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Nausea and Vomiting: Prophylaxis and Treatment

Classification of Chemotherapy-Induced Nausea and Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is among the most common and distressing adverse effects of chemotherapy, and it can markedly reduce quality of life and contribute to premature treatment discontinuation.

Acute-Onset CINV

Acute-onset CINV is nausea or vomiting occurring within 24 hours after chemotherapy administration. A key mechanism of acute emesis is the release of serotonin from the gastrointestinal tract, which activates central 5-HT₃ receptors. Anticipatory CINV is a distinct subtype that occurs before chemotherapy as a result of classical conditioning from prior treatment cycles.

Delayed-Onset Vomiting

Delayed-onset vomiting is emesis occurring 1–5 days after chemotherapy administration. Substance P, with activation of neurokinin-1 (NK₁) receptors, is an important mediator, and additional multifactorial contributors are common.

Breakthrough CINV and Refractory CINV

Breakthrough CINV refers to nausea and/or vomiting that occurs despite guideline-concordant prophylaxis. Refractory CINV refers to recurrence in subsequent cycles despite prophylaxis that has been adjusted based on prior failure.

Severity Grading of Vomiting According to CTCAE

• Grade 0: No vomiting occurs.
• Grade 1: One to two episodes within 24 hours.
• Grade 2: Three to five episodes within 24 hours.
• Grade 3: Six or more episodes within 24 hours, or vomiting that requires hospitalization or parenteral nutrition.
• Grade 4: Life-threatening complications due to vomiting.
• Grade 5: Death due to complications of vomiting.

Differential Diagnosis of Vomiting in Patients With Cancer

Nausea and vomiting in patients with cancer are not automatically caused by chemotherapy. In addition to CINV, medication-related, metabolic, gastrointestinal, infectious, or central nervous system etiologies are common. Use a structured approach to differential diagnosis because some causes require urgent treatment and may be life-threatening; be aware of warning signs.

Common Differential Diagnoses

• Gastrointestinal causes include tumor-related or postoperative obstruction, peritoneal carcinomatosis, constipation (including opioid-induced constipation), mucositis or gastritis, enteritis or colitis (e.g., after radiation therapy or immune checkpoint inhibitors), and pancreatitis.
• Medications include opioids, antibiotics, iron supplements, digoxin, nonsteroidal anti-inflammatory drugs (NSAIDs), and iodinated contrast media.
• Metabolic/endocrine causes include hypercalcemia, hyponatremia, uremia/chronic kidney disease, hepatic failure, diabetic ketoacidosis, adrenal insufficiency (e.g., after glucocorticoid tapering or immune-mediated), and hypoglycemia.
• Infectious causes include gastroenteritis, sepsis, febrile neutropenia, and pyelonephritis.
• Neurologic causes include increased intracranial pressure (e.g., brain metastases, hemorrhage, or hydrocephalus), leptomeningeal carcinomatosis, and vestibular disorders.
• Postoperative causes include postoperative nausea and vomiting (PONV).

Warning Signs

• Dehydration: Hypotension, tachycardia, syncope, oliguria, profound weakness, and acute confusion.
• Fever: Shivering, clinical suspicion of sepsis. Neutropenic fever is a medical emergency.
• Neurologic symptoms: Severe headache, focal neurologic deficits, altered mental status, seizures, and papilledema and/or visual disturbances.
• Ileus or bowel perforation: Severe abdominal pain, absence of stool passage, abdominal distension, involuntary guarding, and feculent vomiting.
• Gastrointestinal bleeding: Hematemesis or melena and clinically significant anemia.
• Severe electrolyte disorders: Muscle cramps, arrhythmias, and somnolence.

Risk-Adapted Prophylaxis of Nausea and Vomiting During Chemotherapy

The emetogenic risk of the regimen determines the prophylactic antiemetic supportive care.

• Dosing examples for 5-HT₃ receptor antagonists: Ondansetron 8 mg orally twice daily, granisetron 1 mg intravenously once daily or 2 mg orally once daily, and palonosetron 0.25 mg intravenously as a single dose on day 1 or 0.5 mg orally as a single dose on day 1.
• Dosing examples for NK₁ receptor antagonists: Aprepitant 125 mg orally on day 1 and 80 mg orally on days 2 and 3, fosaprepitant 150 mg intravenously on day 1 only, or rolapitant 180 mg orally on day 1 only.
• Dexamethasone dosing regimen: 12 mg orally on day 1 and 8 mg orally on the following 2–3 days.
• Dosing example for a dopamine receptor antagonist: Metoclopramide 10 mg orally or intravenously, up to every 8 hours as needed.

High Risk of Vomiting

• High emetogenic risk: ≥90% risk of emesis without prophylaxis.
• Chemotherapy regimens commonly used in urology include cisplatin-containing combinations and carboplatin with an AUC ≥4.
• Antiemetic prophylaxis:
  • Use a 5-HT₃ receptor antagonist plus an NK₁ receptor antagonist plus dexamethasone for up to four days, depending on the regimen and risk of delayed CINV.
  • Consider adding olanzapine 5 mg orally once daily on days 1–4 as an additional option (atypical antipsychotic; off-label in some settings).

Moderate Risk of Vomiting

• Moderate emetogenic risk: ≥30% risk of emesis without prophylaxis.
• Chemotherapy regimens commonly used in urology include carboplatin at AUC <4, ifosfamide, and vinflunine.
• Antiemetic prophylaxis:
  • Use a 5-HT₃ receptor antagonist plus dexamethasone for 1–3 days, based on the risk of delayed CINV.

Low Risk of Vomiting

• Low emetogenic risk: approximately 10–30% risk of emesis without prophylaxis.
• Agents commonly used in urology include docetaxel, enfortumab vedotin, etoposide, everolimus, gemcitabine, methotrexate, paclitaxel, and temsirolimus.
• Antiemetic prophylaxis:
  • Use a single agent such as a 5-HT₃ receptor antagonist, a dopamine receptor antagonist, or dexamethasone 8 mg (typically given on day 1).

Minimal Risk of Vomiting

• Minimal emetogenic risk: <10% risk of emesis without prophylaxis.
• Agents commonly used in urology include bevacizumab, bleomycin, ipilimumab, nivolumab, pazopanib, pembrolizumab, sorafenib, sunitinib, and zoledronic acid.
• Do not prescribe routine pharmacologic prophylaxis, but rescue (as-needed) antiemetics should be available. If the patient repeatedly requires rescue medication with subsequent doses, initiate prophylaxis for future administrations.

Treatment of CINV:

If CINV occurs despite prophylaxis, use antiemetics from drug classes that were not used for prophylaxis and escalate the prophylaxis in the next cycle. See the dosing suggestions above. Additional options:

• Olanzapine 5 mg orally (often at bedtime) for 2–4 days; olanzapine is an atypical antipsychotic and is off-label for CINV in some settings.
• Metoclopramide 10 mg orally or intravenously every 8 hours as needed.
• Lorazepam 0.5–2 mg orally or intravenously as an anxiolytic adjunct, particularly for anticipatory CINV.

References

Paul J. Hesketh et al. Antiemetics: ASCO Guideline Update. J Clin Oncol 38, 2782-2797(2020). https://doi.org/10.1200/JCO.20.01296

Herrstedt et al. (2024) 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. ESMO Open, Volume 9, Issue 2, 102195. https://doi.org/10.1016/j.esmoop.2023.102195

Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Supportive Therapie bei onkologischen PatientInnen https://www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie

  Deutsche Version: Prophylaxe und Therapie von Übelkeit und Erbrechen durch Chemotherapie

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