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Managing Nausea in the Cancer Patient Population

Oncology
Palliative Care
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Introduction

Nausea is an unpleasant sensation of feeling the need to vomit, which often but does not always precede vomiting (emesis). Although nausea is a common symptom among patients with various end-stage illnesses, it is especially prevalent in patients with advanced cancer[1].
In patients undergoing chemotherapy, nausea can persist despite guideline-consistent antiemetic prophylaxis[2], highlighting the difficulty in managing this debilitating symptom. An effective approach to management of nausea in patients with cancer includes:
  1. Understanding the anatomy and physiology of nausea, and common neurotransmitter receptors involved
  2. Using a systematic approach for evaluation and workup of the underlying etiology, including a thorough history, a physical exam, and laboratory and imaging testing, in order to form a differential diagnosis
  3. Selecting interventions targeted at the underlying cause of nausea and, when applicable, using secondary effects of pharmacotherapies to help manage comorbid symptoms

Anatomy and Physiology of Nausea

The anatomic structures and pathways that produce nausea are complex and include central and peripheral inputs[3]. Discussed here are the major areas of the brain and body implicated in producing nausea.
The central mediator of nausea is the “vomiting center”, a collection of neurons in the medulla into which other areas of the brain and body relay information about emetogenic stimuli. Processing of emetogenic stimuli leads to emesis via efferent motor and parasympathetic fibers that induce the expulsion of gastric contents. 
The chemoreceptor trigger zone (CTZ) lies within area postrema in the medulla, dorsal to the vomiting center. In the CTZ, chemoreceptors are not protected by the blood-brain barrier (BBB) and thus can detect chemicals within the bloodstream that otherwise would not be able to traverse the BBB.
In addition to chemoreceptors, neurons in the CTZ express Dopamine 2 (D2), Neurokinin 1 (NK1), and 5-hydroxytryptamine (5HT, also known as serotonin) 3 (5HT3) receptors. Nausea and vomiting related to medications, chemotherapy, and endogenous toxins (such as in the case of uremia) are theorized to use this pathway directly.
The vestibular system also inputs to the vomiting center via histamine 1 (H1) and muscarinic acetylcholine 1 (M1) receptors. Vestibular dysfunction can induce nausea via this pathway. Certain medications, including opioids[4] and platinum-based chemotherapies[5], may sensitize the vestibular system to make a patient more susceptible to vertigo-type nausea.
Other areas in the brain also directly input to the vomiting center, including the cerebral cortex, thalamus, and the meninges. Input from the cerebral cortex has been implicated in “anticipatory nausea,” hypothesized to be a conditioned response to a previously emetogenic stimulus (e.g., nausea in anticipation of a chemotherapy cycle, but prior to any chemotherapy being administered).
Finally, the vomiting center receives direct input from the gastrointestinal tract, peritoneum, and heart via cranial nerves IX and X. Neurons in the GI tract express 5HT3 receptors, chemoreceptors (implicated in nausea due to toxins and irritants), and mechanoreceptors (implicated in nausea due to gut lumen distention). In addition, many organs of the GI tract express cannabinoid (CB1 and CB2) receptors, as do areas of the CNS[6]. 
In summary, the anatomy and physiology of nausea is complex, involving multiple inputs from the CNS and visceral organs. Combined with a thorough history, physical examination, and diagnostic studies, an understanding of nausea pathways and receptors involved can guide pharmacologic management.

Diagnostic Workup

History
As with any debilitating symptom in patients with cancer, a thorough assessment begins with a detailed history of the symptom. Special attention should be paid to the following aspects of the history:
  • Intensity, duration, and temporality of nausea
  • Provoking/aggravating factors – especially any temporal relationship to medications or eating/drinking, nausea in anticipation of chemotherapy or radiation, and movement
  • Palliating/alleviating factors – including medications and nonpharmacologic factors such as distraction techniques or meditation
  • Associated symptoms – especially anorexia, constipation or diarrhea, dyspepsia/reflux, dizziness/vertigo, and anxiety
  • Review of medications – especially recently added or discontinued medications
  • Impact on quality of life
Often, a thorough history alone will be enough to identify the most likely etiology of nausea in patients with cancer. However, further diagnostic studies may be needed in some cases. 
Physical Exam
Physical examination often provides limited information on nausea etiology. However, physical examination may reveal new or worsening abdominal distention (e.g., due to severe constipation, bowel obstruction, or malignant ascites), organomegaly, or new intraabdominal masses. A neurological examination may reveal focal deficits that would suggest an intracranial pathology.
Diagnostic studies
Laboratory testing can reveal metabolic abnormalities that may be contributing to nausea, such as uremia, liver failure, and hypercalcemia. A basic metabolic panel with extended electrolytes (calcium, magnesium, phosphorus) and liver function tests will be sufficient laboratory workup in most cases of nausea. 
Plain film x-ray and, if necessary, abdominal computerized tomography can be helpful in cases where obstruction is suspected, such as severe constipation or malignant bowel obstruction. In addition, brain imaging (preferably MRI) should always be considered to evaluate for intracranial masses in patients with malignancies that are known to metastasize to the CNS.
Differential Diagnosis
Information from a thorough history, physical exam, and data from laboratory results and imaging will assist in forming a differential diagnosis for nausea in the patient with cancer. A suggested framework for nausea differential diagnosis in the cancer patient population organizes common etiologies by anatomical location: CNS, gastrointestinal tract, and bloodstream (toxic/metabolic/medication-related nausea).
This section will review the most common etiologies using this framework as a guide, with findings on history, physical exam, and laboratory or imaging data that would suggest a particular etiology.

Central Nervous System

Psychological/Anticipatory Nausea:
  • History: Nausea strongly associated with anxiety or in anticipation of a previously emetogenic stimulus (e.g., chemotherapy or radiation). May respond to anxiolytic medications.
Increased intracranial pressure or Meningeal Irritation
  • History: Morning nausea, associated with headaches or vision changes, photophobia or phonophobia.
  • Exam findings: Papilledema, focal neurologic deficits or altered mental status, facial plethora (SVC syndrome)
  • Imaging: Intracranial masses or hemorrhage on brain imaging, meningeal inflammation, or leptomeningeal disease.
Vestibular System
  • History: vertigo, dizziness, nausea provoked by motion or head movements, recent infection (labyrinthitis), or medication changes.

Gastrointestinal Tract

Dyspepsia/Gastroesophageal Reflux
  • History: Burning epigastric pain, relief with antacids.
Gastric outlet obstruction/gastroparesis/Slowed Gut Motility
  • History: Early satiety, bloating, regurgitation or vomiting shortly after food/drink ingestion, comorbid poorly controlled diabetes.
Malignant bowel obstruction (small or large bowel)
  • History: Absence of flatus and bowel movements, crampy abdominal pain.
  • Exam findings: Abdominal distention, tympanitic to percussion.
  • Imaging: Plain film abdominal x-ray demonstrating air-fluid levels or abdominal CT showing point of obstruction.
Constipation
  • History: Decreased frequency or absence of bowel movements (but passing flatus), straining with defecation, diffuse abdominal discomfort or pain.
  • Exam findings: Mild distention.
  • Imaging: Large stool burden on abdominal x-ray or CT.
Infection/Inflammation (pancreatitis, hepatitis, cholecystitis, gastroenteritis)
  • History: Epigastric pain (pancreatitis) or right upper quadrant pain (hepatitis, cholecystitis), diarrhea (gastroenteritis).
  • Laboratory studies: Liver function testing showing cholestasis, hepatitis, or elevated pancreatic lipase.
  • Imaging: CT or ultrasound imaging may reveal area of involvement.

Bloodstream/chemical/metabolic

Chemotherapy induced nausea and vomiting (CINV)
  • History: Temporally associated with chemotherapy, either acute (within 24 hours) or delayed.
Radiation treatment
  • History: Temporally associated with radiation treatment.
Medication-related
  • History: Recent additions, discontinuations, or dose adjustments to medications, or new end-organ dysfunction affecting drug clearance.
Hepatic or renal failure
  • History: Altered mental status, pruritus in the absence of rash.
  • Exam findings: Asterixis, jaundice (in hepatic failure), altered mental status.
  • Laboratory studies: Elevated serum ammonia and/or liver enzymes, elevated blood urea nitrogen and creatinine.
Metabolic/electrolyte derangement
  • History: May have altered mental status.
  • Laboratory studies: Markedly elevated or reduced serum electrolyte levels, ketoacidosis.

Management

Treatment and prevention of nausea in patients with cancer relies primarily on pharmacologic interventions. Patients may also benefit from nonpharmacologic interventions which will also be discussed in this section.
The most commonly used antiemetic medications can be grouped by class and the receptors they target.
The major classes of medications include 5HT3 antagonists, D2 antagonists (including the atypical antipsychotic olanzapine), anticholinergics (M1 antagonists), antihistamines (H1 antagonists), corticosteroids, NK1 receptor antagonists, anxiolytics, and cannabinoids. Some commonly used medications are summarized in Table 1, along with their targeted receptors and common side effects. Consultation with a pharmacist is often helpful to select safe and effective agents.
(Note: Table 1 includes antiemetics commonly used by the author, however is not a complete list of all antiemetics available in each class)
Table 1. Major classes of antiemetic medications, and examples, dose range, route of administration, mechanism and area of action, specific indications, and common side effects
Multiple references used for table construction[3,17,18].
GI = gastrointestinal; CTZ = chemoreceptor trigger zone; CNS = central nervous system. PO = oral; IV = intravenous; SQ = subcutaneous; IM = intramuscular; PR = rectal; SL = sublingual. 5HT3 = 5-hydroxytryptamine (serotonin) 3 receptor; NK1 = neurokinin 1 receptor; D2 = dopamine 2 receptor; H1 = histamine  1 receptor; M1 =  muscarinic acetylcholine 1 receptor; CB1 = cannabinoid 1 receptor; CB2 = cannabinoid 2 receptor; GABA = gamma-aminobutyric acid receptor; CINV = chemotherapy induced nausea and vomiting; RT = radiation therapy; SBO = small bowel obstruction; ICP = intracranial pressure; EPS = extrapyramidal symptoms.
* Black box warning: atypical antipsychotics may increase mortality in elderly patients with dementia
† Promethazine also exhibits D2 receptor antagonism; increased risk of EPS symptoms when used with other D2 antagonists
Note that outside of nausea related to chemotherapy and radiotherapy, very few clinical trials have evaluated the efficacy of antiemetics for patients with cancer. Guidelines for cancer treatment-related nausea and are summarized below, followed by a discussion of management for specific syndromes in patients with cancer and general management of chronic nausea.

Chemotherapy Induced Nausea

Chemotherapy induced nausea and vomiting (CINV) is common and can be broken down into acute (within first 24 hours of chemotherapy) and delayed (days 2 to 5 after chemotherapy) phases. Acute phase CINV is thought to be mediated by chemotherapy damaging intestinal enterochromaffin cells which causes peripheral release of serotonin, activating afferent fibers from the gut via peripheral 5HT3 receptors and relaying information to the vomiting center in the medulla.
Delayed phase CINV likely involves chemotherapy-induced release of substance P from afferent fibers in the CNS, which activates central NK1 receptors in the medulla[7].
Chemotherapy regimens can be stratified based on their emetic risk[8], defined as percentage of patients who develop nausea and vomiting within 24 hours of chemotherapy when not given prophylactic antiemetics. Some patients may experience breakthrough nausea and vomiting despite use of guideline antiemetics.
The most recent guidelines from the Multinational Association of Supportive Care in Cancer and the European Society for Medical Oncology (MASCC/ESMO) suggest the following prophylactic regimens[9,10,11] for chemotherapies according to emetogenic potential:
Highly Emetogenic: >90% risk
Non-Anthracycline-cyclophosphamide (non-AC) chemotherapy
  • Acute: 5HT3 antagonist plus dexamethasone plus NK1 antagonist (aprepitant, fosaprepitant, netupitant, or rolapitant) on day 1 given prior to chemotherapy
  • Delayed: dexamethasone on days 2-4 (plus aprepitant on days 2-3 if aprepitant was used on day 1)
Anthracycline-cyclophosphamide (AC) chemotherapy in women with breast cancer
  • Acute: 5HT3 antagonist plus dexamethasone plus NK1 antagonist on day 1 given prior to chemotherapy
  • Delayed: Dexamethasone or aprepitant on days 2-3, or none if a different NK-1 antagonist was used on day 1
Moderately Emetogenic: >30 to 90% risk
  • Acute: 5HT3 antagonist plus dexamethasone (plus a NK1 receptor antagonist for patients receiving carboplatin) on day 1
  • Delayed: Consider dexamethasone on days 2-3 (or use aprepitant on days 2-3 if aprepitant was used on day 1)
Low Emetogenic: >10 to 30% risk
  • Acute: dexamethasone or 5HT3 antagonist or D2 antagonist
  • Delayed: no specific recommendations
Minimally Emetogenic: <10% risk
  • Routine prophylaxis typically is not necessary

Radiotherapy-induced nausea

Radiation treatment is another common etiology of nausea in patients with cancer, with a pathophysiology that is thought to be similar to CINV. Also similar to CINV, emetic risk of radiation therapy has been stratified by MASCC/ESMO into different levels according to treatment area. Most recent MASCC/ESMO guidelines[12] are as follows: 
High risk: Total body irradiation
  • 5HT3 antagonist plus dexamethasone prior to each fraction
Moderate risk: Upper abdomen, craniospinal
  • 5HT3 antagonist, consider dexamethasone
Low risk: cranium, head and neck, thorax, pelvis
  • Consider prophylaxis versus as needed treatment with dexamethasone or 5HT3 antagonist (dexamethasone is preferred for radiation to the cranium)
Minimal risk: extremities, breast
  • Prophylaxis not routinely recommended
  • Use dexamethasone, D2 antagonist, or 5HT3 antagonist as needed for breakthrough nausea

Management of nausea due to specific etiologies in cancer patients

In cases of nausea not related to cancer therapy, when a specific etiology is found then interventions should target the underlying cause. Common etiologies with specific treatments are discussed below.
Constipation
  • Prevent and treat with combination of osmotic laxative (polyethylene glycol) and bowel stimulant (senna or bisacodyl)
  • Enemas, suppositories, or manual disimpaction if necessary
  • Consider subcutaneous methylnaltrexone in patients with opioid-induced constipation (avoid in patients with mechanical obstruction due to risk of bowel perforation)
  • Avoid constipating antiemetics (5HT3 antagonists)
Malignant bowel obstruction
  • Dexamethasone, consider subcutaneous octreotide
  • Evaluate for utility of radiation therapy or surgical intervention
Slowed gut motility
  • Prokinetic antiemetics such as metoclopramide
Intracranial metastases
  • Dexamethasone
  • Evaluate for utility of radiation therapy or neurosurgical intervention
Medication (non-chemotherapy) related nausea
  • Discontinue or adjust dose of offending medication
  • If nausea is related to opioids, consider opioid rotation
Anticipatory nausea
  • Behavioral interventions (guided imagery, biofeedback)
  • Benzodiazepines
Metabolic/electrolyte derangement
  • Identify and treat the underlying cause when possible
  • Consider D2 antagonists as first-line
Infection/inflammation
  • Identify and treat the underlying cause when possible

Management of nausea without a clear etiology

Often, patients with cancer will experience chronic nausea without a clearly identifiable or potentially reversible cause. Few studies exist to guide management in most cases, however MASCC has recently updated their guidelines to recommend the use of metoclopramide and haloperidol as first-line agents[13], as well as other second-line agents based on limited data from randomized controlled trials. A recent small, randomized placebo-controlled trial also found that olanzapine was effective for chronic nausea in patients with cancer[14].
Some antiemetics have secondary effects which can also treat comorbid symptoms that accompany nausea (see Table 1). For example:
  • A patient with nausea and frequent episodes of agitated delirium may get dual benefit from haloperidol for both symptoms
  • A patient with nausea and comorbid anxiety and insomnia may benefit from nightly dosing of olanzapine, which has a long half-life and can be beneficial for anxiolysis and sleep.
  • A patient with diarrhea and nausea may benefit from ondansetron, taking advantage of its constipating side effects
  • A patient with nausea, fatigue, and anorexia may benefit from a trial of dexamethasone
Conversely, some antiemetics should be avoided in particular clinical scenarios due to their side effect profile:
  • Many antiemetics are associated with QTc prolongation (5HT3 antagonists and most D2 antagonists) which can increase the risk of Torsade de Pointes
    • The aggressiveness of QTc monitoring in patients with advanced cancer should be tailored to the clinical scenario (i.e., it is generally not necessary to monitor QTc for patients receiving end-of-life or hospice care)
  • Many antiemetics can have sedative side effects (dopamine antagonists, antihistamines, cannabinoids, benzodiazepines)
  • Dopamine antagonists should be avoided in patients with Parkinsonism due to risk of worsening extrapyramidal symptoms
  • 5HT3 antagonists should be used with caution in patients with constipation as it can worsen this symptom
  • Anticholinergics should generally be avoided in patients with xerostomia or urinary retention, and avoided in elderly patients due to risk of delirium
  • Steroids should be used with caution in patients with extreme anxiety or with poorly controlled diabetes
Other practical considerations include:
  • Antiemetics are often dosed as-needed, but some patients with severe nausea may benefit from at least several days of scheduled, around-the-clock medication administration.
  • For patients without IV access and who cannot take oral medications, many antiemetics can be given subcutaneously (such as metoclopramide, haloperidol, and lorazepam) or by rectal suppository (prochlorperazine, promethazine).

Non-pharmacologic complementary and alternative medicine therapies:

Data on efficacy of non-pharmacologic interventions are limited. Ginger, commonly used for pregnancy-associated nausea, may have some benefit with acute phase CINV[15]. Acupuncture and acupressure may also provide some benefit in CINV[16]. Overall, these interventions outside of CINV have not been studied extensively.

Controversies/Limitations

The etiology-based approach to nausea management in patients with cancer aims to provide a framework to approach this challenging symptom and tailor interventions for the most likely underlying cause of nausea. In clinical practice however, some patients will have an idiopathic response (positive or negative) to a particular antiemetic agent, regardless of what an etiology-based approach suggests “should” be effective or ineffective. A compassionate, patient-centered approach to nausea management will also use empiric observation and treatment when the etiology-based approach fails.

Summary

In patients with cancer, nausea is a prevalent and often difficult to manage symptom that can significantly impact quality of life. While nausea associated with chemotherapy and radiotherapy has well-supported guideline recommendations based on years of data, management of nausea not associated with cancer treatment remains limited. Few clinical trials have shown benefit for one particular agent over another, leading many clinicians to adopt an etiology-based approach described in this chapter. Further study is needed in this area.

References

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