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Chemotherapy Induced Nausea and Vomiting
Chemotherapy-induced nausea and vomiting (CINV) refers to adverse emetic effects associated with the use of systemic therapies used 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
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
Emetogenic Potential of Commonly Used Oral Antineoplastic Agents
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 2010;21(suppl 5):v232-243.
| Risk | Frequency of Emesis (%; Without Prophylaxis) | Agent |
|---|---|---|
| High | >90 | Altretamine |
| Procarbazine | ||
| Moderate | 30-90 | CyclophosphamideCrizotinib Olaparib |
| Temozolomide | ||
| Low | 10-30 | AlectinibAxitinib |
| CapecitabineCeritinib Cobimetinib | ||
| Dasatinib | ||
| EverolimusGefitinib Ibrutinib | ||
| ImatinibIxazomib | ||
| Lapatinib | ||
| Lenalidomide | ||
| NilotinibPalbociclib Panobinostat | ||
| Pazopanib | ||
| Sorafenib | ||
| Sunitinib | ||
| Thalidomide | ||
| Vemurafenib | ||
| Minimal | <10 | AlectinibBusulfan |
| ChlorambucilDabrafenib | ||
| Erlotinib | ||
| HydroxyureaIdelalisib | ||
| Melphalan | ||
| MethotrexateOsimertinib Ruxolitinib | ||
| 6-ThioguanineTrametinib | ||
| Vismodegib |
- 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%).
- •With certain chemotherapy regimens, CINV will occur in the majority of 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.
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.
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 person is highly anxious, reduced if the patient is dehydrated).
- •Symptoms such as diarrhea, fever, headache, 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 illness such as infection.
Pathophysiology
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.
Differential Diagnosis
- •The two main considerations are progression of cancer and infection
- •Intestinal/gastric: Obstruction or partial obstruction of the digestive tract from tumor
- •Neurologic: Metastases to the brain causing vomiting; 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 onset of nausea and vomiting fit the usual presentation for CINV. 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 imaging.
Laboratory Tests
- •If the onset of symptoms is not typical for CINV, then blood tests such as CBC, liver function tests, electrolytes, and kidney function tests and CNS imaging may be indicated to assess for secondary causes of nausea and/or emesis.
- •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.
Treatment
- A management approach to CINV is summarized below.
- Management Approach: Chemotherapy-Induced Nausea and Vomiting (CINV)
- From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.5-HT3, 5-Hydroxytryptamine 3 (serotonin).
- 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.
- •Choice and duration of antiemetic use are dependent on the emesis-potential of the chemotherapy regimen being used. For chemotherapy agents with high emetogenic potential, the use of multidrug antiemetic regimens has proven to be highly effective as prophylaxis
Antiemetic Agents: Recommended Dosing
From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.
| Antiemetic Agent | Recommended Dose | |
|---|---|---|
| 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 hours as needed | |
| Lorazepam | 1-2 mg IV (for anticipatory nausea/vomiting) | |
| Dronabinol | 5 mg/m2 PO every 3-4h as needed |
5-HT 3, 5-Hydroxytryptamine 3; NK1, neurokinin 1; IV, intravenous; PO, by mouth.
- 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).
- •A fixed-dose combination of oral palonosetron and netupitant is now available.
Summary of Recommended Antiemetic Prophylaxis for Patients Receiving Intravenous Chemotherapy
From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.
| 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-HT 3, 5-Hydroxytryptamine 3; NK1, neurokinin 1.
- The commonly used 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.
- •Many other adjunct drugs are available, such as prochlorperazine, metoclopramide, haloperidol, and marinol; 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.
Nonpharmacologic Therapy
Patients who have a significant anxiety component to their CINV may benefit from cognitive behavioral therapy.
Disposition
Although CINV is one of the most feared complications of cancer therapy, its treatment has been revolutionized in the last 20 yr, with a significant majority of patients achieving adequate symptom control.
Pearls & Considerations
- •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 also decreased the incidence of anticipatory CINV.
- •Prevention of symptoms is much easier to achieve than controlling or treating active symptoms.
Seek Additional Information
- Hesketh P.J., et al.: Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017; pp. 3240-3261.
- Jordan K., et al.: Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Ann Oncol 2015; 26 (6): pp. 1081-1090.
- Navari R.M., Aapro M.: Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 2016; 374: pp. 1356-1367.
- Singh K.P., et al.: A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting. Crit Rev Oncol Hematol 2018; 121: pp. 51-61.
