Nausea and Vomiting

Nausea and vomiting are well-known side effects of cancer therapy and affect most patients who have chemotherapy. Radiation therapies to the brain, gastrointestinal tract, or liver also cause nausea and vomiting.

Nausea is controlled by a part of the autonomic nervous system which controls involuntary body functions (such as breathing or digestion. Vomiting is a reflex controlled in part by a vomiting center in the brain. Vomiting can be triggered by smell, taste, anxiety, pain, motion, or changes in the body caused by inflammation, poor blood flow, or irritation to the stomach.

The vomiting center receives input from neuronal pathways including:

• Chemoreceptor trigger zone (CTZ).
• Peripheral stimuli from the gastrointestinal (GI) tract via vagal and splanchnic nerves.
• Cortical pathways (midbrain receptors, limbic system).
• Vestibular labyrinthine apparatus of the inner ear.

Emetic center is located in the nucleus tractus solitarii in brainstem and coordinates afferent signalling from the GI tract and efferent signalling to the salivation and respiratory centers, abdominal muscles, and autonomic nerves. Cortical involvement is also a likely efferent signal which results in anticipatory CINV. Emesis results from the release of neurotransmitters including serotonin from intestinal entero-chromaffin cells.

Types of vomiting

The types of nausea and vomiting include:

• Acute: Nausea and vomiting that happen within 24 hours after treatment starts.
• Delayed: Nausea and vomiting that happen more than 24 hours after chemotherapy. This is also called late nausea and vomiting.
• Anticipatory: Nausea and vomiting that happen before a chemotherapy treatment begins. If a patient has had nausea and vomiting after an earlier chemotherapy session, he or she may have anticipatory nausea and vomiting before the next treatment. This usually begins after the third or fourth treatment. The smells, sights, and sounds of the treatment room may remind the patient of previous times and may trigger nausea and vomiting before the chemotherapy session has even begun.
• Breakthrough: Nausea and vomiting that happen within 5 days after getting anti-emetic treatment. Different drugs or doses are needed to prevent more nausea and vomiting.
• Refractory: Nausea and vomiting that does not respond to drugs.
• Chronic: Nausea and vomiting that lasts for a period of time after treatment ends.

Physical examination

Patients with nausea should be thoroughly examined. The frequency, time of day, and any associated activities (meals, medications, and exertion) should be noted. Similar assessments and observations should be made for emesis to try to determine the severity and the context of the nausea and emesis.

The history taking should include an inquiry regarding any prescription or over-the-counter medications that may be responsible for the nausea/emesis. Nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, antibiotics, opioid analgesics, and oral iron have the potential to cause nausea/emesis. Recent or remote treatment with chemotherapy and/or radiation therapy should also be noted.

The physical examination should include a detailed assessment of the abdomen for abdominal pain or tenderness in order to elicit clues to a possible organic cause of the nausea/emesis—such as bowel obstruction, an inflammatory process, or gastroparesis. Any abdominal distention, abnormal bowel sounds, ascites, hepatomegaly, or splenomegaly should be noted.

A detailed neurologic examination should be performed to determine the presence of focal neurologic signs or papilledema suggestive of elevated intracranial pressure or central nervous system metastases. Vertigo and nystagmus are typical symptoms of vestibular neuritis (labyrinthitis) and other causes of vestibular dysfunction.

Finally, inquiries about weight loss, appetite, anorexia, and/or cachexia should be made in order to further assess the nature of the nausea and emesis and provide insights into their possible etiology.

Management

The most important principle in managing CINV is the prevention of nausea and vomiting. The risk of CINV in patients receiving moderate to high emetogenic chemotherapy persists for at least 2–3 days after the final dose of chemotherapy, and prophylactic therapy should be given during the full period of risk. Antiemetics should be given at the minimal efficacious dose with consideration of their side effect profiles as well as the patient’s prior history with specific antiemetics. Consider the use of an H2 blocker or proton pump inhibitor to prevent dyspepsia, which can mimic nausea. Finally, lifestyle measures such as eating small, frequent and healthy meals may help alleviate CINV.

Five groups of anti-emetics are used:

(1) dopamine receptor antagonists,

(2) corticosteroids,

(3) 5-HT 3 receptor antagonists,

(4) neurokinin-1 receptor (substance P) antagonists, and

(5) cannabinoids.

Antihistamines such as diphenhydramine which affect histaminergic receptors in the CTZ are widely utilized but have not been systematically studied.

Anticipatory Nausea and Vomiting

Prevention of anticipatory nausea and vomiting is achieved through the use of optimal antiemetic prophylaxis with each cycle of chemotherapy. Once symptoms have developed, benzodiazepines can be added to the prophylactic antiemetic regimen for anxiolysis. Patient expectancy of nausea and vomiting is an often under recognized factor and alternative therapies have been shown to effectively treat anticipatory CINV especially when used in combination with anti-emetics.

Breakthrough Nausea and Vomiting 

Breakthrough emesis presents a difficult scenario as correction of refractory ongoing CINV is challenging to reverse. Prevention is far easier than treatment. The general principle of breakthrough treatment is to give an additional agent from a different drug class.

Around the clock dosing is typically preferred rather than as needed dosing, particularly in children who may not know how to properly convey nausea. Typical breakthrough agents include lorazepam, diphenhydramine, metoclopramide (with diphenhydramine), promethazine or metopimazine, and cannabinoids. One can consider maximizing the starting dose of the 5-HT3 antagonist or switching to an alternative 5-HT3 antagonist (e.g., from ondansetron to granisetron or palonosetron). If the patient has dyspepsia, adding an H2 blocker or proton pump inhibitor may be beneficial. Adequate hydration is imperative.

Alternative therapies should be explored and may be of benefit. The patient should also be assessed for other non-chemotherapy-associated aetiologies of nausea and vomiting such as electrolyte imbalances, GI obstruction or gastroparesis, tumor infiltration of bowel or brain, effect of total parenteral nutrition, and other potential diagnoses.

Drugs and dosing

References

• James H, Caroline A, Anurag K. (2015). Supportive Care in Pediatric Oncology, A Practical Evidence-Based Approach. New York: Springer
• Dupuis LL, Boodhan S, Holdsworth M et al (2013) Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60: 1073–1082
• Ettinger D, Akerley W, Benson A et al (2012) National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Antiemesis, V.1.2012
• Grunberg SM, Deuson RR, Mavros P et al (2004) Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100:2261–2268
• Grunberg SM, Warr D, Gralla RJ et al (2010) Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer 19:S43–S47