsorptive, dysmotile,
osmotic, and secretory (due to increased secretion of electrolytes and
fluid—probably the mechanism underlying chemotherapy-induced diarrhea)
factors or combinations of these factors.[13]
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.
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.
  • Bloating.
  • Cramping.
intestinal side effects occur at approximately 10 Gy and may last up to
8 to 12 weeks posttherapy. Chronic radiation enteritis may present
months to years after completion of therapy and necessitates dietary
modification and pharmacological management and, in some instances,
surgical intervention. (Refer to the Radiation Enteritis section of this summary for more information.)
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
Acute GVHD is usually manifested within 100 days posttransplant,
although it can occur as early as 7 to 10 days posttransplant. It may
resolve or develop into a chronic form requiring long-term treatment and
dietary management.
Table 2. Possible Contributions to Diarrhea in Cancer
Cancer-related [5,18]Carcinoid syndrome
Colon cancer
Medullary carcinoma of the thyroid
Pancreatic cancer, particularly islet cell tumors (Zollinger-Ellison syndrome)
Surgery- or procedure-related [14]Celiac plexus block
Cholecystectomy, esophagogastrectomy
Gastrectomy, pancreaticoduodenectomy (Whipple procedure)
Intestinal resection (malabsorption due to short bowel syndrome)
Chemotherapy-related [19-21]Capecitabine,
cisplatin, cytosine arabinoside, cyclophosphamide, daunorubicin,
docetaxel, doxorubicin, 5-fluorouracil, interferon, irinotecan,
leucovorin, methotrexate, oxaliplatin, paclitaxel, topotecan, lapatinib
Radiation therapy–related (Refer to the Radiation Enteritis section of this summary for more information.) [22,23]Irradiation to the abdomen, para-aortics, lumbar, and pelvis
Bone marrow transplantation–related [24]Conditioning
chemotherapy, total-body irradiation, graft-versus-host disease after
allogeneic bone marrow or peripheral blood stem cell transplants
Drug adverse effects [5,18]Antibiotics,
magnesium-containing antacids, antihypertensives, colchicine, digoxin,
iron, lactulose, laxatives, methyldopa, metoclopramide, misoprostol,
potassium supplements, propranolol, theophylline
Concurrent disease [5,18]Diabetes,
hyperthyroidism, inflammatory bowel disease (Crohn disease,
diverticulitis, gastroenteritis, HIV/AIDS, ulcerative colitis),
obstruction (tumor-related)
Infection [25]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)
products (coffee, tea, chocolate); specific fruit juices (prune juice,
unfiltered apple juice, sauerkraut juice)
foods (raw fruits and vegetables, nuts, seeds, whole-grain products,
dried legumes); high-fat foods (deep-fried foods, high fat–containing
Lactulose intolerance or food allergies
foods (candy and chewing gum); hot and spicy foods; gas-forming foods
and beverages (cruciferous vegetables, dried legumes, melons, carbonated
Psychological factors [18]Stress
yet thorough, assessment of diarrhea is imperative because of the
potentially life-threatening nature of diarrhea. Few standardized
assessment tools are available, and studies suggest that, 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, as well as a thorough
description of the diarrhea. Stringent monitoring conducted at least
weekly is indicated during therapy using chemotherapeutic agents known
to cause diarrhea.[9] The NCI’s Common Terminology Criteria for Adverse Events (Table 1) evaluate diarrhea by the following:[8]
  • Number of stools per day.
  • Incontinence.
  • Increase in ostomy output compared with baseline.
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.[26] One author has developed a visual tool to assist patients and families in characterizing the consistency of the stool.[27]
Six diagrams illustrate fecal material consistency ranging from
well-formed, formed, and semiformed to loose, very loose, and liquid.
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.[28]
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.[28]
The time course of diarrhea and concomitant symptom development are key to determining underlying etiology.[26]
Medication and dietary intake, as well as a history of recent travel,
may provide additional clues regarding etiology. Weight loss and reduced
urine output provide additional data regarding the severity of the
effects of diarrhea.
Table 3. National Cancer Institute’s Common Terminology Criteria for Adverse Events: Nausea and Vomitinga
Adverse Event Grade Description 
Nauseab1Loss of appetite without alteration in eating habits
2Oral intake decreased without significant weight loss, dehydration, or malnutrition
3Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated
4Grade not available
5Grade not available
Vomitingc11–2 episodes (separated by 5 min) in 24 h
23–5 episodes (separated by 5 min) in 24 h
3≥6 episodes (separated by 5 min) in 24 h; tube feeding, TPN, or hospitalization indicated
4Life-threatening consequences; urgent intervention indicated
TPN = total parenteral nutrition.
aAdapted from National Cancer Institute.[8]
bDefinition: A disorder characterized by a queasy sensation and/or the urge to vomit.
cDefinition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
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]
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
some cases, radiographic procedures are conducted to identify ileus,
obstruction, or other abnormalities. In rare cases, endoscopy may be
A review of early toxic
deaths in two NCI-sponsored cooperative trials of irinotecan plus
high-dose fluorouracil and leucovorin for advanced colorectal cancer has
led to the revision of previously published clinical practice
guidelines for the treatment of cancer treatment–induced diarrhea, with a
heightened emphasis on assessment and early aggressive interventions.
The guidelines distinguish between uncomplicated and complicated
Uncomplicated symptoms
current treatment of cancer-related diarrhea is often empiric and
nonspecific. Whenever possible, treat underlying causes such as fecal
impaction or modify the stimulant laxative regimen as necessary.
Medications such as bulk laxatives and promotility agents (e.g.,
metoclopramide) are discontinued. Dietary modifications are commonly
implemented to stop or lessen the severity of cancer treatment-related
One author recommends that patients consume foods that build stool
consistency, are low in fiber, contain minerals, and do not stimulate or
irritate the gastrointestinal tract.[20]
In some cases, dietary modification for diarrhea management includes
advising patients to eat small, frequent meals and avoid
lactose-containing food (milk and dairy products), spicy foods, alcohol,
caffeine-containing foods and beverages, certain fruit juices,
gas-forming foods and beverages, high-fiber foods, and high-fat foods.[30]
For mild cases of diarrhea, the BRAT (bananas, rice, apples, toast)
diet may reduce the frequency of stools. When experiencing diarrhea,
patients are encouraged to increase clear liquid intake to at least 3 L
per day (e.g., water, sports drinks, broth, weak decaffeinated teas,
caffeine-free soft drinks, clear juices, and gelatin).[12,31] (Refer to the Diarrhea subsection of the Nutritional Suggestions for Symptom Management section in the PDQ summary on Nutrition in Cancer Care for more information.)
some case reports suggest the efficacy of glutamine in relieving
diarrhea and other gastrointestinal symptoms associated with cancer
therapy, one randomized controlled trial that used oral glutamine to
prevent pelvic radiation-induced diarrhea was unable to demonstrate any
benefit.[32][Level of evidence: I][33,34]
goals of pharmacologic therapy include inhibition of intestinal
motility, reduction in intestinal secretions, and promotion of
absorption. Absorbents include agents that form a gelatinous mass that
gives density to fecal material. Methylcellulose and pectin are most
commonly used, with little data to support their efficacy. These
bulk-forming agents may not be well tolerated in some patients because
of the large volume required for therapeutic effect and the associated
abdominal discomfort and bloating. Adsorbents such as kaolin, clays, and
activated charcoals have been used extensively, but no data support
their use. Furthermore, they may inhibit absorption of other oral
antidiarrheals that may be administered.
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.[5,26] Regardless of the dose, however, loperamide may be less effective in patients with grade 3 or 4 diarrhea.[35][Level of evidence: I]
prostaglandin inhibitors, also referred to as antisecretory agents,
include aspirin, bismuth subsalicylate, corticosteroids, and octreotide.
Aspirin may be useful for radiation-induced diarrhea. Bismuth
subsalicylate is believed to have direct antimicrobial effects on
Escherichia coli, hence its prophylactic use in traveler’s diarrhea.
This agent is contraindicated in patients who should not be taking
aspirin, and large doses can produce toxic salicylate levels.
Corticosteroids reduce edema associated with obstruction and radiation
colitis and can reduce hormonal influences of some endocrine tumors.
pharmacologic therapies for the relief of diarrhea may be specific to
the underlying mechanism. Delayed diarrhea (>24 hours) occurs with
irinotecan and can be severe in 25% of patients.[36]
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.[37][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.[38][Level of evidence: III]
addition to antidiarrheal agents and immunosuppressive medications, a
specialized five-phase dietary regimen may be instituted to effectively
manage the diarrhea associated with GVHD.[24]
Phase 1 consists of total bowel rest until the diarrhea is reduced.
Nitrogen losses associated with diarrhea can be severe and are
compounded by the high-dose corticosteroids used to treat GVHD. Phase 2
reintroduces oral feedings consisting of beverages that are isotonic,
low-residue, and lactose-free to compensate for the loss of intestinal
enzymes secondary to alterations in the intestinal villi and mucosa. If
these beverages are well tolerated, phase 3 may reintroduce solids
containing minimal lactose, low fiber, low fat, low total acidity, and
no gastric irritants. In phase 4, dietary restrictions are progressively
reduced as foods are gradually reintroduced and tolerance is
established. Phase 5 includes the resumption of the patient’s regular
diet; however, most patients usually remain lactose intolerant.
are nutritional supplements that contain a defined amount of viable
microorganisms and, upon administration, confer a benefit to the
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
There are a vast number of different strains of probiotics; however,
much of the clinical research has investigated the species belonging to
the family of Lactobacillus and Bifidobacterium. Probiotics have been
promoted for the following:[41-46]
  • Prevention of antibiotic-induced diarrhea and rotavirus.
  • Treatment or prevention of inflammatory bowel disease, irritable bowel syndrome, and gastroenteritis.
  • Treatment of necrotizing enterocolitis in premature infants.
results of one study among adults with cancer have been published. In a
double-blind, randomized, controlled trial, 450 adults with cancer who
were receiving radiation to the pelvic region were randomly assigned to
receive the blend probiotic product VSL #3 or placebo during radiation
therapy. The authors reported a decrease in the incidence and severity
of diarrhea. No adverse events were reported.[47]
Clinical trials for the following patients are under way:
  • Patients with familial adenomatous polyposis (NCT00319007).
  • Patients undergoing donor stem cell transplantation for hematologic cancer or myelodysplastic syndrome (NCT00946283). This trial is now closed to accrual.
Complicated symptoms
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.[28]
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.[28]
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)
but the patient's constellation of symptoms are considered to determine
the appropriate workup and whether IV fluids or octreotide is indicated.
a somatostatin analog, is currently the most promising agent in the
management of severe diarrhea caused by a variety of diseases and
treatments. The doses used in clinical trials have varied widely.
Regardless of the lack of consensus regarding optimal dose, octreotide
has been shown to be effective in relieving diarrhea associated with
AIDS, carcinoid syndrome, and vasoactive intestinal polypeptide tumors.[48][Level of evidence: II][18]
Several open-label and randomized controlled studies of octreotide in
the relief of chemotherapy-induced diarrhea have demonstrated the
efficacy of this therapy.[49-51][Level of evidence: I];[52-54][Level of evidence: II]
In a prospective trial of 32 patients who had chemotherapy-induced
diarrhea that was refractory to loperamide, octreotide 100 µg SC 3 times
a day produced complete resolution in 30 patients. Resolution occurred
rapidly, with 5 patients responding within 24 hours, 14 patients
responding within 48 hours, and 11 patients responding within 72 hours
after beginning treatment. No adverse effects of the octreotide were
noted.[55] Octreotide has also been shown to be effective in diarrhea associated with GVHD.[56,57]
An expert panel recommended using high-dose loperamide (2 mg every 2
hours) for the first day of chemotherapy-induced diarrhea that is low
grade (1 and 2), followed by octreotide, 100 to 150 µg every 8 hours.[26]
If the patient presents with severe diarrhea (grade 3 or 4),
octreotide, 500 to 1,500 µg SC or IV every 8 hours, 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.[58]
In fact, some gastrointestinal symptoms such as cramping may have been
worse. Parenteral hydration and electrolyte supplementation may be
indicated, and in severe cases, total parenteral nutrition may be
initiated. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)
Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about diarrhea
that are now accepting participants. The list of trials can be further
narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.

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