From the physiopathologic point of view, different mechanisms may produce diarrhea, although it is quite difficult in certain clinical conditions to distinguish among mechanisms that frequently overlap.

The patient should be questioned in detail about dietary habits, the use of drugs, and previous surgery. Frequency, amounts, and consistency of the stools should be carefully obtained. When the stools are consistently large, light in color, watery or greasy, free of blood, or contain undigested food particles, the underlying disorder is likely to be in the small bowel or the proximal colon. Indeed, small stool diarrhea, in which frequent but small quantities of feces that are dark in color and often contain mucus or blood pass in spite of a sense of urgency, is associated with a disorder of the left colon or rectum (4). Widespread inflammation may simultaneously produce both patterns of diarrhea, confirmed by the passage of nonbloody diarrheal fluid, pus, or exudates. Other useful information includes fecal incontinence, change in stool caliber, rectal bleeding, and small, frequent, but otherwise normal stools.

Timing and spontaneous recovery are also important. Although osmotic diarrhea typically stops or reduces after fasting or stopping the drug previously used, secretory diarrhea persists in spite of fasting. Chemotherapy-induced diarrhea typically occurs 2–14 days after therapy. Radiation colitis is probable in patients who have recently received pelvic radiation for malignancies of the urogenital tract and of the prostate.

A physical examination should precede any further investigation. Signs of anemia, fever, postural hypotension, lymphadenopathy, neuropathy, hepatosplenomegaly, ascites, gaseous abdominal distention or lymphadenopathy, reduced anal sphincter tone, a rectal mass or impaction, and deterioration of nutritional status are of paramount importance in defining the type of diarrhea. Some etiologies may have a typical clinical pattern. For example, carbohydrate malabsorption is typically associated with excessive flatus and mushy stools, whereas intermittent diarrhea and constipation are frequent in diabetic neuropathy, as well as in irritable bowel syndrome or subobstructive disorders. Autonomic neuropathy or anal sphincter dysfunction may be characterized by nocturnal diarrhea and fecal soiling. Alternating diarrhea and constipation suggests fixed colonic obstruction. Fecal impaction may cause apparent diarrhea because only liquids pass a partial obstruction. Symptoms of dumping syndrome after gastric
surgery, such as early nausea, abdominal distention, weakness, and diarrhea after a meal followed by hypoglycemia, sweating, dizziness, and tachycardia, are typical. Secretory diarrhea combined with upper gastrointestinal (GI) symptoms caused by refractory peptic ulcer disease is suggestive of a gastrin-secreting tumor. High circulating serotonin levels in carcinoid syndrome cause other effects besides diarrhea, including hypotension, sweating, flushing, palpitation, and wheeziness (4, 15). The association of heat intolerance, palpitations, and weight loss suggests possible hyperthyroidism. Intestinal dysmotility or bacterial overgrowth due to diabetes, neoplastic conditions, or postoperative conditions should be suspected, excluding other causes.

Chronic bowel ischemia should be considered in elderly patients with the clinical features of diffuse atherosclerotic disease. Rectal examination and abdominal palpation should be performed to look for fecal masses and to exclude fecal impaction and intestinal obstruction, as well as for perianal fistula or abscess. Rectal involvement is probable in the presence of tenesmus, commonly defined as the passing of a little or no stool in spite of a sense of rectal urgency.

Of course, the site of neoplasm and metastases is of paramount importance. An abdominal x-ray will help the diagnosis. The location of the tumor will be verified by computed tomography scan, magnetic resonance imaging, angiography, or laparoscopy.

Laboratory findings should complete the investigation. If feasible, collected diarrhea stool specimen should be submitted for qualitative study. A positive finding in either the stool guaiac or leukocyte test leads to a suspicion of an exudative mechanism, as in radiation colitis, colonic neoplasm, or infective diarrhea. Stool cultures for bacterial, fungal, and viral pathogens, as well as a formal evaluation of the GI tract should complete the initial assessment (12). Gram stain of the stool can diagnose the presence of Staphylococcus, Campylobacter, or Candida infection. Multiple stool cultures should be obtained from patients with secretory diarrhea to rule out microorganisms producing enterotoxins that stimulate intestinal secretion. The presence of a microorganism in the stools is diagnostic.

An anion gap of >50 mmol per L due to a reduction of stool content in sodium and potassium suggests an osmotic diarrhea, whereas lower values (<50 mmol per L) indicate a secretory diarrhea due to active secretion of salts and water.

As a general rule, current medication should be revised, considering the use of laxatives, antacids, theophylline preparations, central nervous system drugs, antiarrhythmics, and antibiotics. Dietary advice may be helpful in some circumstances, although difficult to follow by most patients with cancer. A gluten-free diet can reduce abdominal cramping and frequency of bowel movement in the presence of intestinal fermentation with bowel distention. Binders of osmotically active substances (kaolin-pectin) give a thicker consistency to loose stools, producing a viscous, colloidal, absorbent solution, but their antidiarrheal effectiveness is disputable. Apples without the peel are particularly rich in pectin. Other dietary advice include avoiding cold meals, milk, vegetables rich in fibers, fatty meat and fish, coffee, and alcohol.

As diarrhea is associated with the occurrence of dehydration, the patient should be rehydrated, possibly by oral solutions containing glucose, electrolytes, and water. However, clinical signs of dehydration, such as orthostatic hypotension, decreased skin turgor, and a dry mouth, suggest the need for intensive hydration by intravenous route, especially in patients suffering from nausea and vomiting, in whom oral therapy is ineffective (4).

Considering the different mechanisms involved in determining diarrhea in patients with cancer, there are no broadly accepted treatment protocols. Particular strategies have been anecdotally suggested for specific etiologies (Table 15.2). Cholestyramine, aspirin, and sucralfate have been favorably used in radiation-induced diarrhea (16). Silicate smectite has proved a promising drug in the prophylaxis of radiotherapy-induced diarrhea, particularly in patients with a low, irradiated, small bowel volume (17). From recent investigations it seems that the best treatment would be prevention. In gynecologic malignancies, prior operation with low pelvic fields and prior operation with small volume were significantly protective factors for overall diarrhea. Conversely, large volume was a significant factor of overall and moderate to severe diarrhea in patients with large-field operations (18). Hypofractionated and accelerated radiotherapy for prostate cancer were supported with high-dose daily amifostine (1000 mg s.c.) to protect normal tissues against early and late effects, and produced only grade 0–1 cystitis or diarrhea (5/7 grade 0). Amifostine tolerance was excellent (19).

Steroids may exert a positive effect on several conditions associated with diarrhea, including secretory diarrhea, intestinal pseudo-obstruction, radiation-induced enteritis, endocrine tumors due to anti-inflammatory effects, and the capability of reducing the release and effect of inflammation mediators, and promoting salts and water absorption. They are also included in the pharmacologic approach to GVHD-induced diarrhea (12). Budesonide, a topically active steroid, demonstrated a substantial activity in irinotecan and 5-FU–induced diarrhea after failure of loperamide treatment (20).

Antibiotics, such as norfloxacin and amoxicillin-clavulanic acid, are effective in the treatment of bacterial overgrowth–related diarrhea (21). On the contrary, antibiotic-associated diarrhea (pseudomembranous enterocolitis) requires the discontinuation of antibiotics and the starting of either metronidazole or vancomycin (22). Bismuth subsalicylate in doses of 30–60 mL every 30 minutes for eight doses may bring mild symptomatic relief in patients with acute infectious diarrhea with an unknown effect (4). Probiotic bacteria (i.e., live bacteria that survive passage through the GI tract) may
have beneficial effects on the host. In a recent review, probiotic bacteria consistently shortened the diarrheal phase of rotavirus infection, although the evidence for other viral or bacterial infections was less strong (23).

Alkalization of the intestinal tract by oral administration of sodium bicarbonate has been reported to be a promising method for preventing delayed diarrhea, a dose-limiting toxicity in patients receiving chemotherapy with irinotecan, without decreasing the blood levels of irinotecan and its active metabolites, thereby improving the tolerability of long-term chemotherapy without reducing the efficacy (24). An oral adsorbent (2g Kremezin × three times) has been shown to decrease the number of bowel motions, without decreasing the plasma clearance of irinotecan much (25). Activated charcoal, given the evening before the irinotecan dose and then t.i.d. for 48 hours after the dose, reduced irinotecan-induced diarrhea and optimized its dose-intensity, possibly by adsorbing free lumenal SN-38, the irinotecan-active moiety that has a direct effect on mucosal topoisomerase-I (11). Broad-spectrum antibiotics may influence the intestinal toxicity of irinotecan. Although neomycin had no effect on the systemic exposure of irinotecan and its major metabolites, it changed fecal β-glucuronidase activity and decreased fecal concentrations of the pharmacologically active metabolite SN-38. It was associated with an improvement in diarrhea and not with hematologic toxicity, suggesting that bacterial β-glucuronidase plays a crucial role in irinotecan-induced diarrhea without affecting enterocyclic and systemic SN-38 levels (26).

Novel experimental substances may have relevance in this context. RDP58 is an anti-inflammatory agent that inhibits the production of tumor necrosis factor-α, interferon-γ, and interleukin-12. In animals, oral administration of RDP58 significantly decreased the incidence of diarrhea and improved the survival rates of mice treated with toxic doses of irinotecan or 5-FU. RDP58 may have clinical utility in cancer therapy by preventing treatment-associated GI toxicity and potentially increasing the effectiveness of chemotherapy (27).

Clonidine, an α₂-agonist, has been reported to be useful in controlling diarrhea in patients with diabetes or in patients with chronic idiopathic secretory diarrhea who presumably present a denervation sympathetic supersensitivity. However, hypotension and sedation may limit the usefulness of clonidine in dehydrated patients or patients with advanced cancer (4).

Opioids have been traditionally used for their antidiarrheal properties owing to the widespread presence of opioid receptors at different peripheral sites, including smooth muscle, myenteric plexus, and spinal cord. It is well known that their activation increases ileocecal tone and decreases small intestine and colon peristalsis (increasing electrolyte and water absorption), also impairing the defecation reflex by inhibiting anorectal sphincteric relaxation and diminishing anorectal sensitivity to distention. As a consequence, the contact time between intestinal mucosa and luminal contents is enhanced by the reduction of colonic propulsive activity, resulting in greater fluid absorption (4). Antidiarrheal effects can be obtained by both oral and parenteral opioids. Among opioids, loperamide is more specific because of the prevalent peripheral effect due to the inability to cross the blood–brain barrier. Loperamide shows the highest antidiarrheal/analgesic ratio among the opioid-like agents and is proved to be the drug of choice because of its few adverse effects. The standard dose of loperamide is 4 mg followed by 2 mg after every unformed stool. The dosage is titrated against the effect and higher doses of 2 mg every 2 hours have been recommended (up to 12 mg per day or more) in conjunction with chemotherapeutic agents associated with a high incidence of diarrhea (28). Loperamide-simethicone combination was significantly more effective than the drugs taken alone in the treatment of acute diarrhea with gas-related abdominal discomfort (29). However, the risk of developing paralytic ileus in the presence of continuous secretion, should be considered as a life-threatening complication. Of interest, opioids may paradoxically cause diarrhea secondary to fecal impaction.

Data from several clinical trials suggest that octreotide may be useful in the symptomatic treatment of diarrhea refractory to other medications (28, 30). The mechanism by which octreotide produces these beneficial effects is probably multifactorial, as it suppresses the secretion of many of the gut peptides implicated in the control of secretory and motor activity, and inhibits exocrine secretions from the stomach, pancreas, and small intestine, also facilitating water and electrolyte absorption (31). Octreotide has been found to control diarrhea in several conditions, such as carcinoid tumors, vipoma, gastrinoma, small cell lung cancer, as well as acquired immunodeficiency syndrome–related diarrhea (32). However, hormonal responses to the somatostatin analog do not always parallel clinical responses, probably because of the effects of cosecreted peptides. A dose-response effect of octreotide has been demonstrated. Octreotide seems to be an effective agent in the management of chemotherapy-related diarrhea and refractory GVHD-associated diarrhea (33, 34). Doses of 0.3–1.2 mg a day subcutaneously are commonly effective.

Long-acting, biodegradable, microsphere formulation of octreotide for monthly subcutaneous administration (30 mg) has been evaluated for the prophylaxis of diarrhea, speeding the resolution of diarrhea and preventing further episodes during subsequent cycles of chemotherapy (64). A preventive strategy with octreotide LAR as prophylaxis has been proposed for patients with a prior cycle of chemotherapy complicated by persistent diarrhea (35).

The pancreatic secretion of lipase, amylase, and proteases breaks down fat to monoglycerides and fatty acids, carbohydrates to mono- and disaccharides, and proteins to peptides and amino acids. Several processes have been recognized to facilitate the absorption of fat from the aqueous luminal environment. Triglycerides are emulsified together with phospholipids, bile salts, and mono- and diglycerides and dispersed into a variety of phases and particles. Lipid digestion begins in the mouth and in the stomach, active at a low pH, promoting emulsion stability and facilitating the action of pancreatic lipases. Gastric and pyloric motility further promotes emulsification of lipids. This effect is amplified by bile salts and biliary phospholipids, which also influence the absorption of cholesterol and sterol vitamins. Lipolysis to fatty acids and monoglycerides is mediated by pancreatic lipases (4). Protein digestion begins in the stomach. Acid denaturation leads to proteolysis, which is promoted by endopeptidases activated by an acid environment, cleaving the internal bonds of large
proteins to form nonabsorbable peptides. Pancreatic peptidases convert proteins and polypeptides into amino acids and oligopeptides. Hormonal and neural stimulation stimulates the release of proenzymes by the pancreas. Enteropeptidases and trypsin activate a cascade of events that promotes the activation of chymotrypsin, elastase, and carboxypeptidase A and B in the duodenum. Digestion of carbohydrates has been described in the section on Osmotic Diarrhea.