Chemotherapy-Induced Nausea and Vomiting

AUTHOR: Ritesh Rathore, MD

Definition

Chemotherapy-induced nausea and vomiting (CINV) refers to the adverse emetic effects associated with the use of systemic therapies in the treatment of cancer. There are five recognized subtypes:

Acute-phase CINV: Nausea and vomiting starting within 24 hr after receiving chemotherapy.
Delayed-phase CINV: Nausea and vomiting beginning or returning >24 hr after receiving chemotherapy.
Breakthrough CINV: Nausea and vomiting occurring despite appropriate prophylactic treatment.
Anticipatory CINV: Nausea and vomiting beginning prior to receiving therapy as a conditioned response in patients who have developed significant emesis during previous chemotherapy administration.
Refractory CINV: Recurring in subsequent cycles of therapy, excluding anticipatory CINV.

Synonyms

Drug-induced nausea and vomiting

Chemotherapy-induced emesis

CINV

ICD-10CM CODES
R11.2		Nausea with vomiting, unspecified
R11.0		Nausea
R11.10		Vomiting, unspecified
Z51.11		Encounter for antineoplastic chemotherapy

Epidemiology & Demographics

The patient’s risk for development of nausea and vomiting is most strongly dependent on the emetogenicity of the chemotherapy agent(s) being used (Table E1).
Emetogenicity is classified into four categories: Highly emetic (>90%), moderately emetic (>30% to 90%), low emetic (10% to 30%), and minimally emetic (0% to 10%).¹
With certain chemotherapy regimens, CINV will occur in most patients. However, patients’ tolerance may vary, and symptoms may occur in as low as 10% of patients.
Symptoms may be dose dependent (the higher the dose, the greater the risk for symptoms).
CINV is more likely to affect female and younger patients.
Patients expecting CINV before receiving therapy (anticipatory emesis) are at greater risk of experiencing symptoms.

TABLE E1 Emetogenic Potential of Commonly Used Oral Antineoplastic Agents

Risk	Frequency of Emesis (%; Without Prophylaxis)	Agent
High	>90	Altretamine
		Procarbazine
Moderate	30-90	Cyclophosphamide Crizotinib Olaparib
		Temozolomide
Low	10-30	Alectinib Axitinib
		Capecitabine Ceritinib Cobimetinib
		Dasatinib
		Everolimus Gefitinib Ibrutinib
		Imatinib Ixazomib
		Lapatinib
		Lenalidomide
		Nilotinib Palbociclib Panobinostat
		Pazopanib
		Sorafenib
		Sunitinib
		Thalidomide
		Vemurafenib
Minimal	<10	Alectinib Busulfan
		Chlorambucil Dabrafenib
		Erlotinib
		Hydroxyurea Idelalisib
		Melphalan
		Methotrexate Osimertinib Ruxolitinib
		6-Thioguanine Trametinib
		Vismodegib

Modified from Roila F et al: Guideline update for MASCC and ESMO in the prevention of chemotherapy and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference, Ann Oncol 21(suppl 5):232-243, 2010.

Incidence

The highest incidence of CINV is before or during the first cycle of chemotherapy.

Risk Factors

Previous history of CINV
History of motion sickness or vestibular dysfunction
Higher levels of anxiety
History of alcohol use decreases risk

Genetics

It has been demonstrated that three SNPs in 5-hydroxytryptamine receptor (5-HT3R) genes, two alleles of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, and three SNPs in ATP binding cassette subfamily B member 1 (ABCB1) gene are associated with the occurrence and severity of CINV.²

Physical Findings & Clinical Presentation

Symptoms may include anxiety and lightheadedness.
The most common physical findings are increased pulse rate and abnormal blood pressure (elevated if the patient is highly anxious, reduced if the patient is dehydrated).
Symptoms such as fever, headache, diarrhea, and abdominal pain may suggest an alternative diagnosis; physical examination findings such as increased blood pressure, abdominal tenderness, or focal neurologic deficits may suggest symptoms caused by cancer progression or other acute illnesses such as infection.

Pathophysiology

The pathophysiology of nausea and vomiting is illustrated in Fig. E1. CINV is likely the result of chemotherapy acting in two places: Directly in the gastrointestinal tract and in the vomiting center of the brain. In both areas, nausea and vomiting are mediated by the actions of certain neurotransmitters, with serotonin, dopamine, and neurokinin-1 being the most important.

Figure E1 Pathophysiology of nausea and vomiting.

DKA, Diabetic ketoacidosis; GABA,γ-aminobutyric acid; GVHD, graft-versus-host-disease; 5-HT3, serotonin; 5-HT3 R, serotonin receptor.

From Hoffman R: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Differential Diagnosis

The two major considerations are progression of cancer and infection
Intestinal/gastric: Obstruction or partial obstruction of the digestive tract from tumor progression
Neurologic: Brain metastases causing vomiting or metastatic infiltration of nerves affecting the digestive tract
Infectious: Acute bacterial, viral, or parasitic infections of the digestive tract causing symptoms (can be associated with diarrhea or pain)
Renal: Dehydration leading to acute kidney injury and failure, causing worsening of nausea and vomiting

Workup

Additional workup is not indicated if patient’s symptoms and the onset of nausea and vomiting fit the typical CINV presentation. If other symptoms or unexpected physical examination findings are present, then other likely causes need to be ruled out with a combination of blood work and CT scan imaging.

Laboratory Tests

If the onset of symptoms is not typical for CINV, then blood tests such as CBC, comprehensive chemistry panel, and CNS imaging are indicated for assessing secondary causes.
Stool studies looking for infections from viruses, bacteria, or parasites may be ordered if diarrhea is also present.

Imaging Studies

Abdominal radiographs may reveal ileus or obstruction of the digestive tract.
Abdomen and pelvic CT scans may provide more detailed information about local cancer progression/invasion in relation to the digestive tract and whether ileus or obstruction is present.
CNS imaging with CT or MRI scanning of the brain may provide information about possible brain or leptomeningeal metastases.

A management approach to CINV is summarized in Box E1. Table E2 summarizes antiemetic drugs based on class.
Recently, a proposed prediction tool for identifying patients at high-risk for CINV has listed eight risk factors:
1. Patient age <60 yr
2. The first two cycles of chemotherapy
3. Anticipatory nausea and vomiting
4. History of morning sickness
5. Hours of sleep the night before chemotherapy
6. CINV in the prior cycle
7. Patient self-medication with nonprescribed treatments
8. Use of platinum or anthracycline-based regimens

TABLE E2 Antiemetic Drugs

Antiemetic Class	Mechanism of Action	Recommended Uses	Level of EvidenceTo Support Use inCancer-RelatedNausea and Vomiting
Corticosteroid: Dexamethasone	Unknown, possibly reduced prostaglandin activity in the brain	Treatment-related nausea and vomiting Nausea and vomiting secondary to raised intracranial pressure	High
		Vomiting secondary to bowel obstruction	Low
5-HT₃ antagonist: Granisetron Ondansetron Palonasetron Dolasetron	Inhibit visceral afferents by blocking binding of peripheral 5-HT to serotonin (type 3) receptors along the vagus nerve in the GI tract	Treatment-related nausea and vomiting Opioid-induced nausea and vomiting Nausea of advanced cancer	High
NK₁ antagonist: Aprepitant Fosaprepitant	Blockade of the binding of substance P to NK₁ receptors in the chemotrigger zone of the area postrema	Treatment-related nausea and vomiting	High
Benzodiazepine: Lorazepam Alprazolam	Presumably due to anxiolytic, sedative and anterograde amnesic effects of these medications centrally Especially useful in delayed or anticipatory nausea as adjuvant agents	Adjuvant support for the management of treatment-related nausea and vomiting, particularly when nausea associated with anxiety	High
Atypical antipsychotic: Olanzapine	Antipsychotic in the thienobenzodiazepine drug class that blocks multiple neurotransmitters, including: - Dopamine at D₁, D₂, D₃, and D₄ brain receptors - Serotonin at 5-HT_2a, 5-HT_2c, 5-HT₃, and 5-HT₆ receptors - Catecholamines at alpha-1 adrenergic receptors - Acetylcholine at muscarinic receptors - Histamine at H₁ receptors	Adjuvant agent to manage treatment-related nausea and vomiting	Moderate
Antihistamine: Diphenhydramine Promethazine	Predominantly histamine antagonist in vestibular nucleus and chemotrigger zone Central dopamine and acetylcholine antagonist	Adjuvant, especially when the extra-pyramidal effects of dopamine antagonists are considered problematic	Moderate
Butyrophenone: Haloperidol Droperidol	Dopaminergic (D₂ subtype) receptor antagonists	Adjuvant	Moderate
Phenothiazine: Prochlorperazine	Dopamine antagonist Histamine antagonist Acetylcholine antagonist	Adjuvant	High
Dopamine₂-antagonist: Metoclopramide	Competitive antagonist at central dopaminergic (D₂) receptors Weak competitive antagonist peripherally at GI 5-HT₃ receptors (at high dose) 5-HT₄ agonist Increased lower esophageal sphincter pressure Enhanced rate of gastric emptying	Adjuvant Gastric stasis Opioid-induced nausea and vomiting Nausea of advanced disease	High

5-HT, 5-hydroxytryptamine; GI, gastrointestinal; NK₁, neurokinin-1.

From Talley NJ et al: Essentials of internal medicine, ed 4, Chatswood, NSW, 2021, Elsevier Australia.

BOX E1 Management Approach: Chemotherapy-Induced Nausea and Vomiting (CINV)

Antiemetic therapy for CINV should be based on the emetic potential of the chemotherapy regimen being used and should take into account individual patient factors (e.g., sex, age, history of alcohol use, and previous emesis with chemotherapy). Excellent methods for predicting the likelihood of emesis with single chemotherapeutic agents or combination regimens have been developed.

All patients receiving chemotherapy with moderate or high emetogenic potential should receive antiemetic prophylaxis for acute (day 1) and delayed (days 2-5) nausea and vomiting. Patients receiving highly emetogenic regimens should receive prophylaxis on day 1 with a 5-HT3 receptor antagonist (preferably palonosetron) plus neurokinin-1 (NK1) receptor antagonist plus dexamethasone, followed on days 2-4 by dexamethasone. Olanzapine should be added in patients judged to be at high risk. For moderately emetogenic regimens, treatment with a 5-HT3 receptor antagonist (preferably palonosetron) plus dexamethasone on day 1, followed by dexamethasone on days 2 and 3, is recommended.

Patients receiving therapy with low emetic potential should receive dexamethasone (8 mg intravenously or orally); a 5-HT3 receptor antagonist should be added with subsequent courses only if antiemetic control is inadequate. Routine prophylaxis is not necessary for patients receiving agents or regimens of minimal risk. Patients with inadequate control should have intensification of their antiemetic prophylaxis during subsequent treatment cycles.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

On a 32-point scale, calculated before each cycle of therapy, patients with risk scores ≥16 units are considered at high risk for developing moderate CINV.³

Choice and duration of antiemetic use are dependent on the emesis-potential of the chemotherapy regimen being used. Commonly used antiemetic agents and recommended dosing are described in Table E3. For chemotherapy agents with high emetogenic potential, the use of multidrug antiemetic regimens has proven to be highly effective as prophylaxis.
The most common treatment combination includes a serotonin-receptor (5-HT3) antagonist (ondansetron, granisetron, dolasetron, or palonosetron), a corticosteroid (dexamethasone), and a neurokinin-1 (NK-1) receptor antagonist (aprepitant, rolapitant, or fosaprepitant).⁴
A fixed-dose combination of oral palonosetron and netupitant is now available and has the potential advantage of decreasing dexamethasone requirements for emesis control.
Table E4 summarizes recommended antiemetic prophylaxis for patients receiving intravenous chemotherapy.
The antipsychotic drug olanzapine has been demonstrated across multiple clinical trials to be effective and safe at reducing emesis during the delayed and overall phases of CINV prevention in highly-emetogenic chemotherapy regimens.
Many other adjunct drugs are available, such as prochlorperazine, metoclopramide, haloperidol, and droanbinol; comparatively, they are less effective and have greater potential for adverse effects.
Benzodiazepines (usually lorazepam) may help in patients with significant anxiety levels that lead to anticipatory CINV.
Patients with uncontrolled symptoms may require hospitalization for supportive care including intravenous medications and fluids.

TABLE E3 Antiemetic Agents: Recommended Dosing

Antiemetic Agent	RECOMMENDED DOSE
Antiemetic Agent	Acute Emesis (Before Chemotherapy)	Delayed Emesis
5-HT₃ antagonists
Ondansetron	0.15 mg/kg or 8 mg IV; 12-16 mg PO	8 mg PO twice a day × 2-3 days
Granisetron	1 mg IV or PO; 10 mg subcutaneous (extended release)
Dolasetron	1.8 mg/kg or 100 mg IV; 100-200 mg PO
Palonosetron	0.25 mg IV or 0.5 mg PO
NK1 receptor antagonists
Aprepitant	125 mg PO	80 mg PO days 2 and 3
Fosaprepitant	150 mg IV
Rolapitant	180 mg PO
Combination 5-HT₃/NK1 receptor antagonist
NEPA (palonosetron 0.5 mg/netupitant 300 mg)	1 tablet PO
Multireceptor antagonist
Olanzapine	10 mg PO	10 mg PO days 2-4
Corticosteroids
Dexamethasone
With NK1 antagonist	12 mg IV or PO	8 mg PO for 2-3 days
Without NK1 antagonist	8 mg (moderate risk) or 20 mg (high risk) IV or PO	4-8 mg PO twice a day for 2-3 days
Other agents
Prochlorperazine		10 mg PO or IV every 3-4 h as needed
Lorazepam	1-2 mg IV (for anticipatory nausea/vomiting)
Dronabinol		5 mg/m² PO every 3-4 h as needed

5-HT₃, 5-Hydroxytryptamine 3; NK1, neurokinin 1; IV, intravenous; PO, by mouth.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE E4 Summary of Recommended Antiemetic Prophylaxis for Patients Receiving Intravenous Chemotherapy

Risk of Emesis	Day 1 (Prechemotherapy)	After Day 1
High (includes cyclophosphamide and doxorubicin)	5-HT₃ receptor antagonist (palonosetron preferred) + NK1 receptor antagonist + dexamethasone + olanzapine (if patient considered high risk)	Dexamethasone days 2-4 + aprepitant days 2-3 (if used on day 1) + olanzapine days 2-4 (high-risk patients)
Moderate	5-HT₃ receptor antagonist (palonosetron preferred) + dexamethasone	Dexamethasone days 2 and 3
Low	Dexamethasone	None
Minimal	As needed	None

5-HT3, 5-Hydroxytryptamine 3; NK1, neurokinin 1.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Nonpharmacologic Therapy

Patients who have a significant anxiety component to their CINV may benefit from cognitive behavioral therapy.

Disposition

CINV treatment has been revolutionized with the introduction of newer classes of antiemetics leading to a significant majority of patients achieving adequate symptom control.

Comments

Aggressive symptom control in the acute phase of CINV is the key initial therapeutic approach. Prevention of the acute phase has led to much improved control of delayed CINV and decreased the incidence of anticipatory CINV.
Prevention of symptoms is much easier to achieve than controlling or treating active symptoms.

Hesketh P.J. : Antiemetics: American Society of Clinical Oncology clinical practice guideline updateJ Clin Oncol. ;35(28):3240-3261, 2017.
Singh K.P. : A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomitingCrit Rev Oncol Hematol. ;121:51-61, 2018.
Dranitsaris G. : The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomitingAnn Oncol. ;28(6):1260-1267, 2017.
Navari R.M., Aapro M. : Antiemetic prophylaxis for chemotherapy-induced nausea and vomitingN Engl J Med. ;374:1356-1367, 2016.

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