Nausea, Vomiting (Emesis), Constipation, and Bowel Obstruction in Advanced Cancer

Frequency

Nausea and vomiting (emesis) (N&V) are common symptoms in patients with advanced cancer, occurring in approximately 21% to 68% of these patients.[1,2] The underlying pathophysiology and treatment differs somewhat from nausea related to radiation treatment or chemotherapy. Chronic nausea can significantly impair a patient's quality of life.

Pathophysiology and Causes

Chronic nausea in the advanced cancer setting is often multifactorial in origin.[1,2,3] Medications, including some that are frequently prescribed in this setting—such as opioids, nonsteroidal anti-inflammatory drugs, and selective serotonin reuptake inhibitor (SSRI) antidepressants—may be responsible.

In the case of opioids, nausea frequently resolves spontaneously a few days after initiation of treatment. In some cases, however, it may persist. Nausea resulting from the accumulation of active opioid metabolites (morphine-6-glucuronide) has been described,[4] and patients with impaired renal function may be at increased risk. Opioids invariably produce constipation if prophylactic measures are not taken (namely, the use of a regular laxative regimen), and constipation is one of the most common causes of nausea in patients with advanced cancer.[5,6,7,8]

Opioid-induced gastrointestinal (GI) motility problems may compound the problem of diminished GI motility that many patients experience as part of the anorexia-cachexia syndrome of advanced cancer. The autonomic dysfunction that often accompanies this syndrome results in decreased GI motility, early satiety, and chronic nausea.[9,10,11] Other causes of chronic nausea in these patients include the following:[12]

• Raised intracranial pressure (from metastatic brain disease or primary brain tumors).
• Metabolic abnormalities such as hypercalcemia, hyponatremia, and uremia.
• Dehydration.
• Malignant bowel obstruction.
• Gastroduodenal ulcers.
• Infections of the mouth, pharynx, or esophagus.

Nausea, like many other symptoms, may have psychological undercurrents that either exacerbate or induce chronic nausea.

Assessment

A comprehensive history that includes determining the frequency and effectiveness of bowel movements and laxative therapy is essential. Concurrent medications should be reviewed, and the frequency and nature of N&V should be documented. Examination should attempt to exclude bowel obstruction, fecal impaction, dehydration, and raised intracranial pressure. History and physical examination are poor at determining the extent of constipation.[5] A plain flat-plate x-ray of the abdomen can be very useful to this end.[13] Surgical x-ray views of the abdomen may be helpful if a bowel obstruction is suspected. Investigations to determine blood levels of electrolytes, calcium, and renal parameters may also be helpful.

Management

Management centers on identifying the underlying causes, addressing these when possible, and controlling the symptoms.[1,2] A basic working knowledge of the emetic pathways and identification of possible underlying causes should guide antiemetic selection.

Multiple antiemetic regimens have been proposed for the management of chronic nausea in the advanced cancer setting. Prospective studies comparing one regimen with another are lacking. Metoclopramide or domperidone are generally recommended as first-line agents because they improve GI motility and act on the chemoreceptor trigger zone (as a result of their antidopaminergic properties).[14] Metoclopramide can be administered orally or parenterally (subcutaneously or intravenously [IV]) at doses of 10 mg, 4 times a day, or on an every-4-hour basis, depending on the severity of the nausea. Rescue doses should also be ordered on an as-needed basis to manage the episodic worsening of nausea that may occur.

Extrapyramidal-related adverse effects are a potential complication of these medications but appear to occur infrequently. Domperidone, which is currently unavailable in the United States, is associated with fewer of these adverse effects. Unfortunately, this drug is not available in a parenteral formulation. Dimenhydrinate (Dramamine) or antihistamine agents may be used if a complete bowel obstruction is suspected (in which case prokinetic agents are contraindicated) or if patients are intolerant to other antiemetic agents. Haloperidol, a potent antidopamine agent, may be considered if bowel obstruction is the underlying problem.[15]

The phenothiazine drugs are sometimes used,[16][Level of evidence: II] but the high incidence of adverse effects such as somnolence and anticholinergic-related effects (orthostatic hypotension and confusion) limit their role. Chlorpromazine has modest antiemetic activity but a high incidence of sedation, postural hypotension, and anticholinergic adverse effects, while piperazine derivatives such as prochlorperazine are stronger antiemetics but cause more extrapyramidal side effects. Hyoscine butylbromide, on the other hand, can be useful for patients experiencing colic from complete bowel obstruction.

A continuous parenteral infusion of metoclopramide, at doses of 60 to 120 mg/day, may be helpful for patients with intractable chronic nausea.[17] The judicious use of corticosteroids such as dexamethasone in selected patients may be useful in conjunction with a more traditional antiemetic, although one study has suggested that dexamethasone was not better than placebo in patients who were not controlled with metoclopramide.[18][Level of evidence: I] The exact mechanism of action and the optimal dose of corticosteroids for this indication are not known.

In contrast to radiation therapy–induced nausea or chemotherapy-induced nausea, the role of 5-HT₃ receptor antagonists (such as ondansetron) is not clear in the setting of chronic nausea in advanced cancer, but it appears to be limited to a small number of highly selected cases, specifically those that have failed all other treatments.[19]

A case series study has suggested an antiemetic effect for olanzapine (an atypical antipsychotic) in advanced cancer patients being treated with opioids who are complaining of apparent opiate-induced nausea. However, further study and comparison with standard management are required.[20]

The management of constipation can be divided into general interventions and therapeutic measures.[21] The general interventions include the prevention of constipation by initiating regular laxative regimens, particularly in patients on opioid treatment, and where possible, the elimination of medical factors that may be contributing to constipation (e.g., discontinuation of nonessential constipating drugs). Prophylactic laxative regimens may consist of stool softeners such as docusate and bowel stimulants such as sennosides. Occasionally lactulose may be added. If necessary, a hyperosmolar laxative such as lactulose or polyethylene glycol may be added.[22] These regimens should be reviewed on a regular basis and their doses adjusted, depending on the regularity of bowel movements. High-fiber diets, while generally recommended, may be difficult for patients with very advanced cancer. Bulk agents such as psyllium or cellulose are unsuitable for patients with advanced cancer because the high fluid intake required with these agents is often intolerable to patients. (Refer to the PDQ summaries on Gastrointestinal Complications and Pain for more information on the management of constipation caused by opioids.)

Therapeutic interventions for the routine management of constipation may be administered orally or rectally, as follows:

• Oral laxatives, including bulk agents, osmotic agents, contact cathartics, and agents for colonic lavage.
• Saline laxatives, including sodium salts (sodium phosphate) and magnesium salts (magnesium citrate), may be useful to treat established constipation.
• Sodium phosphates are generally administered rectally as an enema, but oral solutions are also available.
• Magnesium citrate is generally administered orally and can be especially useful if the constipation is primarily in the proximal bowel.
• The contact cathartic bisacodyl, available as a suppository, may also be useful for treating established constipation.

Once the constipation is cleared, the background laxative regimen (e.g., sennoside and docusate) should be reviewed with a view to optimizing it. The action of the saline and magnesium salts is not physiological, and regular ongoing administration should be avoided. Saline laxatives should be used with caution in patients with renal impairment or cardiac failure. Mineral oil enemas are used occasionally and act as both lubricants and stool softeners; however, they may interfere with the absorption of fat-soluble vitamins, and there is a risk of lipoid pneumonia in debilitated patients. The use of enemas and rectal suppositories is usually limited to the acute short-term management of more severe episodes of constipation. However, patients with neurogenic bowel problems (e.g., patients with irreversible spinal cord compression) often require regular ongoing treatment with suppositories as part of their bowel care. The rectal route is contraindicated in patients with mucosal integrity/bowel-wall compromise. (Refer to the PDQ summary on Gastrointestinal Complications for more information.)

There have been no adequate comparative studies between the various laxatives to make evidence-based recommendations on which laxative regimen is optimal. Patients with advanced cancer are at risk of becoming constipated and generally require a regular bowel regimen, even if they are not eating. This need is amplified when they are on opioid treatment. On occasion, patients may present with a refractory narcotic bowel syndrome despite aggressive bowel care. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[23][Level of evidence: I];[24,25] Methylnaltrexone should be avoided in cases of bowel obstruction and suspected bowel obstruction. This has not been studied in children.

Malignant Bowel Obstruction

The initial approach to assessing and managing malignant bowel obstruction in the advanced cancer patient involves determining whether the obstruction is reversible and whether the obstruction is partial or complete.[26,27,28] Suitability for surgery such as resection or intestinal bypassing should be assessed. Several medical options are available to improve the comfort of patients with inoperable bowel obstructions.[29,30] Less aggressive surgical procedures such as the insertion of a venting gastrostomy tube can provide considerable relief. When the obstruction is complete and irreversible, the creation of ostomies may also provide relief. Nasogastric tubes may be used temporarily until the obstruction resolves; however, when the obstruction is irreversible, other options such as the insertion of a gastrostomy tube should be considered.

Antiemetic agents with prokinetic properties are relatively contraindicated in the presence of a complete obstruction, and alternative agents such as an antihistamine or haloperidol may be required. Clinical experience suggests that corticosteroids (e.g., dexamethasone at a starting dose of 6–10 mg subcutaneously, 3–4 times a day) may be useful for malignant bowel obstruction.[26,27] The optimal dose and duration of treatment has not been clarified.

Hydration and drugs such as opioids and antiemetics should be administered via routes other than the oral route. The subcutaneous route can be very convenient and effective for both hydration and opioid administration. This route is as effective as IV administration, is less invasive, and requires less maintenance than the IV route. Octreotide, a somatostatin analog, can be useful at doses of 100 µg to 200 µg subcutaneously, 3 times a day, for refractory obstruction.[26,27,31] In the United States, octreotide is often administered as a continuous infusion. If the obstruction causes severe colic, hyoscine butylbromide may be considered. The use of colonic endoluminal stenting devices in selected patients is gaining increasing attention.[32,33]

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