Chemotherapy-induced nausea and vomiting (CINV)

Pathophysiology, emetogenic pathways

• Three afferent inputs converge on the medullary vomiting center (nucleus tractus solitarius):
  • Chemoreceptor trigger zone (CTZ, area postrema): outside the blood-brain barrier; detects emetogenic toxins. Dense in D2 dopamine, 5-HT3 serotonin, and NK1 (substance P) receptors.
  • Vagal afferents from the GI tract: chemotherapy damages enterochromaffin cells, causing 5-HT release, 5-HT3 stimulation, and vagal afferent firing. Dominant pathway for ACUTE CINV.
  • Higher cortical inputs: anxiety, conditioning, sights/smells. Drive anticipatory CINV.
• Acute CINV (0 to 24 h after chemo) is primarily 5-HT3 mediated.
• Delayed CINV (24 h to 5 days) is primarily NK1/substance-P mediated, with contributions from central mechanisms responsive to dexamethasone.
• Anticipatory CINV (pre-chemo, in patients with prior poorly controlled CINV) is conditioned and cortically driven; benzodiazepines plus behavioral therapy work best.

Types of nausea

• Acute: <24 hours; peak 4 to 6 hours post-treatment.
• Delayed: >24 hours, can last up to 7 days after treatment; peak 2 to 3 days.
• Anticipatory: triggered by negative past experience; occurs before chemo administration.
• Breakthrough: occurs despite appropriate antiemetic prophylaxis and requires rescue therapy.
• Refractory: occurs despite optimal antiemetic prophylaxis and treatment in previous cycles.
• Risk factors: female sex, young age, history of motion sickness, history of depression and anxiety, and low/rare alcohol use.

Emetogenic risk stratification (parenteral chemo)

• High emetic risk (HEC, >90%): cisplatin (any dose), carboplatin AUC ≥4 (NCCN classifies as high; ASCO/MASCC classify carboplatin as moderate but add an NK1 antagonist at AUC ≥4), AC (doxorubicin + cyclophosphamide), high-dose cyclophosphamide >1500 mg/m², ifosfamide ≥2 g/m²/dose, dacarbazine, mechlorethamine, streptozocin, carmustine >250 mg/m².
• Moderate emetic risk (MEC, 30 to 90%): oxaliplatin, irinotecan, daunorubicin, doxorubicin (<60 mg/m²), epirubicin (<90 mg/m²), idarubicin, bendamustine, clofarabine, cytarabine >1 g/m², ifosfamide <2 g/m², methotrexate ≥250 mg/m², romidepsin, temozolomide, trabectedin.
• Low emetic risk (10 to 30%): 5-FU, gemcitabine, paclitaxel, docetaxel, eribulin, etoposide, methotrexate <250 mg/m², mitomycin, pemetrexed, topotecan, bortezomib, brentuximab vedotin, cetuximab, panitumumab, ramucirumab (ipilimumab, nivolumab, and pembrolizumab are MINIMAL risk per ASCO 2020 and MASCC/ESMO).
• Minimal emetic risk (<10%): bleomycin, vincristine, vinblastine, vinorelbine, fludarabine, cladribine, rituximab, ofatumumab, obinutuzumab, trastuzumab, pertuzumab, bevacizumab.

Emetogenic potential

Note: NCCN (since v1.2023) classifies sacituzumab govitecan and fam-trastuzumab deruxtecan as high emetic risk; MASCC/ESMO 2023 keeps both moderate but notes emetogenicity comparable to carboplatin AUC ≥5 (consider an NK1-containing 3-drug regimen). Doxorubicin ≥60 mg/m² and melphalan ≥140 mg/m² are high-risk cutoffs. Oral anticancer drugs are grouped as moderate/high vs minimal/low over a course; some (e.g., procarbazine, altretamine) are high emetic risk; for a MEC oral agent give one antiemetic drug.

Modifiers, adjust risk upward

• Female sex
• Age <50
• History of motion sickness or pregnancy-related nausea/vomiting
• Low chronic alcohol use (heavy alcohol use is paradoxically protective)
• Anxiety, prior poorly controlled CINV
• Concurrent radiation (especially upper abdominal)
• Multi-day chemotherapy regimens

Antiemetic drug classes

5-HT3 receptor antagonists

• First-generation (ondansetron, granisetron, dolasetron): equivalent for acute CINV. T½ 4 to 9 h. QT prolongation risk; IV dolasetron no longer recommended due to torsades reports. Dolasetron (Anzemet) is PO only, 100 mg. Granisetron can be IV, SQ, PO, or transdermal patch (SQ extended-release given q7d). Ondansetron (Zofran) PO or IV, max single IV dose 16 mg (oral 24 mg for HEC), has a higher rate of QTc prolongation.
• Palonosetron (Aloxi, IV; oral 0.5 mg capsule also approved): long T½ (~40 h), higher receptor binding affinity. Superior to first-generation for delayed CINV in MEC and HEC (Saito M et al, Lancet Oncol 2009; PMID 19135415). Preferred 5-HT3 antagonist when an NK1 antagonist is not added. Effective for 2 to 3 days.
• AE: all cause constipation and headache; mild QTc prolongation; rare serotonin syndrome; rare sedation. Tachyphylaxis with repeated dosing across cycles.
• After palonosetron, a granisetron transdermal patch, or an extended-release injection, breakthrough 5-HT3 drugs play a limited role for the first 2 to 3 days, so a drug with a different mechanism should be used.

NK1 (neurokinin-1) receptor antagonists

• Aprepitant (Emend PO) / fosaprepitant (Emend IV) / aprepitant emulsion (Cinvanti IV): 3-day PO course (125 mg day 1, 80 mg days 2 to 3) or single IV dose (fosaprepitant 150 mg; aprepitant emulsion 130 mg). Fosaprepitant contains polysorbate 80 (infusion hypersensitivity); aprepitant emulsion and fosnetupitant do not. CYP3A4 inhibitor; reduce the dexamethasone dose ~50% when given together.
• Rolapitant: single 180 mg PO dose. Long T½ (~7 days), given q2wk. Moderate CYP2D6 inhibitor (effect persists ≥28 days); contraindicated with thioridazine, pimozide. Do NOT use as a breakthrough medication (not studied that way); best for delayed nausea.
• Netupitant/fosnetupitant + palonosetron (NEPA, Akynzeo PO or IV): single-dose convenience option for HEC.
• NK1 antagonists primarily prevent DELAYED CINV. Adding an NK1 to 5-HT3 + dexamethasone for HEC reduces delayed emesis by ~15 to 20% absolute (Hesketh PJ et al, J Clin Oncol 2003; PMID 14559886).
• NK1 drug interactions: CYP3A4 (reduce dexamethasone dose, except rolapitant); CYP2C9 (warfarin); decreased efficacy of oral contraceptives; increased ifosfamide neurotoxicity.

Corticosteroids, dexamethasone

• Mechanism poorly understood; central plus peripheral anti-inflammatory effects on chemoreceptor pathways.
• Dosing for HEC: 12 mg PO/IV day 1, then 8 mg days 2 to 4 when given with aprepitant, fosaprepitant, or NEPA (this already reflects the ~50% CYP3A4 dose reduction); 20 mg day 1 if no NK1 antagonist is used or with rolapitant.
• Dexamethasone-sparing regimens: growing evidence that limiting dexamethasone to day 1 is non-inferior with palonosetron-based regimens in MEC/AC (Aapro M et al, Ann Oncol 2010, MEC; Celio L et al, BMC Cancer 2019 meta-analysis) and with NEPA plus olanzapine in HEC (Meng Y et al, J Clin Oncol 2026, PMID 42241642). Useful for diabetics, insomnia, steroid intolerance.
• AE: insomnia (consider AM dosing), hyperglycemia (careful in diabetes), mood lability, GI ulceration/dyspepsia (give PPI/H2), hiccups, immunosuppression. Limit duration where possible.

Olanzapine

• Atypical antipsychotic, broadest mechanistic coverage of any antiemetic. Blocks D2, 5-HT2, 5-HT3, histamine (H1), and muscarinic receptors.
• Pivotal trial: Navari RM et al, NEJM 2016 (PMID 27410922). Olanzapine 10 mg PO days 1 to 4 added to the standard 3-drug regimen for HEC improved complete response (no emesis, no rescue) 64% vs 41%, P<.001; nausea-free 37% vs 22%, P<.01.
• Standard dose: 10 mg PO daily ×3 to 4 days. Start at 5 mg if concerned about sedation (especially elderly); use 2.5 mg if sedation persists; increase to 10 mg if 5 mg is ineffective. Use PM dosing due to somnolence.
• Most effective addition for delayed CINV AND for nausea (5-HT3 and NK1 antagonists control vomiting better than nausea).
• AE: sedation (especially day 1), weight gain (irrelevant for short courses), hyperglycemia. Avoid stacking with benzodiazepines in the elderly.

Dopamine receptor antagonists (D2 blockers) and phenothiazines

• Metoclopramide (Reglan): peripheral plus central D2 blockade; increases gut motility (useful for gastroparesis). 10 to 40 mg PO/IV q6h PRN (10 to 20 mg q4 to 6h). EPS at high doses; FDA black box for tardive dyskinesia with chronic use >12 weeks.
• Prochlorperazine (Compazine): 5 to 10 mg PO/IV q6h (max 40 mg/day) or 25 mg PR. EPS risk; use particular caution in older patients with dementia (boxed warning: increased mortality in dementia-related psychosis).
• Promethazine (Phenergan): multiple routes; the IM formulation can cause severe tissue injury.
• Haloperidol: 0.5 to 2 mg PO/IV q4 to 6h. Useful for refractory CINV. QTc prolongation. Do not combine haloperidol, metoclopramide, and these agents with each other.
• Now typically RESCUE/breakthrough agents rather than first-line prophylaxis. AEs: anticholinergic effects, EPS, arrhythmias, CNS depression (falls, orthostasis, dystonic reactions).

Benzodiazepines

• Lorazepam (Ativan) 0.5 to 2 mg PO/SL/IV: primary role in ANTICIPATORY CINV (0.5 to 1 mg the night before and morning of chemo, 1 to 2 hours before). Not a stand-alone antiemetic; useful as an adjunct for breakthrough or anticipatory CINV, especially with anxiety. Avoid with other CNS depressants and in older patients.

Cannabinoids

• Dronabinol (synthetic THC, Marinol) or nabilone (Cesamet): are cannabinoid (CB1) receptor agonists. Reserved for breakthrough/refractory CINV. Modest efficacy. AE: dysphoria, sedation, dizziness; poorly tolerated in the elderly.

Other / adjunctive

• Scopolamine patch 1.5 mg q72h: blocks acetylcholine; causes dry mouth and sedation. Consider for a motion/positional/secretion-triggered component.
• H1 antihistamines (diphenhydramine, meclizine): useful for a vestibular nausea component or motion-sickness overlay.
• Ginger, acupuncture, P6 acupressure: modest adjunctive benefit per meta-analyses (Marx W et al, J Natl Cancer Inst 2013).
• Dystonic reactions (from phenothiazines, olanzapine, or haloperidol): treat with diphenhydramine 25 to 50 mg PO/IV q4 to 6h; if allergic, benztropine 1 to 2 mg IV/IM once then 1 to 2 mg PO daily or BID (amantadine is not used for acute dystonia; it is an option for drug-induced parkinsonism).

CINV prophylaxis regimens, by emetic risk

• HEC: 3- to 4-drug combination, dexamethasone + 5-HT3 + olanzapine ± NK1.
• MEC: 2- to 3-drug combination, dexamethasone + 5-HT3 ± olanzapine or NK1.
• LEC: monotherapy, either a 5-HT3 antagonist, dexamethasone, metoclopramide, or prochlorperazine.
• Oral anticancer drugs: rarely HEC (e.g., procarbazine, altretamine); for MEC oral agents give one drug.

HEC (high emetic risk)

• Day 1 (acute): 5-HT3 antagonist + NK1 antagonist + dexamethasone 12 mg + olanzapine 10 mg.
  • Preferred 5-HT3: palonosetron 0.25 mg IV or 0.50 mg PO (substitute ondansetron 16 to 24 mg if needed).
  • NK1: fosaprepitant 150 mg IV, aprepitant 125 mg PO, rolapitant 180 mg PO, or fosnetupitant + palonosetron combo IV.
  • Dexamethasone 12 mg is the dose already reduced for the aprepitant/fosaprepitant/NEPA CYP3A4 interaction; use 20 mg with rolapitant (no CYP3A4 interaction).
• Days 2 to 4 (delayed): continue aprepitant 80 mg days 2 to 3 (if PO course), dexamethasone 4 to 8 mg/day, olanzapine 5 to 10 mg/day.
• Evidence: olanzapine added to NK1 + 5-HT3 + dexamethasone (4-drug regimen), Navari RM, NEJM 2016 (PMID 27410922). Aprepitant 3-day course, Hesketh PJ, JCO 2003 (PMID 14559886).

AC regimen (anthracycline + cyclophosphamide)

• Reclassified as HEC. Use the HEC day 1 regimen; for AC, dexamethasone may be limited to day 1, continue olanzapine days 2 to 4 (aprepitant days 2 to 3 if PO course).

MEC (moderate emetic risk)

• Day 1: 5-HT3 antagonist + dexamethasone 8 to 12 mg, ± olanzapine 5 to 10 mg.
• Carboplatin AUC ≥4 is treated as HEC in most regimens. Olanzapine is a reasonable alternative if an NK1 antagonist is contraindicated.
• Days 2 to 3: if palonosetron used day 1, no further 5-HT3 needed. For most MEC, dexamethasone day 1 only; continue days 2 to 3 only for selected agents with appreciable delayed-emesis risk.

LEC (low emetic risk)

• Single agent on day 1: dexamethasone 8 mg, or a single-dose 5-HT3 antagonist, or metoclopramide/prochlorperazine.
• No routine delayed prophylaxis.

Minimal emetic risk

• No routine prophylaxis. PRN agents for breakthrough symptoms.

Breakthrough CINV management

• Reassess for non-CINV causes first: dehydration, electrolyte abnormality, CNS metastases, gastric outlet/bowel obstruction, hypercalcemia, opioid-induced nausea/vomiting, tumor GI infiltration.
• Add a drug from a DIFFERENT class than the prophylaxis regimen already in use:
  • On 5-HT3 + NK1 + dexamethasone baseline, add olanzapine 5 to 10 mg PO daily.
  • On olanzapine baseline, add metoclopramide 10 mg PO/IV q6h or haloperidol 0.5 to 2 mg PO/IV q4 to 6h.
  • For a vestibular component, add a scopolamine patch or diphenhydramine.
  • For an anxiety/anticipatory component, add lorazepam 0.5 to 1 mg PO/SL.
• Schedule (not PRN) when breakthrough is ongoing. The PO route may not be feasible due to vomiting, so rectal or IV is often required. Ensure hydration and correct electrolytes.
• Before the next cycle: add an NK1 if not already included; consider switching from an NK1-containing regimen to an olanzapine-containing regimen (or vice versa) or combining them; consider a different NK1 with a different pharmacokinetic profile; add a dopamine antagonist (metoclopramide or haloperidol); possibly switch to a different 5-HT3 antagonist; add an anxiolytic; add an antacid (H2 blocker or PPI) for dyspepsia.

Anticipatory CINV

• Driven by classical conditioning: sights, smells, and infusion-center cues trigger nausea before chemo arrives.
• Best prevention: excellent acute and delayed CINV control from cycle 1 onward. Once anticipatory CINV develops, it is difficult to extinguish.
• Treatment: lorazepam 0.5 to 2 mg the night before AND the morning of chemo. Behavioral therapy (CBT, systematic desensitization, hypnotherapy) is an effective adjunct.

Multi-day chemotherapy regimens

• Examples: BEP for testicular cancer (cisplatin days 1 to 5), HSCT conditioning, 5-day FluMel, daily radiation plus concurrent chemo.
• Acute and delayed CINV overlap across days; single-day prophylaxis is insufficient.
• Approach: daily 5-HT3 antagonist (palonosetron preferred for long T½; or granisetron transdermal patch (one patch applied 24 to 48 h before chemo, worn up to 7 days; not reapplied daily) / ondansetron). Daily dexamethasone through the chemo course and 2 to 3 days after. Aprepitant 125 mg day 1 then 80 mg/day continued through about 2 days after the last cisplatin dose (extended NK1 coverage has randomized support for multiday cisplatin: Albany JCO 2012). Daily olanzapine as an add-on.
• HSCT-specific: many centers add scheduled olanzapine plus lorazepam given protracted CINV during conditioning. Long-acting palonosetron has the strongest evidence here.

Radiation-induced emesis

• Risk is highest with TBI, upper abdominal RT, and concurrent chemoradiation.
• High-risk RT (TBI): 5-HT3 antagonist plus dexamethasone before EVERY fraction.
• Moderate-risk RT (upper abdomen, hemi-body, craniospinal): 5-HT3 antagonist before each fraction; dexamethasone optional.
• Low/minimal-risk RT (head/neck, brain, pelvis, breast, extremity): PRN.

Special situations

Hematopoietic stem cell transplant (HSCT)

• Conditioning regimens (cyclophosphamide-based, busulfan, BEAM, FluMel, TBI) are HEC by definition in the HSCT setting.
• 5-HT3 + NK1 + dexamethasone + olanzapine, daily through conditioning and 2 to 3 days after.
• Consider scheduled lorazepam for the anticipatory component (common in repeat transplants).

Immunotherapy

• Single-agent ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) are minimal-to-low emetogenic; no routine prophylaxis needed.
• BUT immune-mediated colitis (irColitis) can present with nausea/vomiting; exclude before treating as CINV.

Antibody-drug conjugates (ADCs)

• Emetogenicity tracks with the cytotoxic payload class.
• T-DXd (trastuzumab deruxtecan, exatecan-derivative payload) is HIGH-emetic per NCCN (moderate per MASCC/ESMO 2023); use an NK1 + 5-HT3 + dexamethasone regimen (± olanzapine).
• Sacituzumab govitecan (SN-38 payload) is also HIGH-emetic per NCCN (moderate per MASCC/ESMO 2023).
• T-DM1 (emtansine payload), brentuximab vedotin (MMAE), enfortumab vedotin (MMAE) are LOW-emetic.

Pediatric patients

• Children tolerate 5-HT3 antagonists and NK1 antagonists well; relative dosing by weight or BSA.
• Olanzapine has growing pediatric data (Flank J et al, Pediatr Blood Cancer 2018) but use cautiously in young patients (sedation, EPS risk).
• Aprepitant approved for children ≥6 months; granisetron transdermal patch is not established in pediatric patients (adult label).
• Behavioral interventions (distraction, child-life specialists) are especially valuable.
• POGO antiemetic guideline (Patel P et al, Pediatr Blood Cancer 2021; PMID 33686754) is the pediatric-specific reference.

Practical pearls

• Olanzapine is the highest-yield single addition: adds nausea control on top of vomiting control and works across multiple receptors. Strongly consider in any HEC regimen.
• NK1 antagonists primarily prevent DELAYED CINV. They are given on day 1 before chemo and improve both acute and delayed emesis (larger benefit in the delayed phase).
• Palonosetron is the preferred 5-HT3 antagonist for delayed CINV given its long T½ and superior anti-emetic potency.
• If breakthrough occurs, re-escalate the NEXT cycle's prophylaxis; do not just treat breakthroughs reactively.
• Always rule out non-CINV causes: brain mets/raised ICP, hypercalcemia, hyponatremia, bowel obstruction, opioid-induced nausea/vomiting, gastroparesis, anxiety.
• Anticipatory CINV is prevented by excellent cycle 1 control. Once established, it is much harder to manage.
• Dexamethasone-sparing regimens (omitting steroids days 2 to 4) are increasingly accepted in select patients: diabetics, insomnia, steroid intolerance.
• Patients with low alcohol intake have HIGHER CINV risk than heavy drinkers; counterintuitive but well validated.

2024-2026 antiemetic updates

• Dexamethasone-sparing regimen validated for HEC: Meng et al (JCO 2026), phase III, 644 patients: NEPA day 1 + olanzapine days 1 to 4 with dexamethasone 6 mg day 1 only (CR 72.2%) or no dexamethasone (CR 70.1%) both non-inferior to standard 4-day dexamethasone (CR 72.4%), with fewer steroid toxicities (PMID 42241642); particularly beneficial in diabetics, insomnia, and prolonged-steroid patients.
• Fosnetupitant + palonosetron (Akynzeo IV, 235 mg fosnetupitant + 0.25 mg palonosetron): single-dose IV formulation approved for HEC prophylaxis; convenience option when PO NEPA is logistically difficult; equivalent efficacy.
• Aprepitant IV single-dose (Cinvanti, 130 mg IV): emulsion formulation avoiding polysorbate 80, lower infusion-site reactions than fosaprepitant; single-dose day 1 replaces the 3-day PO course when combined with palonosetron.
• Olanzapine 5 mg vs 10 mg: Yanai T et al, Int J Clin Oncol 2018 (randomized phase II: delayed CR 85.7% with 5 mg vs 77.6% with 10 mg; somnolence 45.5% vs 53.3%) and J-FORCE (Hashimoto H et al, Lancet Oncol 2020; 5 mg superior to placebo); similar efficacy with less sedation; 5 mg increasingly preferred, especially in the elderly.
• ADC-specific CINV: T-DXd (trastuzumab deruxtecan) is HIGH emetic risk per NCCN (since v1.2023), so use an NK1-containing HEC regimen; MASCC/ESMO 2023 lists it as moderate but comparable to carboplatin AUC ≥5. Sacituzumab govitecan similar. T-DM1, brentuximab, enfortumab: low.
• Amisulpride (Barhemsys): FDA-approved for PONV; off-label breakthrough CINV, dopamine D2/D3 antagonist, single 10 mg IV dose, carries a QT prolongation warning, with no established EPS/QT advantage over metoclopramide/haloperidol.
• Ondansetron QTc caveat: FDA 2011 warning, avoid single doses >16 mg IV; consider ECG in patients on other QT-prolonging drugs.

Key references

• Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO guideline update. J Clin Oncol 2020;38:2782 to 2797. PMID 32658626. DOI
• Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. Ann Oncol 2016;27:v119 to v133. PMID 27664248.
• Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. NEJM 2016;375:134 to 142. PMID 27410922. DOI
• Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin. J Clin Oncol 2003;21:4112 to 4119. PMID 14559886.
• Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 2009;10:115 to 124. PMID 19135415.
• Patel P, Robinson PD, Devine KA, et al. Prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting in pediatric cancer patients and hematopoietic stem cell transplant recipients: clinical practice guideline update. Pediatr Blood Cancer 2021;68:e29101. PMID 33686754.