NCCN Antiemesis Guideline 2018 v3 PDF

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Antiemesis
Version 3.2018 — June 11, 2018
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients
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Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
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NCCN Guidelines Version 3.2018 NCCN Guidelines Index

Table of Contents
Antiemesis Discussion
David S. Ettinger, MD/Chair † Steve Kirkegaard, PharmD Σ † Kim Noonan, MS, ANP, AOCN, RN # ‡
The Sidney Kimmel Comprehensive Huntsman Cancer Institute Dana-Farber/Brigham and Women’s
Cancer Center at Johns Hopkins at the University of Utah Cancer Center | Massachusetts General
Hospital Cancer Center
*Michael J. Berger, PharmD/BCOP, Vice Chair Σ Dwight D. Kloth, PharmD, BCOP Σ
The Ohio State University Comprehensive Fox Chase Cancer Center Grazyna Riebandt, PharmD, BCOP ‡
Cancer Center - James Cancer Hospital Roswell Park Cancer Institute
and Solove Research Institute Kelsey Klute, MD
Fred and Pamela Buffett Cancer Center Eric Roeland, MD † £
Jonathan Aston, PharmD, BCOP Σ † Massachusetts General Hospital Cancer
Vanderbilt-Ingram Cancer Center Dean Lim, MD † Center
City of Hope Comprehensive Cancer Center
Sally Barbour, PharmD, BCOP, CPP Σ ‡ † Hope S. Rugo, MD † ‡
Duke Cancer Institute Charles Loprinzi, MD UCSF Helen Diller Family
Mayo Clinic Cancer Center Comprehensive Cancer Center
Jason Bergsbaken, PharmD, BCOP Σ
University of Wisconsin Cynthia X. Ma, MD, PhD † Þ Lee S. Schwartzberg, MD, FACP
Carbone Cancer Center Siteman Cancer Center at Barnes-Jewish St. Jude Children’s Research Hospital/The
Hospital and Washington University School of University of Tennessee Health Science
Debra Brandt, DO † Medicine Center
Yale Cancer Center/Smilow Cancer Hospital
Victoria Maurer, MSN, OCN, RN † Bridget Scullion, PharmD, BCOP £
Jennie R. Crews, MD † Robert H. Lurie Comprehensive Cancer Center Dana-Farber/Brigham and Women’s
Fred Hutchinson Cancer Research Center/ of Northwestern University Cancer Center | Massachusetts General
Seattle Cancer Care Alliance Hospital Cancer Center
Rutika Mehta, MD †
Elizabeth Dolan, MD Moffitt Cancer Center Susan G. Urba, MD † £
Case Comprehensive Cancer Center/ University of Michigan Comprehensive
University Hospitals Seidman Cancer Center Laura Boehnke Michaud, PharmD, BCOP † Σ Cancer Center
and Cleveland Clinic TaussigCancer Institute The University of Texas
MD Anderson Cancer Center
Eun Jeong Kim, PharmD, MS Σ NCCN
Stanford Cancer Institute Rudolph M. Navari, MD, PhD, FACP †
University of Alabama at Birmingham Miranda Hughes, PhD
Comprehensive Cancer Center Dorothy A. Shead, MS
* Discussion section € Pediatric oncology

committee member Σ Pharmacology
‡ Hematology/ £ Supportive care
NCCN Guidelines Panel Disclosures Continue Hematology oncology including palliative,
Þ Internal medicine pain management,
† Medical oncology pastoral care, and
# Nursing oncology social work

Table of Contents
NCCN Antiemesis Panel Members

Clinical Trials: NCCN believes that
Summary of Guidelines Updates
the best management for any patient
Principles of Emesis Control for the Cancer Patient (AE-1) with cancer is in a clinical trial.
Participation in clinical trials is
Chemotherapy-Induced Emesis: especially encouraged.
Emetogenic Potential of Intravenous Anticancer Agents (AE-2)
To find clinical trials online at NCCN
Emetogenic Potential of Oral Anticancer Agents (AE-4) Member Institutions, click here:
High Emetic Risk Intravenous Chemotherapy - Acute and Delayed Emesis Prevention (AE-5) nccn.org/clinical_trials/clinicians.aspx.
Moderate Emetic Risk Intravenous Chemotherapy - Acute and Delayed Emesis Prevention (AE-6)
Low and Minimal Emetic Risk Intravenous Chemotherapy - Emesis Prevention (AE-8) NCCN Categories of Evidence and
Consensus: All recommendations
Oral Chemotherapy - Emesis Prevention (AE-9)
are category 2A unless otherwise
Breakthrough Treatment for Chemotherapy-Induced Nausea/Vomiting (AE-10) indicated.
Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A)
Pharmacologic Considerations for Antiemetic Prescribing (AE-B) See NCCN Categories of Evidence
and Consensus.
Principles for Managing Breakthrough Emesis (AE-C)
Radiation-Induced Emesis:
Radiation-Induced Emesis Prevention/Treatment (AE-11)
Anticipatory Emesis:
Anticipatory Emesis Prevention/Treatment (AE-12)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2018.

Table of Contents
Updates in Version 3.2018 of the NCCN Guidelines for Antiemesis from Version 2.2018 include:
AE-5 and AE-6 concentrations. Rolapitant does not inhibit dexamethasone

• Added intravenous formulation of fosnetupitant/palonosetron metabolism."
as an option for use in combination antiemetic regimens for AE-B (1 of 3)
patients receiving highly emetogenic and moderately emetogenic • NK1 antagonists, added fosnetupitant to the following bullet:
chemotherapy: Fosnetupitant 235 mg / Palonosetron 0.25 mg Aprepitant, aprepitant injectable emulsion, fosaprepitant,
(available as fixed combination product only) IV once. netupitant, and fosnetupitant inhibit the metabolism of
AE-7 dexamethasone, thus increasing dexamethasone serum levels
• Footnote "n", added fosnetupitant/palonosetron. when administered concomitantly. Rolapitant does not share this
AE-A (2 of 2) interaction with dexamethasone.
• NK1 antagonists, added fosnetupitant to the following bullets:
"For single-day chemotherapy regimens, category 1 evidence
is available for aprepitant, aprepitant injectable emulsion,
fosaprepitant, netupitant, fosnetupitant or rolapitant administered in
combination with a 5-HT3 RA and steroid."
"Fosaprepitant, aprepitant, aprepitant injectable emulsion,
netupitant, and fosnetupitant inhibit the metabolism of
dexamethasone and may cause higher dexamethasone
AE-5 and AE-6 AE-B (2 of 3)
• Removed "Rolapitant 166.5 mg IV once" from the guidelines. • Modified the following bullet: Parenteral olanzapine use with
AE-10 concomitant parenteral benzodiazepine use is contraindicated by
• Modified dronabinol recommendation: Dronabinol capsules 5-10 mg, adding "Toxicity may occur with this combination regardless of
or dronabinol oral solution 2.1-4.2 mg/m², PO 3-4 times daily. the route of administration."
• Removed Dronabinol capsules 5-10 mg, or dronabinol oral solution Discussion
2.1-4.2 mg/m², PO 3-4 times daily. from footnote "bb"; it is included in • The Discussion section has been updated to reflect the changes
the body of the algorithm. in the algorithm.
AE-1 encouraged."Okuyama A, Nakamura F, Higashi T. Prescription
• The last bullet is new: "While chemotherapy or radiation therapy- of prophylactic antiemetic drugs for patients receiving
induced nausea and vomiting can significantly impact a patient's chemotherapy with minimal and low emetic risk. JAMA Oncol.
quality of life and lead to poor outcomes, providers must be aware of 2017;3(3):344-350. doi:10.1001/jamaoncol.2016.4096
the potential for the overuse of prophylactic antiemetics, especially Encinosa W, Davidoff AJ. Changes in Antiemetic Overuse in
for chemotherapy with minimal and low emetic risks, which may Response to Choosing Wisely Recommendations. JAMA Oncol.
expose the patient to potential adverse effects from antiemetic drugs 2017;3(3):320–326. doi:10.1001/jamaoncol.2016.2530.
and pose an undue economic burden. Guideline adherence is always
Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES

Table of Contents
AE-2, AE-3, and AE-4 oral bioavailability than dronabinol capsules. 2.1 mg oral solution =
• "Antineoplastic" was replaced with "Anticancer". 2.5 mg capsules. Dronabinol capsules 5-10 mg PO or dronabinol oral
AE-2 solution 2.1-4.2 mg/m² PO, given three-four times daily."
• Moderate emetic risk AE-12
Added "Dual-drug liposomal encapsulation of cytarabine and • Behavioral therapy bullet:
daunorubicin." Relaxation exercises sub-bullet: "Progressive muscle relaxation
AE-3 (PMR)" and "Biofeedback" bullets are new
• Low emetic risk "Cognitive distraction" and "Yoga (if approved by physician)" are
Added "Olaratumab" new
• Minimal emetic risk • Last bullet, sub-bullet was modified: alprazolam and dosing were
Added "Avelumab" and "Rituximab and hyaluronidase human removed
injection for SQ use." AE-A (1 of 2)
"(2-chlorodeoxyadenosine)" was removed from cladribine. • General principles, the following was added to the last bullet: "If
AE-4 patients cannot tolerate dexamethasone, consider replacing with
• Moderate to high emetic risk olanzapine."
Added "Enasidenib", "Midostaurin", and "Niraparib." AE-A (2 of 2)
• Minimal to low emetic risk • NK1 antagonists: "aprepitant injectable emulsion" was added to the
Added "Abemaciclib", "Brigatinib", "Neratinib", and "Ribociclib." second, fifth, and sixth bullets
AE-5 and AE-6 AE-B (1 of 3)
• The dose of dexamethasone was reduced to 12 mg for day 1 • NK1 antagonists: "aprepitant injectable emulsion" was added to the
throughout. first bullet
• New: Aprepitant injectable emulsion 130 mg IV once. AE-B (2 of 3)
• AE-5 and AE-6 formatting was extensively revised. • The following reference was added to the last sub-bullet under
AE-7 Olanzapine: Yanai T, Iwasa S, Hashimoto H, et al. A double-blind
• The footnotes were extensively revised and references were updated. randomized phase II dose-finding study of olanzapine 10 mg or 5
• Footnote "k" is new "Aprepitant injectable emulsion is a unique mg for the prophylaxis of emesis induced by highly emetogenic
formulation of aprepitant and is NOT interchangeable with the cisplatin-based chemotherapy. Int J Clin Oncol 2018;23:382-388.
intravenous formulation of fosaprepitant." • The third and fourth bullets under benzodiazepines are new:
AE-8 Parenteral olanzapine use with concomitant parenteral
• Footnotes j and v were added to metoclopramide and prochlorperazine. benzodiazepine use is contraindicated.
• Footnote v was added to 5-HT3-RA. Use caution in patients with scheduled opioids.
AE-10
• Cannabinoid bullet, first sub-bullet was modified: "Dronabinol 5-10
mg PO every 4-6 h 3-4 times daily"
• Footnote bb is new to the page. "Dronabinol oral solution has greater
Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES

Table of Contents
PRINCIPLES OF EMESIS CONTROL FOR THE CANCER PATIENT

• Prevention of nausea/vomiting is the goal.
The risk of nausea/vomiting (acute ≤24 hours vs. delayed nausea >24 hours) for persons receiving chemotherapy of high and moderate
emetic risk lasts for at least 3 days for high and 2 days for moderate after the last dose of chemotherapy. Patients need to be protected
throughout the full period of risk.
• Oral and intravenous serotonin receptor antagonists (5-HT3 RA) have equivalent efficacy when used at the appropriate doses and intervals.
• Consider the toxicity of the specific antiemetic(s). See Pharmacologic Considerations for Antiemetic Prescribing (AE-B).
• Choice of antiemetic(s) used should be based on the emetic risk of the therapy, prior experience with antiemetics, and patient factors.
• There are other potential causes of emesis in patients with cancer.
These may include:
Partial or complete bowel obstruction
Vestibular dysfunction
Brain metastases
Electrolyte imbalance: hypercalcemia, hyperglycemia, or hyponatremia
Uremia
Concomitant drug treatments, including opioids
Gastroparesis: tumor or chemotherapy (eg, vincristine) induced or other causes (eg, diabetes)
Excessive secretions (eg, seen in patients with head and neck cancer)
Malignant ascites
Psychophysiologic:
◊◊Anxiety
◊◊Anticipatory nausea/vomiting
• For use of antiemetics for nausea/vomiting that are not related to radiation and/or chemotherapy, see NCCN Guidelines for Palliative Care.
• For multi-drug regimens, select antiemetic therapy based on the drug with the highest emetic risk. See Emetogenic Potential of
Intravenous Antineoplastic Agents (AE-2, AE-3, and AE-4).
• Consider using an H2 blocker or proton pump inhibitor to prevent dyspepsia, which can mimic nausea.
• Lifestyle measures may help to alleviate nausea/vomiting, such as eating small frequent meals, choosing healthful foods, controlling the
amount of food consumed, and eating food at room temperature. A dietary consult may also be useful. See NCI’s “Eating Hints: Before,
During, and After Cancer Treatment.” (http://www.cancer.gov/cancertopics/coping/eatinghints/page2#4)
• While chemotherapy or radiation therapy-induced nausea and vomiting can significantly impact a patient's quality of life and lead to poor
outcomes, providers must be aware of the potential for the overuse of prophylactic antiemetics, especially for chemotherapy with minimal
and low emetic risks, which may expose the patient to potential adverse effects from antiemetic drugs and pose an undue economic burden.
Guideline adherence is always encouraged. Okuyama A, Nakamura F, Higashi T. Prescription of prophylactic antiemetic drugs for patients
receiving chemotherapy with minimal and low emetic risk. JAMA Oncol. 2017;3(3):344-350. doi:10.1001/jamaoncol.2016.4096
Encinosa W, Davidoff AJ. Changes in Antiemetic Overuse in Response to Choosing Wisely Recommendations. JAMA Oncol. 2017;3(3):320–
326. doi:10.1001/jamaoncol.2016.2530
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-1

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EMETOGENIC POTENTIAL OF INTRAVENOUS ANTICANCER AGENTSa
LEVEL AGENT
High emetic risk • AC combination defined as any • Carmustine >250 mg/m2 • Epirubicin >90 mg/m2
(>90% frequency of emesis)b,c chemotherapy regimen that • Cisplatin • Ifosfamide ≥2 g/m2 per dose
contains an anthracycline and • Cyclophosphamide >1,500 mg/m2 • Mechlorethamine
cyclophosphamide • Dacarbazine • Streptozocin
• Carboplatin AUC ≥4 • Doxorubicin ≥60 mg/m2
Moderate emetic risk • Aldesleukin >12–15 million IU/m2 • Dactinomycind • Melphalan
(>30%–90% frequency of emesis)b,c • Amifostine >300 mg/m2 • Daunorubicind • Methotrexated ≥250 mg/m2
• Arsenic trioxide • Dual-drug liposomal encapsulation • Oxaliplatind
• Azacitidine of cytarabine and daunorubicin • Temozolomide
• Bendamustine • Dinutuximab • Trabectedind
• Busulfan • Doxorubicind <60 mg/m2
• Carboplatin AUC <4d • Epirubicind ≤90 mg/m2
• Carmustined ≤250 mg/m2 • Idarubicin
• Clofarabine • Ifosfamided <2 g/m2 per dose
• Cyclophosphamide ≤1500 mg/m2 • Interferon alfa ≥10 million IU/m2
• Cytarabine >200 mg/m2 • Irinotecand
Adapted with permission from:

Hesketh PJ, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-109.
Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer
2010;19:S43-47.
aPotential drug interactions between antineoplastic agents/antiemetic therapies and various other drugs should always be considered.
bProportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Low Emetic Risk (See AE-3)
cContinuous infusion may make an agent less emetogenic. Minimal Emetic Risk (See AE-3)
dThese agents may be highly emetogenic in certain patients. Oral Chemotherapy (See AE-4)


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EMETOGENIC POTENTIAL OF INTRAVENOUS ANTICANCER AGENTSa
LEVEL AGENT
Low emetic risk • Ado-trastuzumab emtansine • Etoposide • Omacetaxine
(10%–30% frequency of emesis)b • Aldesleukin ≤12 million IU/m2 • 5-Fluorouracil (5-FU) • Paclitaxel
• Amifostine ≤300 mg/m2 • Floxuridine • Paclitaxel-albumin
• Atezolizumab • Gemcitabine • Pemetrexed
• Belinostat • Interferon alfa >5 - <10 million • Pentostatin
• Blinatumomab international units/m2 • Pralatrexate
• Brentuximab vedotin • Irinotecan (liposomal) • Romidepsin
• Cabazitaxel • Ixabepilone • Talimogene laherparepvec
• Carfilzomib • Methotrexate >50 mg/m2 - <250 mg/m2 • Thiotepa
• Cytarabine (low dose) 100–200 mg/m2 • Mitomycin • Topotecan
• Docetaxel • Mitoxantrone • Ziv-aflibercept
• Doxorubicin (liposomal) • Necitumumab
• Eribulin • Olaratumab
Minimal emetic risk • Alemtuzumab • Elotuzumab • Ramucirumab
(<10% frequency of emesis)b • Avelumab • Fludarabine • Rituximab
• Asparaginase • Interferon alpha ≤5 million IU/m2 • Rituximab and hyaluronidase
• Bevacizumab • Ipilimumab human injection for SQ use
• Bleomycin • Methotrexate ≤50 mg/m2 • Siltuximab
• Bortezomib • Nelarabine • Temsirolimus
• Cetuximab • Nivolumab • Trastuzumab
• Cladribine • Obinutuzumab • Valrubicin
• Cytarabine <100 mg/m2 • Ofatumumab • Vinblastine
• Daratumumab • Panitumumab • Vincristine
• Decitabine • Pegaspargase • Vincristine (liposomal)
• Denileukin diftitox • Peginterferon • Vinorelbine
• Dexrazoxane • Pembrolizumab
• Durvalumab • Pertuzumab
2010;19:S43-47.
High Emetic Risk (See AE-2)

aPotential drug interactions between antineoplastic agents/antiemetic therapies and various other drugs should always be considered. Moderate Emetic Risk (See AE-2)
bProportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Oral Chemotherapy (See AE-4)


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EMETOGENIC POTENTIAL OF ORAL ANTICANCER AGENTSa
LEVEL AGENT
Moderate to high emetic riskb • Altretamine • Etoposide • Panobinostat
(≥30% frequency of emesis) • Busulfan (≥4 mg/d) • Lenvatinib • Procarbazine
• Ceritinib • Lomustine (single day) • Rucaparib
• Crizotinib • Midostaurin • Temozolomide (>75 mg/m2/d)
• Cyclophosphamide (≥100 mg/m2/d) • Mitotane • Trifluridine/tipiracil
• Enasidenib • Niraparib
• Estramustine • Olaparib
Minimal to low emetic riskb • Abemaciclib • Gefitinib • Regorafenib
(<30% frequency of emesis) • Afatinib • Hydroxyurea • Ribociclib
• Alectinib • Ibrutinib • Ruxolitinib
• Axitinib • Idelalisib • Sonidegib
• Bexarotene • Imatinib • Sorafenib
• Brigatinib • Ixazomib • Sunitinib
• Bosutinib • Lapatinib • Temozolomide (≤75 mg/m2/d)e
• Busulfan (<4 mg/d) • Lenalidomide • Thalidomide
• Cabozantinib • Melphalan • Thioguanine
• Capecitabine • Mercaptopurine • Topotecan
• Chlorambucil • Methotrexate • Trametinib
• Cobimetinib • Nilotinib • Tretinoin
• Cyclophosphamide (<100 mg/m2/d) • Neratinib • Vandetanib
• Dasatinib • Osimertinib • Vemurafenib
• Dabrafenib • Palbociclib • Venetoclax
• Erlotinib • Pazopanib • Vismodegib
• Everolimus • Pomalidomide • Vorinostat
• Fludarabine • Ponatinib
2010;19:S43-47.
High Emetic Risk (See AE-2)

aPotential drug interactions between antineoplastic agents/antiemetic therapies and various other drugs should always be considered. Moderate Emetic Risk (See AE-2)
bProportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Low Emetic Risk (See AE-3)
eTemozolomide ≤75 mg/m2/d should be considered moderately emetogenic with concurrent radiotherapy. Minimal Emetic Risk (See AE-3)


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HIGH EMETIC RISK INTRAVENOUS CHEMOTHERAPY — ACUTE AND DELAYED EMESIS PREVENTIONf,g,h,i,j
DAY 1: Select option A, B, or C (order does not imply preference) DAYS 2, 3, 4:
All are category 1, start before chemotherapy:h
A A
• NK-1RA (choose one): • Aprepitant 80 mg PO daily on days 2, 3
Aprepitant 125 mg PO once (if aprepitant PO used on day 1)
Aprepitant injectable emulsion 130 mg IV oncek • Dexamethasone 8 mgq PO/IV daily on days 2, 3, 4
Fosaprepitant 150 mg IV once
Netupitant 300 mg / palonosetron 0.5 mg (available as fixed combination product only) PO oncel
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only) IV oncel
Rolapitant 180 mg PO oncem
• 5-HT3 RA (choose one):n,o
Dolasetron 100 mg PO once
Granisetron 10 mg SQ oncep, or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24-h
transdermal patch applied 24–48 h prior to first dose of chemotherapy.
Ondansetron 16–24 mg PO once, or 8-16 mg IV once
Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onceq
B B
• Olanzapine 10 mg PO oncer • Olanzapine 10 mg PO daily on days 2, 3, 4r
• Palonosetron 0.25 mg IV once
C C
• Olanzapine 10 mg PO oncer,s,t • Olanzapine 10 mg PO daily on days 2, 3, 4r
• NK-1RA (choose one): • Aprepitant 80 mg PO daily on days 2, 3
Aprepitant 125 mg PO once (if aprepitant PO used on day 1)
Aprepitant injectable emulsion 130 mg IV oncek • Dexamethasone 8 mgq PO/IV daily on days 2, 3, 4
Fosaprepitant 150 mg IV once
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only) IV oncel
Granisetron 10 mg SQ oncep, or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once,
or 3.1 mg/24-h transdermal patch applied 24–48 h prior to first dose of chemotherapy.
Footnotes

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MODERATE EMETIC RISK INTRAVENOUS CHEMOTHERAPY — ACUTE AND DELAYED EMESIS PREVENTIONf,g,h,i,j
DAY 1: Select option D, E, or F (order does not imply preference). DAYS 2, 3:
All are category 1, start before chemotherapy:h
D D
• 5-HT3 RA (choose one): • Dexamethasone 8 mgq PO/IV daily on days 2, 3
Granisetron 10 mg SQ oncep (preferred), or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once, OR
or 3.1 mg/24-h transdermal patch applied 24–48 h prior to first dose of chemotherapy.
Ondansetron 16–24 mg PO once, or 8–16 mg IV once • 5-HT3 RA monotherapyu:
Palonosetron 0.25 mg IV once (preferred) Granisetron 1–2 mg (total dose) PO daily or
• Dexamethasone 12 mg PO/IV onceq 0.01 mg/kg (max 1 mg) IV daily on days 2 and 3
Ondansetron 8 mg PO twice daily or 16 mg PO
daily or 8–16 mg IV daily on days 2, 3
Dolasetron 100 mg PO daily on days 2, 3
E E
• Olanzapine 10 mg PO oncer • Olanzapine 10 mg PO daily on days 2, 3r
• Palonosetron 0.25 mg IV once
F F
Note: an NK-1RA should be added (to dexamethasone and a 5-HT3 RA regimen) for select patients • Aprepitant 80 mg PO daily on days 2, 3
with additional risk factors or previous treatment failure with a steroid + 5HT3 RA alone. See AE-5 (if aprepitant PO used on day 1)
• NK-1RA (choose one): • ± Dexamethasone 8 mgq PO/IV daily on days 2, 3
Aprepitant 125 mg PO once
Aprepitant injectable emulsion 130 mg IV oncek
Fosaprepitant 150 mg IV oncel
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only) IV
oncel
Granisetron 10 mg SQ oncep, or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once,
or 3.1 mg/24-h transdermal patch applied 24-48 h prior to first dose of chemotherapy.
Footnotes

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Footnotes for pages AE-5 and AE-6

fSee Emetogenic Potential of Intravenous Antineoplastic Agents (AE-2).
gAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors.
hSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A).
iWith or without lorazepam 0.5–2 mg PO or IV or sublingual every 6 hours as needed days 1–4. With or without H2 blocker or proton pump inhibitor. For olanzapine-
containing regimens, only use PO lorazepam if needed. See Principles of Emesis Control for the Cancer Patient (AE-1).
jSee Pharmacologic Considerations for Antiemetic Prescribing (AE-B).
kAprepitant injectable emulsion is a unique formulation of aprepitant and is NOT interchangeable with the intravenous formulation of fosaprepitant.
lAvailable as a fixed combination product only.
mRolapitant has an extended half-life and should not be administered at less than 2-week intervals.
nIf Netupitant/palonosetron or fosnetupitant/palonosetron fixed combination product used, no further 5-HT3RA is required.
oWhen used in combination with an NK-1 antagonist, there is no preferred 5-HT3 RA. See Prinicples of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A)
pGranisetron extended-release injection is a unique formulation of granisetron using a polymer-based drug delivery system. This formulation is specifically intended
for subcutaneous administration and is NOT interchangeable with the intravenous formulation. Granisetron extended-release injection has an extended half-life and
should not be administered at less than 1-week intervals.
qEmerging data and clinical practice suggests dexamethasone doses may be individualized. Higher doses may be considered, especially when a NK-1RA is not given
concomitantly. Lower doses, given for shorter durations, or even elimination of dexamethasone on subsequent days (for delayed nausea and emesis prevention) may
be acceptable for non-cisplatin regimens based on patient characteristics. See Discussion
rConsider 5 mg dose for elderly or over-sedated patients. Yanai T, Iwasa S, Hashimoto H, et al. A double-blind randomized phase II dose-finding study of olanzapine
10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy. Int J Clin Oncol 2018;23:382-388. See Pharmacologic
Considerations for Antiemetic Prescribing (AE-B).
sConsider escalating to this option (C) when emesis occurred during a previous cycle of chemotherapy using an olanzapine regimen (B, E) or an NK1 antagonist-
containing regimen (A, D, or F). See Principles for Managing Breakthrough Emesis (AE-C).
tCombination of olanzapine, aprepitant or fosaprepitant, any 5-HT3RA and dexamethasone, was studied in patients receiving Cisplatin or AC. Navari RM, Qin R, Ruddy
KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 2016; 375:134-142.
uNo further therapy required if palonsetron, granisetron extended-release injection, or granisetron transdermal patch given on day 1.


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LOW AND MINIMAL EMETIC RISK INTRAVENOUS CHEMOTHERAPY - EMESIS PREVENTIONf,g,h,j
Start before chemotherapy (order does not imply preference) g,h,v

Repeat daily for multiday doses of chemotherapy
Dexamethasone 8–12 mg PO/IV oncej,v
or
Metoclopramide 10–20 mg PO/IV oncej,v
or
Low Prochlorperazine 10 mg PO/IV oncej,v
or
5-HT3 RAj,v (select one):
◊◊Dolasetron 100 mg PO once
Breakthrough Treatment for Chemotherapy-
◊◊Granisetron 1–2 mg (total dose) PO once
Induced Nausea/Vomiting (AE-10)
◊◊Ondansetron 8–16 mg PO once
Minimal No routine prophylaxis
fSee Emetogenic Potential of Intravenous Antineoplastic Agents (AE-3).

gAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors.
hSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A).
vWith or without lorazepam 0.5–2 mg PO or IV or sublingual every 6 hours as needed days 1–4. With or without H2 blocker or proton pump inhibitor. See Principles of
Emesis Control for the Cancer Patient (AE-1).

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ORAL CHEMOTHERAPY - EMESIS PREVENTIONg,h,w,x
Start before chemotherapy and continue daily (order does not imply preference)v
• 5-HT3 RA (Choose one):j
High to Breakthrough Treatment
moderate Dolasetron 100 mg PO daily
for Chemotherapy-Induced
emetic risk Granisetron 1–2 mg (total dose) PO daily or 3.1 mg/24 h transdermal patch every
Nausea/Vomiting (AE-10)
7 days
Ondansetron 8–16 mg (total dose) PO daily
Start before chemotherapy and continue daily

(order does not imply preference)v
Metoclopramide 10–20 mg PO and then every 6 h Breakthrough Treatment
PRNj for Chemotherapy-Induced
or Nausea/Vomiting (AE-10)
Low to and
minimal PRN Nausea/ Prochlorperazine 10 mg PO and then every 6 h PRN
recommended vomiting (maximum 40 mg/d)j Consider changing
emetic risk
or antiemetic therapy to
5-HT3 RA (Choose one):j higher level primary
◊◊Dolasetron 100 mg PO daily PRN therapy for the next cycle
◊◊Granisetron 1–2 mg (total dose) PO daily PRN
◊◊Ondansetron 8–16 mg (total dose) PO daily PRN
gAntiemetic regimens should be chosen based on the drug with the highest emetic
risk as well as patient-specific risk factors. wSee Emetogenic Potential of Oral Antineoplastic Agents (AE-4).
hSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). xThese antiemetic recommendations apply to oral chemotherapy only.
jSee Pharmacologic Considerations for Antiemetic Prescribing (AE-B). When combined with IV agents in a combination chemotherapy regimen,
vWith or without lorazepam 0.5–2 mg PO or IV or sublingual every 6 hours as needed the antiemetic recommendations for the agent with the highest level of
days 1–4. With or without H2 blocker or proton pump inhibitor. See Principles of emetogenicity should be followed. If multiple oral agents are combined, emetic
Emesis Control for the Cancer Patient (AE-1). risk may increase and require prophylaxis.

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BREAKTHROUGH TREATMENT FOR RESPONSE SUBSEQUENT

CHEMOTHERAPY-INDUCED NAUSEA/VOMITINGh,y CYCLES
The general principle of breakthrough treatment is to add one agent
from a different drug class to the current regimen.
(order does not imply preference)
• Atypical antipsychotic:j
Olanzapine 5–10 mg PO daily (category 1)z,aa
• Benzodiazepine:j Continue
Nausea and breakthrough
Lorazepam 0.5–2 mg PO/SL/IV every 6 haa vomiting
• Cannabinoid:j medications, on a
controlled schedule, not PRN
Dronabinol capsules 5–10 mg, or dronabinol oral solution
2.1-4.2 mg/m², PO 3-4 times dailybb
Nabilone 1–2 mg PO BID
• Other: Consider
Any Haloperidol 0.5–2 mg PO/IV every 4–6 hj changing
nausea/ Metoclopramide 10–20 mg PO/IV every 4–6 hj antiemetic therapy
vomiting Scopolamine 1.5 mg transdermal patch 1 patch every 72 h to higher level
• Phenothiazine:j primary treatment
Prochlorperazine 25 mg supp PR every 12 h or 10 mg PO/IV for next cycle
every 6 hj Re-evaluate and
Promethazine 25 mg supp PR every 6 h or 12.5–25 mg PO/IV Nausea and/ consider dose
(central line only) every 4–6 hj or vomiting adjustments and/
• 5-HT3 RA:j uncontrolled or sequentially add
Dolasetron 100 mg PO daily one agent from a
Granisetron 1–2 mg PO daily or 1 mg PO BID or 0.01 mg/kg different drug class
(maximum 1 mg) IV daily or 3.1 mg/24-h transdermal patch every
7 days
Ondansetron 16–24 mg PO daily or 8-16 mg IV
• Steroid:j zWhen not used as part of the acute and delayed emesis prevention
Dexamethasone 12 mg PO/IV daily regimen. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus
metoclopramide for the treatment of breakthrough chemotherapy-
induced nausea and vomiting in patients receiving highly emetogenic
chemotherapy. Support Care Cancer 2013;21:1655-1663.
aaFor olanzapine-containing regimens, only use PO lorazepam. See
hSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). Principles of Emesis Control for the Cancer Patient (AE-1).
jSee Pharmacologic Considerations for Antiemetic Prescribing (AE-B). bbDronabinol oral solution has greater oral bioavailability than dronabinol
ySee Principles of Managing Breakthrough Emesis (AE-C). capsules; 2.1 mg oral solution = 2.5 mg capsules.


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RADIATION-INDUCED EMESIS PREVENTION/TREATMENT

EMETOGENIC TYPE OF RADIATION THERAPY BREAKTHROUGH TREATMENT
POTENTIAL
Start pretreatment for each day of RT treatment

Radiation therapy (RT) - (order does not imply preference):j
upper abdomen/localized • Granisetron 2 mg PO daily
sites or
• Ondansetron 8 mg PO BID
• ± Dexamethasone 4 mg PO daily
See Breakthrough
Treatment (AE-10)
Start pretreatment for each day of RT treatment
(order does not imply preference):j
Radiation-induced Total body irradiation • Granisetron 2 mg PO daily
nausea/vomiting (TBI) or
• Ondansetron 8 mg PO BID-TID
• ± Dexamethasone 4 mg PO daily
Chemotherapy and RT See emesis prevention for chemotherapy-induced nausea/vomiting

(including TBI) (High [AE-5], Moderate [AE-6], Low [AE-8], and Oral [AE-9])


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ANTICIPATORY EMESIS PREVENTION/TREATMENT
• Prevention is key:
Use optimal antiemetic therapy during every cycle of treatment
Avoidance of strong smells that may precipitate symptoms
• Behavioral therapy:
Relaxation/systematic desensitization
Hypnosis
Relaxation exercises
See Emesis Prevention and
◊◊Guided imagery
Anticipatory Breakthrough Treatment for
◊◊Progressive muscle relaxation (PMR)
nausea/vomiting Chemotherapy-Induced Nausea
◊◊Biofeedback
and Vomiting (Antiemesis Table
◊◊Music therapy
of Contents)
Cognitive distraction
Yoga (if approved by physician)
• Acupuncture/acupressure
• Consider anxiolytic therapy:
For example, lorazepam 0.5–2 mg PO beginning on the night
before treatment and then repeated the next day 1–2 hours
before chemotherapy begins
See Principles of Emesis Control

for the Cancer Patient (AE-1)

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PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1

Summary: General principles:
• Patients receiving multi-day chemotherapy are at risk for both acute Steroids:
and delayed nausea/vomiting based on the emetogenic potential of • Dexamethasone should be administered once daily (either orally
the individual chemotherapy agents administered on any given day or intravenously) for moderately emetogenic chemotherapy (MEC)
and their sequence. It is therefore difficult to recommend a specific or highly emetogenic chemotherapy (HEC), then continued for 2
antiemetic regimen for each day, especially since acute and delayed to 3 days after chemotherapy for regimens that are likely to cause
emesis may overlap after the initial day of chemotherapy until the last significant delayed emesis.
day of chemotherapy. • Dexamethasone dose may be modified or omitted when the
• After chemotherapy administration concludes, the period of risk chemotherapy regimen already includes a steroid.
for delayed emesis also depends on the specific regimen and the • Dexamethasone-sparing strategies - for patients receiving MEC or
emetogenic potential of the last chemotherapy agent administered non-cisplatin HEC, especially those patients with few identifiable
in the regimen. chemotherapy-induced nausea and vomiting (CINV) risk factors
• Practical issues also need to be considered when designing the or who are intolerant to steroids, limiting the administration
antiemetic regimen, taking into account the administration setting of dexamethasone to day 1 only is an option that may not be
(eg, inpatient versus outpatient), preferred route of administration associated with a significant reduction in antiemetic control.2,3,4,5
(parenteral, oral, or transdermal), duration of action of the 5-HT3 If patients cannot tolerate dexamethasone, consider replacing with
RA and appropriate associated dosing intervals, tolerability of olanzapine.
daily antiemetics (eg, steroids), adherence/compliance issues, and
individual risk factors.
3Rolia F, Ruggeri B, Ballatori E, et al Aprepitant versus dexamethasone for

preventing chemotherapy-induced delayed emesis in patients with breast
cancer: A randomized double-blind study. J Clin Oncol 2014;32:101-106.
1The panel acknowledges that evidence is lacking to support every clinical scenario. 4Aapro M, Fabi A, Nole F, et al. Double-blind, randomized, controlled study of
Decisions should be individualized for each chemotherapy regimen and each the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with
patient. An extensive knowledge of the available clinical data, pharmacology, or without dexamethasone on days 2 and 3 in the prevention of nausea and
pharmacodynamics, and pharmacokinetics of the antiemetics and the vomiting induced by moderately emetogenic chemotherapy. Ann Oncol 2010;
chemotherapy and experience with patients (regarding tolerability and efficacy) are 21(5):1083-1088.
all paramount to successfully implementing these guidelines into clinical practice. 5Celio L, Bonizzoni E, Bajetta E, et al. Palonosetron plus single-dose
2Matsuzaki K, Ito Y, Fukuda M, et al. Placebo-controlled phase III study comparing dexamethasone for the prevention of nausea and vomiting in women receiving
dexamethasone on day 1 to day 1-3 with NK1 receptor antagonist and anthracycline/cyclophosphamide-containing chemotherapy: meta-analysis of
palonosetron in high emetogenic chemotherapy. J Clin Oncol 2016;34: abstract individual patient data examining the effect of age on outcome in two phase III
10019. trials. Supportive Care Cancer 2013; 21(2): 565-573.
Continued
AE-A
Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2

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PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1

Serotonin receptor antagonists (5-HT3 RA): NK1 antagonists:
• A 5-HT3 RA should be administered prior to the first (and subsequent) • NK1 antagonists may be used for multi-day chemotherapy regimens
doses of moderately or highly emetogenic likely to be moderately or highly emetogenic and associated with
chemotherapy. The frequency or need for repeated administration of the significant risk for delayed nausea and emesis.
5-HT3 RA depends on the agent chosen and its mode of administration • For single-day chemotherapy regimens, category 1 evidence is available
(parenteral/oral/transdermal). for aprepitant, aprepitant injectable emulsion, fosaprepitant, netupitant,
• Palonosetron: fosnetupitant or rolapitant administered in combination with a 5-HT3 RA
A single intravenous palonosetron dose of 0.25 mg may be sufficient prior and steroid (see AE-5 and AE-6).
to the start of a 3-day chemotherapy regimen instead of multiple daily • If the oral aprepitant regimen is chosen, limited data exist to
doses of another oral or intravenous 5-HT3 RA. support administration of aprepitant on days 4 and 5 after multiday
Repeat dosing of palonosetron 0.25 mg IV is likely to be safe, based on chemotherapy.
available evidence. • Data from a small phase III randomized study support the use of
In terms of efficacy, limited data are available for multi-day dosing.6 aprepitant (125 mg day 3, 80 mg days 4–7) with 5-HT3 RA (days 1–5)
• Granisetron extended-release injection: and dexamethasone (20 mg days 1, 2) in patients with germline cancers
Granisetron extended-release injection is a unique formulation treated with a 5-day cisplatin-based chemotherapy.10
of granisetron using a polymer-based drug delivery system. This • Studies investigating repeat dosing of aprepitant injectable emulsion,
formulation is specifically intended for subcutaneous administration and fosaprepitant, netupitant, fosnetupitant and rolapitant are not available.
is NOT interchangeable with the intravenous formulation. Granisetron • Fosaprepitant, aprepitant, aprepitant injectable emulsion, netupitant, and
extended-release injection has an extended half-life and should not be fosnetupitant inhibit the metabolism of dexamethasone and may cause
administered at less than 1-week intervals higher dexamethasone concentrations. Rolapitant does not inhibit
A single subcutaneous dose of 10 mg was found to be non-inferior to a dexamethasone metabolism.
single intravenous dose of palonosetron 0.25 mg for the prevention of • Rolapitant has an extended half-life and should not be administered at
acute and delayed CINV following MEC or HEC when both are used in less than 2-week intervals.
combination with dexamethasone.7
A single subcutaneous dose of 10 mg was found to be superior 6Giralt SA, Mangan KF, Maziarz RT, et al. Three palonosetron regimens to prevent CINV in myeloma patients
to a single intravenous dose of ondansetron for the prevention of receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation. Ann Oncol
2011;22:939-946.
delayed CINV following HEC when both are used in combination with 7Raftopoulos H, Cooper W, O’Boyle E, et al. Comparison of an extended-release formulation of granisetron
fosaprepitant and dexamethasone.8 (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated
• When palonosetron or granisetron extended-release injection is used as with moderately or highly emetogenic chemotherapy: results of a prospective, randomized, double-blind,
noninferiority phase 3 trial. Supportive Care Cancer 2015 Mar; 23(3):723-732.
part of an antiemetic regimen that does NOT contain an NK1 antagonist, 8Schnadig ID, Agajanian R, Dakhil C, et al. APF530 (granisetron injection extended-release) in a three-drug
palonosetron or granisetron extended-release injection are the preferred regimen for delayed CINV in highly emetogenic chemotherapy. Future Oncol 2016;12:1469-1481.
5-HT3 RA.7,9
9Saito M 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
1The panel acknowledges that evidence is lacking to support every clinical scenario. Decisions should trial. Lancet Oncol 2009 Feb;10(2):115-24.
be individualized for each chemotherapy regimen and each patient. An extensive knowledge of the 10Albany C, Brames MJ, Fausel C, et al. Randomized, double-blind, placebo-controlled, phase III cross-over
available clinical data, pharmacology, pharmacodynamics, and pharmacokinetics of the antiemetics and study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and
the chemotherapy and experience with patients (regarding tolerability and efficacy) are all paramount to dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens:
successfully implementing these guidelines into clinical practice. a hoosier oncology group study. J Clin Oncol 2012;30:3998-4003.

AE-A

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PHARMACOLOGIC CONSIDERATIONS FOR ANTIEMETIC PRESCRIBING

(In Order As The Drugs Appear In The Guideline)
To ensure safe and effective treatment with antiemetic therapy, • Granisetron extended-release injection is a unique formulation
develop a treatment plan with the patient that includes medication of granisetron using a polymer-based drug delivery system. This
access, screening of concomitant medications, goals of therapy, formulation is specifically intended for subcutaneous administration
instructions for proper use and side effect management, and and is NOT interchangeable with the intravenous formulation.
adherence assessment. Many of the antiemetic agents contained Granisetron extended-release injection has an extended half-life and
within this guideline have multiple potential drug-drug or drug- should not be administered at less than 1-week intervals.
disease interactions. Review patient medical profile and drug package • Clinical pearl: non-sedating, most common side effects are
insert for specific interactions and recommendations. headache and constipation. Optimal effects seen with scheduled
administration, not PRN use. Educate patients regarding
NK1 antagonists: constipation and its management.
• Aprepitant, aprepitant injectable emulsion, fosaprepitant, netupitant,
and fosnetupitant inhibit the metabolism of dexamethasone, Steroids
thus increasing dexamethasone serum levels when administered • The use of steroids as an antiemetic is not recommended with
concomitantly. Rolapitant does not share this interaction with immunotherapies and cellular therapies.
dexamethasone. • Side effects associated with prolonged dexamethasone
• Rolapitant has an extended half-life and should not be administered administration should be carefully considered.
at less than 2-week intervals. • Dexamethasone may increase serum glucose; consider monitoring
• Clinical pearl: place in therapy is for prevention of CINV, not prior to therapy and as clinically indicated.
treatment of CINV. Largest benefit seen in delayed CINV setting. • Use with caution in patients with diabetes mellitus.
• Dexamethasone may cause dyspepsia; consider acid-blocking
Serotonin receptor (5-HT3 RA) antagonists: therapy with H2 antagonist or proton pump inhibitor as clinically
• Depending on the route of administration and dose, 5-HT3 RA may indicated.
increase the risk of developing prolongation of the QT interval of the • Clinical pearl: for patients suffering from extended delayed CINV,
electrocardiogram (ECG).1 The palonosetron, granisetron extended- consider extending the course of delayed dexamethasone as
release injection, and granisetron transdermal patch drug package clinically appropriate. Consider AM dosing to minimize insomnia.
inserts do not contain this warning.
• The FDA recommends a maximum of 16 mg for a single dose of
intravenous ondansetron.
• Clinical pearl: After receiving palonosetron, granisetron transdermal
patch, or extended-release injection, breakthrough 5-HT3 RAs
play a limited role in the delayed infusion period and breakthrough
antiemetic should focus on a different mechanism of action.
1Use caution and monitor ECG in patients with other risk factors for QT prolongation.
Continued
AE-B

Table of Contents

Atypical antipsychotic vomiting. N Engl J Med 2016; 375:134-142.
• Olanzapine Benzodiazepines
Use caution when prescribing olanzapine with metoclopramide • CNS depression; use caution in patients at risk for falls (eg, elderly,
or haloperidol, as excessive dopamine blockade can increase debilitated, frail) or in patients at risk for dependence.
the risk of extrapyramidal symptoms (EPS). Use of intermittent • Clinical pearl: consider for anticipatory CINV or when breakthrough
phenothiazine antiemetics (prochlorperazine or promethazine) CINV has an anxiety component.
for breakthrough CINV was safe in randomized clinical trials • Parenteral olanzapine use with concomitant parenteral
investigating the use of olanzapine but should be used with benzodiazepine use is contraindicated. Toxicity may occur with this
caution. combination regardless of the route of administration.
Olanzapine may increase the risk of developing prolongation of • Use caution in patients with scheduled opioids.
the QT interval of the ECG, when used in combination with other
QT-prolonging agents.1 Phenothiazines
Parenteral olanzapine use with concomitant parenteral • CNS depression; use caution in patients at risk for falls (eg, elderly,
benzodiazepine use is contraindicated. Toxicity may occur with debilitated, frail).
this combination regardless of the route of administration. • When administered parenterally, promethazine may cause severe
Monitor for dystonic reactions2 tissue injury.
CNS depression; use olanzapine with caution in patients at risk • The concomitant prescribing of any combination of
for falls (eg, elderly, debilitated, frail) or at risk for orthostatic prochlorperazine, promethazine, metoclopramide, or haloperidol
hypotension. should be used with caution, as excessive dopamine blockade can
Clinical pearl: Consider a dose of 5 mg if the previously increase the risk of EPS.
administered 10 mg dose caused excessive sedation. Data • Monitor for dystonic reactions2
suggest that sedation is most notable on day 2 and improves • Clinical pearl: promethazine has more histamine blockade than
over time. Yanai T, Iwasa S, Hashimoto H, et al. A double-blind prochlorperazine and is therefore more sedating.
randomized phase II dose-finding study of olanzapine 10 mg or 5
mg for the prophylaxis of emesis induced by highly emetogenic
cisplatin-based chemotherapy. Int J Clin Oncol 2018;23:382-388.
(AE-5 and AE-6). Navari RM, Qin R, Ruddy KJ, et al. Olanzapine
for the prevention of chemotherapy-induced nausea and
2Use diphenhydramine 25–50 mg PO/IV either every 4 or every 6 h for dystonic reactions. If allergic to diphenhydramine, use benztropine at 1–2 mg IV or IM x 1 dose,
followed by oral dose of 1–2 mg daily or BID if needed.
Continued
AE-B

Table of Contents

Other • Scopolamine
• Metoclopramide CNS depression; use caution in patients at risk for falls (eg,
May cause tardive dyskinesia; the risk increases with increasing elderly, debilitated, frail).
cumulative dose and duration of treatment. Clinical pearl: consider using when positional changes,
Avoid concomitant prescribing with olanzapine, the movement, or excessive secretions are triggering episodes of
phenothiazines, or haloperidol, as excessive dopamine blockade nausea/vomiting.
can increase the risk of EPS. • Cannabinoid
Use caution in patients at risk for falls (eg, elderly, debilitated, frail) CNS depression; use caution in patients at risk for falls (eg,
given the increased risk for EPS. elderly, debilitated, frail), at risk for dependence or orthostatic
Monitor for QT prolongation1 hypotension, or with underlying psychiatric disorders.
Monitor for dystonic reactions2 Clinical pearl: may stimulate appetite. To minimize paranoia/
Clinical pearl: metoclopramide increases gut motility and may hallucinations, consider starting with lower doses (especially
cause diarrhea and can be utilized to help manage gastroparesis. in elderly or marijuana-naïve patients) and titrate upwards to
• Haloperidol effect as clinically appropriate.
CNS depression; use caution in patients at risk for falls (eg,
elderly, debilitated, frail).
Avoid concomitant prescribing with olanzapine, the
phenothiazines, or metoclopramide, as excessive dopamine
blockade can increase the risk of EPS.
Monitor for QT prolongation.1 Higher-than-recommended doses
(regardless of route) and intravenous administration of haloperidol
appear to be associated with a higher risk of QT prolongation.3
Monitor for dystonic reactions.2
Clinical pearl: generally, lower doses of haloperidol (see AE-9 and
AE-10) are required to produce an antiemetic effect than what is
required for an antipsychotic effect.
2Use diphenhydramine 25–50 mg PO/IV either every 4 or every 6 h for dystonic reactions. If allergic to diphenhydramine, use benztropine at 1–2 mg IV or IM x 1 dose,
followed by oral dose of 1–2 mg daily or BID if needed.
3Haloperidol prescribing information. January 2016.

AE-B

Table of Contents
PRINCIPLES FOR MANAGING BREAKTHROUGH EMESIS

• Breakthrough emesis presents a difficult situation, as correction of • Prior to the next cycle of chemotherapy, reassess both the day 1
refractory ongoing nausea/vomiting is often challenging to reverse. and post-chemotherapy antiemetic regimen, which did not protect
It is generally far easier to prevent nausea/vomiting than it is to treat the patient during the present cycle, and consider alternatives:
it. (Suggestions are not in order of preference)
• The general principle of breakthrough treatment is to give an Add an NK1-antagonist if not previously included.
additional agent from a different drug class. The choice of agent Consider changing from NK1-antagonist–containing regimens to
should be based on assessment of the current prevention strategies olanzapine-containing regimen, or vice versa.
used. Some patients may require several agents utilizing differing Consider combining an NK1 antagonist regimen with olanzapine;
mechanisms of action. see High Emetic Risk Intravenous Chemotherapy - Acute And
• One should strongly consider routine, around-the-clock Delayed Emesis Prevention, option C (AE-5).
administration rather than PRN dosing. Add other concomitant antiemetics, (eg, dopamine antagonists
• The PO route is not likely to be feasible due to ongoing vomiting; such as metoclopramide or haloperidol) if applicable.
therefore, rectal or IV therapy is often required. Possibly adjust dose(s), either intensity or frequency, of the
• Multiple concurrent agents, perhaps in alternating schedules or by 5-HT3 RA. Based on the patient’s experiences, the chemotherapy
alternating routes, may be necessary. Dopamine antagonists (eg, regimen in question may actually be more emetogenic than
phenothiazines, olanzapine, metoclopramide, haloperidol), steroids, generally classified (eg, Hesketh method).
and agents such as lorazepam may be required. Possibly switch to a different 5-HT3 RA. Although not necessarily
• Ensure adequate hydration or fluid repletion, simultaneously likely to be effective, anecdotal and limited investigational trial
checking and correcting any possible electrolyte abnormalities. data suggest it may sometimes be efficacious. 5-HT3 RAs have
• Prior to administering the next cycle of chemotherapy the patient different pharmacokinetics/pharmacodynamics and different
should be reassessed, with attention given to various possible non- routes of metabolism that may account for different efficacy in
chemotherapy-related reasons for breakthrough emesis with the certain populations.
current cycle: If the goal of chemotherapy is non-curative, consider other
Brain metastases appropriate regimens, if any, that might be less emetogenic.
Electrolyte abnormalities It may be beneficial to add an anxiolytic agent in combination with
Tumor infiltration of the bowel or other gastrointestinal abnormality the antiemetic agents.
Other comorbidities • Consider antacid therapy if patient has dyspepsia (H2 blocker or
proton pump inhibitor).

Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-C

Table of Contents
Discussion Emetogenicity of Chemotherapy ................................................. MS-5
Types of Antiemetic Therapies .................................................... MS-6

NCCN Categories of Evidence and Consensus
Serotonin (5-HT3) Antagonists ................................................ MS-6
Category 1: Based upon high-level evidence, there is uniform
Ondansetron, Granisetron, and Dolasetron ................................................. MS-6
NCCN consensus that the intervention is appropriate.
Palonosetron .............................................................................................. MS-9
Category 2A: Based upon lower-level evidence, there is uniform
NCCN consensus that the intervention is appropriate. Neurokinin-1-Receptor Antagonists ........................................MS-10
Category 2B: Based upon lower-level evidence, there is NCCN Aprepitant ................................................................................................. MS-10
consensus that the intervention is appropriate. Netupitant (or Fosnetupitant) and Palonosetron (NEPA) ........................... MS-14
Category 3: Based upon any level of evidence, there is major Rolapitant ................................................................................................. MS-14
NCCN disagreement that the intervention is appropriate.
Other Antiemetics...................................................................MS-15
All recommendations are category 2A unless otherwise
Dexamethasone ....................................................................................... MS-15
indicated.
Olanzapine ............................................................................................... MS-17
Treatment Issues .......................................................................MS-19

Table of Contents
Principles of Emesis Control ...................................................MS-19
Overview ..................................................................................... MS-3
Prevention of Acute and Delayed Emesis ...............................MS-19
Literature Search Criteria and Guidelines Update Methodology .... MS-3
Prechemotherapy Emesis Prevention ....................................................... MS-19
Pathophysiology of Emesis .......................................................... MS-4 Postchemotherapy/Delayed Emesis Prevention ........................................ MS-22
Nausea........................................................................................ MS-4 Breakthrough Nausea and/or Vomiting Treatment...................MS-23

Types of Nausea and/or Vomiting ................................................ MS-4 Radiation-Induced Nausea and/or Vomiting ............................MS-24
Chemotherapy-Induced Nausea and/or Vomiting ...................... MS-4 Anticipatory Nausea and/or Vomiting ......................................MS-25
Radiation-Induced Nausea and/or Vomiting .............................. MS-5 Multiday Emetogenic Chemotherapy Regimens ......................MS-25
Version 3.2018, 06/11/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-1

Table of Contents
Dexamethasone ........................................................................................ MS-26
5-HT3 Antagonists ..................................................................................... MS-26
NK1 RAs ................................................................................................... MS-26
Summary ................................................................................... MS-28
References ................................................................................ MS-29

Table of Contents
Overview This Discussion text for antiemesis describes the algorithms in greater
Anticancer therapy-induced, or radiation therapy (RT)-induced, vomiting detail, for example, by including the clinical trial data and references
(emesis) and nausea can significantly affect a patient’s quality of life, that support the NCCN Panel’s recommendations. The NCCN
leading to poor compliance with further chemotherapy or RT.1 In Guidelines® for Antiemesis are updated at least once a year by a
addition, nausea and vomiting can result in dehydration, metabolic multidisciplinary panel of experts. The Summary of the Guidelines
imbalances, degeneration of self-care and functional ability, nutrient Updates section in the algorithm briefly describes the new changes for
depletion, anorexia, decline of the patient’s performance status and 2018, which are described in greater detail in this Discussion; recent
mental status, wound dehiscence, esophageal tears, and withdrawal references have been added (see the NCCN Guidelines for
from potentially useful or curative anticancer treatment.2-5 Anticancer Antiemesis). Major updates for 2018 are summarized in this Discussion
therapy includes chemotherapy, targeted therapy, and immunotherapy, (see Summary in this Discussion). Additional supplementary material in
which will all be referred to as chemotherapy throughout this Discussion the NCCN Guidelines for Antiemesis includes Principles of Managing
text. Multiday Emetogenic Chemotherapy Regimens, Pharmacologic
Considerations for Antiemetic Prescribing, and Principles for Managing
The incidence and severity of nausea and/or vomiting in patients Breakthrough Emesis. The NCCN Guidelines have also been modified
receiving chemotherapy, RT, or chemoradiation is affected by for resource-restricted settings.13 By definition, the NCCN Guidelines
numerous factors, including: 1) the specific therapeutic agents used; 2) cannot incorporate all possible clinical variations and are not intended to
dosage of the agents; 3) schedule and route of administration of the replace good clinical judgment or individualization of treatments.
agents; 4) target of the RT (eg, whole body, upper abdomen); and 5)
individual patient variability (eg, age, sex, prior chemotherapy, history of Literature Search Criteria and Guidelines Update
alcohol use).6,7 More than 90% of patients receiving highly emetogenic Methodology
chemotherapy (HEC) will have episodes of vomiting. However, if An electronic search of the PubMed database was performed to obtain
patients receive prophylactic (preventive) antiemetic regimens before key literature in antiemesis using the following search terms:
treatment with HEC, then only about 30% of these patients will vomit.6,8,9 chemotherapy induced nausea vomiting, antiemetics chemotherapy.
Although vomiting can often be prevented or substantially decreased by The PubMed database was chosen, because it is the most widely used
using prophylactic antiemetic regimens, nausea is harder to control.10-12 resource for medical literature and indexes only peer-reviewed
biomedical literature. The search results were narrowed by selecting
The NCCN Clinical Practice Guidelines in Oncology (NCCN studies in humans published in English. Results were confined to the
Guidelines®) for Antiemesis are intended to provide an overview of the following article types: Clinical Trial, Phase 2; Clinical Trial, Phase 3;
treatment principles for preventing anticancer therapy-induced or Clinical Trial, Phase 4; Guideline; Meta-Analysis; Randomized
RT-induced vomiting and nausea, and recommendations for antiemetic Controlled Trial; Systematic Reviews; and Validation Studies.
prophylaxis according to the emetogenic potential of anticancer agents.

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The data from key PubMed articles selected by the NCCN Panel for Antiemetic agents can block different neuronal pathways, exert their
review during the NCCN Guidelines update meeting, as well as articles effects at different points during the course of emesis, or behave
from additional sources deemed as relevant to these guidelines and synergistically with other antiemetic agents to potentiate an antiemetic
discussed by the NCCN Panel, have been included in this version of the effect. When used at a certain concentration, each antiemetic agent
Discussion section (eg, e-publications ahead of print, meeting predominantly blocks one receptor type. Olanzapine is the exception in
abstracts). If high-level evidence is lacking, recommendations are that it acts on multiple receptors involved in the emetic pathway.20 A
based on the panel’s review of lower-level evidence and expert opinion. final common pathway for emesis has yet to be identified. Therefore, no
The complete details of the development and update of the NCCN single agent can be expected to provide complete protection from the
Guidelines are available on the NCCN website (www.nccn.org). various emetic phases of chemotherapy.
Pathophysiology of Emesis Nausea

Vomiting results from stimulation of a multistep reflex pathway With use of effective antiemetic regimens, patients receiving
controlled by the brain.6,14,15 Vomiting is triggered by afferent impulses to emetogenic chemotherapy often experience more nausea than
the vomiting center (located in the medulla) from the chemoreceptor vomiting.10,21-25 Vomiting and nausea are related; however, they may
trigger zone, pharynx and gastrointestinal (GI) tract (via vagal afferent occur via different mechanisms.26,27 In general, younger patients are
fibers), and cerebral cortex. Vomiting occurs when efferent impulses are more likely to have nausea than older patients. Younger women
sent from the vomiting center to the salivation center, abdominal receiving chemotherapy for breast cancer are more prone to nausea
muscles, respiratory center, and cranial nerves.16 than other populations.12 Delayed nausea is more common than acute
nausea, is often more severe, and tends to be resistant to treatment
The chemoreceptor trigger zone, vomiting center, and GI tract have (see Delayed Nausea in this Discussion).25
many neurotransmitter receptors. Activation of these receptors by
chemotherapeutic agents or their metabolites may be responsible for Types of Nausea and/or Vomiting
chemotherapy-induced emesis. The principal neuroreceptors involved in Chemotherapy-Induced Nausea and/or Vomiting
the emetic response are the serotonin (5-hydroxytryptamine [5-HT3])
Nausea and/or vomiting induced by anticancer agents is often referred
and dopamine receptors; 5-HT3 receptors are associated with acute
to as chemotherapy-induced nausea and/or vomiting (CINV); it is
emesis via a peripheral pathway.14,17,18 Other neuroreceptors involved in
commonly classified as acute, delayed, anticipatory, breakthrough, or
emesis include acetylcholine, corticosteroid, histamine, cannabinoid,
refractory. Acute-onset nausea and/or vomiting usually occurs within a
opioid, and neurokinin-1 (NK1) receptors, which are located in the
few minutes to several hours after drug administration and commonly
vomiting and vestibular centers of the brain.19 NK1 receptors are
resolves within the first 24 hours. The intensity of acute-onset emesis
associated with delayed emesis via a central pathway.14
generally peaks after 5 to 6 hours. The occurrence of acute emesis is
increased in younger (<50 years) women with low ethanol use, history

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of motion sickness, and history of morning sickness. Other factors that are particularly sensitive to RT. In addition, the potential for nausea
influence acute emesis include history of nausea and vomiting, and/or vomiting increases with larger daily fractional doses of RT, larger
environment in which chemotherapy is administered, dosage of the total doses, and larger amounts of irradiated tissue. Total body
emetogenic agent, and efficacy of the antiemetic regimen.28 irradiation, when given before bone marrow transplantation, commonly
induces nausea and/or vomiting.34,39
Delayed-onset CINV develops in patients more than 24 hours after
chemotherapy administration.29,30 It occurs commonly with the Emetogenicity of Chemotherapy
administration of cisplatin, carboplatin, cyclophosphamide, and/or The frequency of chemotherapy-induced emesis depends primarily on
doxorubicin. For cisplatin, emesis reaches its maximal intensity 48 to 72 the emetogenic potential of the specific chemotherapeutic agents used.
hours after administration and can last 6 to 7 days. Several classifications have been developed to define the
emetogenicity of chemotherapy; however, none has been universally
Anticipatory CINV occurs before patients receive their next
accepted.16,40-43
chemotherapy treatment. Because it is primarily considered a
conditioned response, anticipatory emesis typically occurs after a Hesketh and colleagues developed a classification of the acute
negative past experience with chemotherapy. The incidence of emetogenicity of anticancer chemotherapeutic agents and developed
anticipatory CINV ranges from 18% to 57%, and nausea is more an algorithm to define the emetogenicity of combination
common than vomiting.31,32 Younger patients may be more susceptible chemotherapeutic regimens.8 The classification was updated by
to anticipatory nausea and vomiting, because they generally receive Grunberg et al and more recently by Jordan et al; it divides
more aggressive chemotherapy and, overall, have poorer emesis chemotherapeutic agents into 4 levels according to the percentage of
control than older patients.33 patients who experience acute emesis when they do not receive
antiemetic prophylaxis.11,44,45 This classification is used in these NCCN
Breakthrough CINV refers to nausea and/or vomiting that occurs
Guidelines and is updated each year by the NCCN Panel with recently
despite prophylactic treatment and/or requires rescue with antiemetic
introduced drugs. For example, the NCCN Panel classified the
agents.34 Refractory CINV refers to nausea and/or vomiting that occurs
emetogenic potential of 11 new drugs for the 2018 update—such as
during subsequent treatment cycles when antiemetic prophylaxis and/or
enasidenib, midostaurin, niraparib, and dual-drug liposomal
rescue has not been effective in earlier cycles.35
encapsulation of cytarabine/daunorubicin—which are classified as
Radiation-Induced Nausea and/or Vomiting moderate emetic risk. See Emetogenic Potential of Intravenous [and
Oral] Anticancer Agents in the algorithm. The percentage of nausea and
Patients receiving total body RT (>90% emesis) have the greatest
vomiting for each anticancer therapy agent is based on clinical trial data
likelihood of developing nausea and/or vomiting; those receiving upper
(see the package inserts).46-50
abdominal RT are at moderate risk of emesis (30%-90%).34,36-38 The GI
tract (specifically, the small intestine) contains rapidly dividing cells that

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The NCCN Guidelines currently outline treatment using 4 categories of Types of Antiemetic Therapies
emetogenic potential for intravenous agents, which correspond to the In general, to provide maximal protection against
Grunberg classification as follows: chemotherapy-induced emesis, antiemetic therapy should be initiated
before chemotherapy. The antiemetic therapy should also be continued
• High emetic risk—more than 90% of patients experience acute
for the same length of time as the duration of the emetic activity of the
emesis;
chemotherapeutic agent being used. However, daily use of certain
• Moderate emetic risk—more than 30% to 90% of patients experience
antiemetics, such as dexamethasone, may not be recommended for
acute emesis;
some therapeutic agents that are taken long term on a regular basis
• Low emetic risk—10% to 30% of patients experience acute emesis;
(eg, the oral anticancer agents of moderate/high emetic risk that are
• Minimal emetic risk—fewer than 10% of patients experience acute listed in the algorithm). Antiemetic agents can be administered by the
emesis. oral, sublingual, rectal, intravenous, intramuscular, subcutaneous, or
transdermal route. Oral and intravenous 5-HT3 antagonists have
In addition, the NCCN Guidelines attempt to define antiemetic regimens
equivalent efficacy when used at the appropriate doses.9,39 However,
for particular chemotherapy drugs that cover the entire duration of time
subcutaneous granisetron extended-release injection and intravenous
a patient is at risk for nausea and/or vomiting. Panel members were
granisetron are not interchangeable; the subcutaneous formulation
concerned that some patients may not receive adequate prophylaxis for
should not be given intravenously and vice versa. Aprepitant injectable
delayed emesis; therefore, the NCCN Guidelines incorporate a dosing
emulsion and intravenous fosaprepitant are also not interchangeable.
schedule that covers both acute and delayed emesis into a single
The dosing is different for all of these formulations. For patients at risk
algorithm. The NCCN Panel has also categorized the emetogenic
for CINV or unable to swallow or digest tablets because of emesis,
potential of oral anticancer agents.11
non-oral routes are recommended. Although studies may show drugs to
For the 2018 update, panel members added a caveat that clinicians be equally effective on a population basis, individual patients may
should avoid overuse of antiemetic agents, especially in settings where respond differently. Therefore, some drug options may be based on a
the anticancer therapy is of minimal or low emetic risk, to avoid patient’s individual experience.
exposing patients to adverse effects from antiemetic agents and to
Serotonin (5-HT3) Antagonists
prevent unnecessary expense (see Principles of Emesis Control for the
Cancer Patient in the algorithm).36,51,52 If clinicians use the emetogenic Ondansetron, Granisetron, and Dolasetron
classification of anticancer agents in the algorithm, this will decrease All of the 5-HT3 antagonists—dolasetron mesylate, granisetron,
unnecessary prescribing of antiemetic agents. ondansetron, and palonosetron—have been shown to be effective in
controlling the acute nausea and/or vomiting associated with cancer
chemotherapy.53-69 Ondansetron, granisetron, and dolasetron mesylate
are first-generation 5-HT3 antagonists. Many clinical trials have

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compared ondansetron, granisetron, dolasetron mesylate, and dexamethasone for preventing delayed emesis.93 Another study found
palonosetron. These trials have used various doses, routes, and that 5-HT3 antagonists (except palonosetron, which was not studied)
schedules of administration.70-87 A meta-analysis found no difference in were not more effective than prochlorperazine in preventing delayed
efficacy between the first-generation 5-HT3 antagonists.88 Another emesis.25 A single dose of intravenous palonosetron appears to be
meta-analysis of studies comparing ondansetron with granisetron has effective for preventing both delayed and acute emesis.
also confirmed the similar efficacy of these first-generation 5-HT3
antagonists in controlling acute and delayed nausea and vomiting, with The NCCN Guidelines recommend intravenous palonosetron as a
similar safety profiles between these agents.89 preferred 5-HT3 antagonist for MEC when used with dexamethasone
but without an NK1 RA (see Principles of Managing Multiday
A meta-analysis of randomized controlled trials comparing palonosetron Emetogenic Chemotherapy Regimens in the algorithm).71 Several
with the first-generation 5-HT3 antagonists reported that palonosetron studies94-97 have evaluated the efficacy of a 3-drug combination regimen
was significantly more effective in preventing acute and delayed nausea with palonosetron, dexamethasone, and NK1 RAs as prophylaxis in
and vomiting for both HEC and moderately emetogenic chemotherapy patients receiving MEC (see Neurokinin-1-Receptor Antagonists in this
(MEC); most patients receiving MEC actually received anthracycline Discussion). However, these studies do not provide evidence that a
and cyclophosphamide (AC regimens).90 However, AC regimens are single dose of palonosetron is better than a single dose of a
now classified as HEC, although they were previously classified as first-generation 5-HT3 antagonist when using an
MEC.36,91 Based on this meta-analysis and clinical practice, some NCCN NK1-antagonist-containing regimen for MEC.
Panel Members feel that palonosetron should be a preferred 5-HT3
antagonist for both HEC and MEC. However, the majority of the NCCN A phase 3 trial assessed subcutaneous granisetron extended-release
Panel previously decided that palonosetron is only preferred for MEC if injection versus intravenous palonosetron in a 2-drug regimen with
the regimen does not contain an NK1 receptor antagonist (RA) (see dexamethasone for patients receiving HEC or MEC.92 Two doses of
Palonosetron in this Discussion).71 Similar to palonosetron, the panel subcutaneous granisetron extended-release injection were assessed: 5
also recommends subcutaneous granisetron extended-release injection and 10 mg. The data show that subcutaneous granisetron
as a preferred 5-HT3 antagonist option when used with dexamethasone extended-release injection is not inferior to intravenous palonosetron for
in antiemetic regimens that do not contain an NK1 RA (see Principles of preventing acute and delayed CINV after either HEC or MEC. For
Managing Multiday Emetogenic Chemotherapy Regimens in the patients receiving HEC, acute complete responses (CRs) for the 5- or
algorithm).92 10-mg granisetron dose were 77.7% (−12.1, 6.1) and 81.3% (−8.2, 9.3),
respectively, compared with 80.7% for those receiving palonosetron
Ondansetron, granisetron, and dolasetron are effective in preventing 0.25 mg intravenous dose. For patients receiving MEC, acute CRs for 5
acute emesis but appear to be less effective for delayed emesis. A mg or 10 mg of subcutaneous granisetron were 74.8% (−9.8, 9.3) and
meta-analysis of randomized controlled trials found that adding a 5-HT3 76.9% (−7.5, 11.4), respectively, compared with 75.0% for
antagonist to dexamethasone did not improve the antiemetic effect of palonosetron. The FDA approved the use of a 10-mg dose of

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subcutaneous granisetron extended-release injection when used in either palonosetron or subcutaneous granisetron, and the FDA
antiemetic regimens for MEC or AC combination chemotherapy approval.92,98 It is important to note that granisetron extended-release
regimens. Based on this trial and the FDA approval, the NCCN Panel injection is a unique formulation of granisetron using a polymer-based
now recommends intravenous palonosetron or subcutaneous drug delivery system. This formulation is specifically intended for
granisetron extended-release injection as preferred 5-HT3 antagonists subcutaneous administration and is NOT interchangeable with the
for MEC when used with dexamethasone in antiemetic regimens that do intravenous formulation; the subcutaneous formulation should not be
not contain an NK1 RA. The panel does not recommend a 2-drug injected and vice versa. Subcutaneous granisetron extended-release
antiemetic regimen containing dexamethasone with either palonosetron injection has an extended half-life and should not be administered at
or subcutaneous granisetron extended-release injection for HEC; the less than 1-week intervals.
panel recommends a 3-drug regimen, which should include an NK1 RA
or olanzapine, or a 4-drug regimen (which includes olanzapine and an Ondansetron and granisetron can be delivered orally or intravenously;
NK1 RA). granisetron extended-release injection is administered subcutaneously.
Note that intravenous dolasetron is no longer recommended for the
A phase 3 trial (MAGIC) assessed a single dose of subcutaneous prevention of nausea and vomiting, because it has been associated
granisetron extended-release injection compared with a single dose of with an increased risk for cardiac arrhythmias.99,100 Oral dolasetron is
intravenous ondansetron in a 3-drug regimen with dexamethasone and still recommended. A single intravenous dose of 32 mg of ondansetron
fosaprepitant for patients receiving HEC.98 The data show that the is no longer recommended based on FDA review of clinical data
regimen containing granisetron extended-release injection improved the suggesting prolongation of the QT interval at this dose.99,101,102 At this
CR rate (no emesis or rescue medication) for delayed-phase CINV time, the FDA recommends a maximum single intravenous dose of 16
(24-120 hours) when compared with the ondansetron regimen (P = mg of ondansetron given once on the first day; the dose
.014). This is the first published trial that compared a single dose of 2 recommendations for oral administration of ondansetron are 16 to 24
different 5-HT3 antagonists when used in combination with mg given once on the first day.102 Oral administration of ondansetron
dexamethasone and an NK1 RA. As a result, granisetron poses less of a risk of cardiac arrhythmias than intravenous
extended-release injection is the first FDA-approved 5-HT3 antagonist administration.99
indicated for the prevention of delayed CINV associated with AC
chemotherapy. When administered subcutaneously, granisetron In addition, the FDA has approved the use of a granisetron transdermal
extended-release injection is effective for 5 or more days. system for CINV. The patch containing 3.1 mg of granisetron/24 hours
is applied approximately 24 to 48 hours before the first dose of
The NCCN Panel recommends a 10-mg dose of subcutaneous chemotherapy; the maximum duration of the patch is 7 days. A phase 3
granisetron extended-release injection on day 1 only for patients randomized trial compared the patch to oral granisetron in patients
receiving either HEC or MEC when used in the antiemetic regimens receiving either HEC or MEC. The patch proved non-inferior to repeat
based on the MAGIC trial, the trial comparing dexamethasone with dosing of the oral antiemetic granisetron over 3 to 5 days.103,104 A phase

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4 trial assessed a transdermal granisetron regimen versus a nausea and vomiting because it has been associated with an increased
palonosetron regimen for patients receiving MEC; transdermal risk for cardiac arrhythmias.99,100
granisetron was not inferior to palonosetron in preventing nausea and
vomiting in the acute stage.105 Palonosetron
Palonosetron is a 5-HT3 antagonist with an approximately 100-fold
The addition of dexamethasone improves the efficacy of the antiemetic higher binding affinity for the 5-HT3 receptor compared to ondansetron,
regimen containing 5-HT3 antagonists (see Dexamethasone in this granisetron, and dolasetron. Palonosetron has a half-life of
Discussion). However, dexamethasone is associated with side effects approximately 40 hours, which is significantly longer than other
(such as insomnia). When dexamethasone is used with palonosetron commercially available 5-HT3 antagonists.55 Data suggest that
for MEC, a randomized trial suggests that the dose of dexamethasone palonosetron is associated with prolonged inhibition of the 5-HT3
can be decreased to 8 mg on day 1 and also eliminated on days 2 to receptor and thus differs from ondansetron, granisetron, and
3.106 dolasetron.116,117 By suppressing cross talk between 5-HT3 and NK1
signaling pathways, palonosetron may indirectly inhibit substance P.
Cardiac Side Effects
Ondansetron, granisetron, and dolasetron have been associated with Several randomized phase 3 trials have assessed the efficacy of
an increased risk for developing abnormal electrical activity of the heart palonosetron compared with other 5-HT3 antagonists in preventing
(detectable on ECG, including prolongation of electrocardiographic emesis associated with both moderate and high emetic risk
intervals such as PR or QT intervals).99,100,107-114 However, this warning is chemotherapy regimens, particularly for delayed emesis.70-73 In these
not in the package inserts for palonosetron, granisetron studies, the primary efficacy endpoint was CR, defined as having no
extended-release injection, and the granisetron transdermal patch. emesis and no rescue treatments. In a study in patients receiving MEC
Although the ECG changes can be reversible and asymptomatic, (N = 563 evaluable), a single dose of palonosetron (0.25 mg
abnormal activity can also result in potentially fatal cardiac arrhythmias intravenous) was found to be superior to a single dose of ondansetron
(including torsade de pointes) in some cases.99 Patients who may be (32 mg intravenous) in preventing both acute (CR rate, 81% vs. 69%; P
particularly at risk for developing torsade de pointes include those with < .01) and delayed emesis (CR rate, 74% vs. 55%; P < .01); no
congenital long QT syndrome or other underlying cardiac diseases, concomitant corticosteroids were given in this study.73 The safety and
congestive heart failure, bradycardia, those with electrolyte side-effect profiles of palonosetron were indistinguishable from the
abnormalities (eg, hypokalemia, hypomagnesemia), and those taking control 5-HT3 antagonists (ondansetron and dolasetron). Note that the
other medications that can lead to QT prolongation.100,111,115 Routine FDA now recommends a maximum of 16 mg for a single dose of
ECG monitoring during treatment with regimens that include 5-HT3 intravenous ondansetron.99
antagonists may be useful for these patients who may have
In a phase 3 randomized trial that compared palonosetron with
concomitant risk factors for QT prolongation. As previously mentioned,
ondansetron in patients receiving HEC (N = 667), the majority (67%)
intravenous dolasetron is no longer recommended for the prevention of

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had received dexamethasone on day 1 of antiemetic therapy; NK1 RAs Intravenous palonosetron is superior to other first-generation 5-HT3
were not used in this trial.70 Among this subgroup of patients who antagonists in preventing delayed nausea.23,70-73 Repeat dosing of
received concomitant dexamethasone (n = 447), palonosetron (0.25 mg palonosetron on days 2 or 3 after chemotherapy is likely to be safe.
intravenous) was similar to ondansetron (32 mg intravenous) in However, in the setting of multiday chemotherapy, limited data are
preventing acute emesis (CR rate, 65% vs. 56%); however, available to recommend multiday dosing with palonosetron (see
palonosetron was significantly more effective in preventing delayed Principles of Managing Multiday Emetogenic Chemotherapy Regimens
emesis (CR rate, 41% vs. 25%; P = .021). in the algorithm).118
Another phase 3 randomized trial in patients treated with HEC (N = Neurokinin-1-Receptor Antagonists
1114 evaluable) compared a single dose of palonosetron (at a higher For patients receiving HEC and MEC, the NCCN Panel recommends
dose of 0.75 mg intravenous) with a single dose of granisetron (40 several options for prophylactic antiemetic regimens based on clinical
mcg/kg intravenous), both in combination with dexamethasone; NK1 trial data and FDA approvals, including: 1) NK1 RA-containing
RAs were not used in this trial. Palonosetron showed similar activity to regimens, which are discussed in this section; and 2)
granisetron in preventing acute emesis (CR rate, 75% vs. 73%), with olanzapine-containing regimens. NK1 RA regimens include aprepitant,
superior activity in preventing delayed emesis (CR rate, 57% vs. 44.5%; fosaprepitant, rolapitant, netupitant, or fosnetupitant. It is important to
P < .0001).71 However, the NCCN Panel does not recommend note that netupitant (or fosnetupitant) is only available in combination
palonosetron as the preferred 5-HT3 antagonist in regimens for HEC, with palonosetron (NEPA) and not as a single agent. A 2-drug regimen
because an NK1 RA was not used in this study and it is unknown if a of one of the 5-HT3 options plus dexamethasone, but without an NK1
single dose of palonosetron would be superior to a single dose of RA or olanzapine, is recommended for MEC but not HEC. For the 2018
granisetron in the presence of an NK1 RA. As previously mentioned, the update, the panel clarified the use of NK1 RAs in patients receiving
NCCN Panel now recommends either palonosetron or subcutaneous MEC as follows. An NK1 RA should be added to a
granisetron extended-release injection as preferred 5-HT3 antagonists 5-HT3/dexamethasone regimen (2-drug antiemetic regimen) for patients
for MEC when used with dexamethasone in antiemetic regimens that do receiving MEC anticancer therapy who have additional risk factors or
not contain an NK1 RA (see Ondansetron, Granisetron, and Dolasetron previous treatment failure with the 2-drug regimen. Patients receiving
in this Discussion and Principles of Managing Multiday Emetogenic anticancer therapy that is associated with a higher risk for emesis (eg,
Chemotherapy Regimens in the algorithm).92 Palonosetron (0.25 mg irinotecan, oxaliplatin) are at greater risk for emesis and may need the
intravenous) is FDA approved as a single dose on day 1 for the addition of an NK1 RA.
prevention of acute and delayed nausea and vomiting associated with
MEC and for the prevention of acute nausea and vomiting associated Aprepitant
with HEC. Aprepitant selectively blocks the binding of substance P at the NK1
receptor in the central nervous system. Thus, aprepitant provides a
different and complementary mechanism of action to other commercially

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available antiemetics. Aprepitant has been shown to augment the in patients receiving emetogenic chemotherapy with high-dose cisplatin
antiemetic activity of the 5-HT3 antagonists and the corticosteroid (N = 521 evaluable). The addition of oral aprepitant was significantly
dexamethasone to prevent both acute and delayed cisplatin-induced more effective than the 2-drug regimen in controlling both acute (CR
emesis.119-121 Most of the clinical trial data described in this Discussion rate, 89% vs. 78%; P < .001) and delayed emesis (CR rate, 75% vs.
are based on studies with oral aprepitant. Aprepitant injectable emulsion 56%; P < .001).120 Another similarly designed randomized phase 3 study
is a new formulation of aprepitant that was recently approved by the (N = 523 evaluable) also showed a significant benefit of adding oral
FDA for HEC and MEC when used in combination with other antiemetic aprepitant to ondansetron and dexamethasone compared with the
regimens.122 2-drug regimen alone for controlling both acute (CR rate, 83% vs. 68%;
P < .001) and delayed emesis (CR rate, 68% vs. 47%; P < .001).121 A
Aprepitant Injectable Emulsion pooled analysis of data combined from these two phase 3 trials found
Intravenous fosaprepitant contains polysorbate 80 and other surfactants that the oral aprepitant regimen was particularly beneficial in improving
that may cause infusion-site reactions including pain, erythema, and CR rates for patients receiving concomitant emetogenic therapy with
swelling.122,123 Aprepitant injectable emulsion is a new formulation of doxorubicin and cyclophosphamide (AC regimen) or cyclophosphamide,
aprepitant that does not contain polysorbate 80 and other surfactants. A along with high-dose cisplatin therapy.119
recent phase 1 bioequivalence sturdy (n = 100) compared intravenous
fosaprepitant with aprepitant injectable emulsion.122 The data showed A meta-analysis (of 7 randomized controlled trials) of patients receiving
that patients receiving aprepitant injectable emulsion had fewer HEC found that oral aprepitant used alone or with control antiemetic
treatment-emergent adverse effects when compared with those therapy did not significantly increase protection from acute emesis or
receiving intravenous fosaprepitant (1% vs. 20%), which all resolved. nausea; however, for delayed emesis and nausea, oral aprepitant was
Three patients receiving intravenous fosaprepitant had dyspnea. None associated with significantly increased protection compared with
of the patients had severe treatment-emergent adverse effects, serious control.124 A larger meta-analysis (of 17 randomized controlled trials)
adverse events, or died. Aprepitant injectable emulsion was evaluated outcomes with typical antiemetic therapy with or without oral
bioequivalent to intravenous fosaprepitant (bioequivalence bounds, aprepitant in patients receiving MEC or HEC. The addition of oral
80%-125%). For the 2018 update, the NCCN Panel now recommends aprepitant was associated with significantly improved CR (no emetic
that aprepitant injectable emulsion be considered as an NK1 RA option episodes and no rescue medication) rate compared with control
based on the phase 1 bioequivalence sturdy and the recent FDA antiemetic therapy (72% vs. 54%; P < .001) during the overall time
approval.122 As previously mentioned, aprepitant injectable emulsion is frame from 0 to 120 hours after starting chemotherapy.125 The
not interchangeable with intravenous fosaprepitant. significant increase in CR rate associated with oral aprepitant was
observed for both the acute and delayed periods. Based on data from 3
Oral Aprepitant trials that reported on infectious complications, both oral aprepitant
A randomized phase 3 trial compared ondansetron 32 mg intravenous regimens and other antiemetic regimens were associated with a low
and oral dexamethasone with or without the addition of oral aprepitant

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rate of severe infections (6% vs. 2%; P < .001); the risk of febrile A phase 3 trial added oral aprepitant to a control antiemetic regimen of
neutropenia or other hematologic toxicities was not increased.125 A oral granisetron and oral dexamethasone in patients receiving MEC.
randomized phase 3 trial (N = 866) showed that an oral aprepitant The data showed that the addition of oral aprepitant improved control of
regimen was more effective than a control antiemetic regimen in nausea, vomiting, and quality of life when compared with granisetron
preventing vomiting in patients receiving HEC during 120 hours after and dexamethasone.127 A phase 2 study (N = 58) found that combining
initiation of chemotherapy (CR rate, 51% vs. 43%, P = .015); no palonosetron (0.25 mg intravenous day 1), oral aprepitant (125 mg day
delayed dexamethasone was used in this trial. However, approximately 1; 80 mg days 2, 3), and dexamethasone (12 mg day 1; 8 mg days 2, 3)
40% of patients (receiving either regimen) still experienced significant was effective in preventing both acute and delayed emesis and nausea
nausea.126 The oral aprepitant regimen included ondansetron and when using various chemotherapeutic regimens (moderate to
dexamethasone; the control antiemetic regimen included ondansetron moderately highly emetogenic); 78% of patients had a CR (no emetic
and dexamethasone. episodes and no rescue medication) during the overall time frame, from
0 to 120 hours after initiation of emetogenic therapy.94 A phase 2 study
A 3-drug antiemetic regimen with palonosetron, dexamethasone, and in patients with breast cancer (N = 41) receiving MEC also found that a
oral aprepitant has also been investigated in patients undergoing single-day regimen of palonosetron (0.25 mg intravenous), oral
treatment with HEC. A phase 2 study in patients receiving HEC with aprepitant (285 mg oral), and dexamethasone (20 mg) was effective;
cisplatin-containing regimens (N = 222) showed that the 3-drug 76% and 66% of patients had a CR during the acute and delayed
combination of palonosetron (0.25 mg intravenous day 1), oral phases, respectively.95
aprepitant (125 mg day 1; 80 mg days 2, 3), and dexamethasone (20
mg intravenous day 1; 4 mg oral days 2, 3) resulted in a CR rate (no A randomized double-blind phase 3 trial compared the effectiveness of
emetic episodes and no rescue medication) of 70% during the overall combining ondansetron (8 mg oral twice daily [BID] day 1), oral
study period (0-120 hours).96 In addition, 93% of patients had no emesis aprepitant (125 mg day 1; 80 mg days 2, 3), and dexamethasone (12
and 60% had no nausea during the study period. Constipation was the mg day 1) versus control antiemetic therapy with ondansetron (8 mg
most commonly reported adverse event (39%).96 A phase 2 study oral BID days 1-3) and dexamethasone (20 mg day 1) in patients
evaluated a higher dose of palonosetron (0.75 mg intravenous day 1) receiving MEC (N = 585).128 Dexamethasone was only given on day 1
with oral aprepitant (125 mg day 1; 80 mg days 2, 3), and for both treatment groups. A significantly higher proportion of patients in
dexamethasone (10 mg oral day 1; 8 mg oral days 2-4) in patients with the 3-drug regimen with oral aprepitant had no vomiting compared with
lung cancer undergoing HEC (N = 63); the CR rate during the overall the control antiemetic regimen (76% vs. 62%; P < .001) during the
study period (0-120 hours) was 81%.97 The CR rates during the acute overall time frame from 0 to 120 hours after starting chemotherapy. In
and delayed phases were 97% and 81%, respectively. In addition, 54% addition, the CR (no emetic episodes, no rescue medications) rate was
of patients had no nausea during the overall study period. Grade 1 or 2 significantly increased in the oral aprepitant group (69% vs. 56%; P <
constipation was the most commonly reported adverse event.97 .001) during the overall time period. The significant improvement in

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antiemetic activity (with regard to no emesis as well as CR rate) in the intravenous forms because of first-pass metabolism. Patients should not
oral aprepitant group was observed for both the acute and delayed take oral aprepitant or aprepitant injectable emulsion with pimozide or
phases. The 3-drug regimen was well tolerated, and the incidence of astemizole; these combinations are contraindicated because they may
adverse events was similar between treatment groups.128 cause serious or life-threatening reactions (see the aprepitant package
inserts). Chemotherapeutic agents known to be metabolized by
Oral aprepitant is FDA approved for the prevention of nausea and CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide,
vomiting in patients receiving HEC (eg, cisplatin-containing) and MEC. imatinib, vinorelbine, vinblastine, and vincristine. In clinical trials, oral
The oral doses of aprepitant are 125 mg on day 1 (before aprepitant was used concurrently with etoposide, vinorelbine, or
chemotherapy) and then 80 mg on days 2 and 3 (after paclitaxel; although chemotherapy doses were not adjusted for potential
chemotherapy).129 An intravenous version of aprepitant (fosaprepitant drug interactions in phase 3 trials, caution is urged when using any
dimeglumine), which can be given on day 1 only, is also FDA approved. chemotherapeutic agent that is metabolized by CYP3A4.
As previously mentioned, intravenous fosaprepitant is NOT
interchangeable with aprepitant injectable emulsion. Intravenous Aprepitant has been shown to interact with several
fosaprepitant is given 30 minutes before chemotherapy on day 1 non-chemotherapeutic drugs (including warfarin, dexamethasone,
only, per the package insert. If a higher dose of fosaprepitant is used methylprednisolone, and oral contraceptives). Again, these interactions
(150 mg intravenous) on day 1, then it is not necessary to give oral are more significant with orally administered forms of these drugs than
aprepitant on days 2 to 3.130,131 Note that the dexamethasone dosing is with intravenous forms because of first-pass metabolism. Induction of
slightly different on days 3 and 4 (8 mg PO/IV BID) when using the warfarin metabolism by aprepitant may lead to clinically significant
higher dose of fosaprepitant (150 mg intravenous) per the package reductions in INR (international normalized ratio) values, particularly for
insert. A single dose of 150 mg intravenous fosaprepitant was shown to patients on therapeutic (as compared to prophylactic) warfarin
be non-inferior to the control antiemetic regimen with 3-day oral regimens. These changes, although brief in duration, may require
aprepitant in a randomized study.132 There are no studies showing increased patient monitoring. Aprepitant decreases the AUC for patients
efficacy or safety of chronic dosing with oral aprepitant. It is possible taking oral contraceptives; thus, other methods of birth control should
that the drug-drug interaction profile may change with chronic dosing. be used during treatment with aprepitant and for 1 month after the last
dose of aprepitant. Additionally, certain drugs can affect the AUCs of
Drug Interactions aprepitant. Concomitant administration with CYP3A4 inhibitors (eg,
Aprepitant is simultaneously a substrate, moderate inducer, and ketoconazole, itraconazole, erythromycin) may lead to increased
moderate inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4); aprepitant AUCs, whereas concomitant administration with CYP3A4
aprepitant also induces CYP2C9.133 Thus, aprepitant can alter the inducers (eg, carbamazepine, rifampin, phenytoin) may lead to
metabolism of certain drugs and change their plasma concentrations decreased levels of aprepitant.
(ie, areas under the curve [AUCs]). However, these interactions are
more significant with orally administered forms of these drugs than with

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Netupitant (or Fosnetupitant) and Palonosetron (NEPA) trial in patients receiving AC regimens assessed oral NEPA plus
Netupitant is a highly selective NK1 RA that targets serotonin and dexamethasone compared with palonosetron plus dexamethasone.136
substance P-mediated pathways involved in CINV. Oral netupitant is More patients in the oral NEPA arm had CR during the delayed phase
combined with oral palonosetron (NEPA) in a single tablet and is not when compared with the control arm (76.9% vs. 69.5%; P = .001). In
available as a single agent; oral NEPA is approved by the FDA for the addition, patients in the oral NEPA arm also had more CRs in the
prevention of nausea and vomiting in patients receiving HEC and MEC overall phases (0-120 h) (74.3% vs. 66.6%; P = .001) and acute phases
based on several randomized trials.134-137 Intravenous fosnetupitant is (0-24 h) (88.4% vs. 85.0%; P = .047).
combined with intravenous palonosetron (NEPA) and is also not
available as a single agent; IV NEPA is approved by the FDA for the A recent phase 3 randomized trial assessed a single dose of oral NEPA
prevention of nausea and vomiting in patients receiving HEC. For the compared with a 3-day aprepitant/granisetron regimen in patients (n =
2018 update (Version 3), the NCCN Panel added a recommendation 828) receiving HEC; all patients received oral dexamethasone on days
(category 1) for IV NEPA for HEC and MEC based on recent data 1 through 4.139 The oral NEPA regimen was non-inferior to the
showing that IV NEPA is safe and on FDA approval.138 Similar to the aprepitant regimen (overall CR: oral NEPA, 73.8% vs.
other NK1 RAs (ie, aprepitant, fosaprepitant, and rolapitant), netupitant aprepitant/granisetron, 72.4% [95% CI, -4.5%-7.5%]). Similar rates were
and fosnetupitant improve control for delayed emesis when compared observed for both groups for no emesis (oral NEPA, 75.0% vs.
with traditional antiemetic regimens. For patients receiving HEC and aprepitant/granisetron, 74.0% [95% CI, -4.8%-6.9%]) and no significant
MEC, the NCCN Panel recommends several options for prophylactic nausea (oral NEPA, 75.7% vs. aprepitant/granisetron, 70.4% [95%
antiemetic regimens; oral or IV NEPA combined with dexamethasone is CI, -0.6%-11.4%]).
recommended (category 1) for acute and delayed emesis prevention
Rolapitant
based on the FDA approval and randomized trials. Netupitant and
Rolapitant is another NK1 RA that is approved by the FDA for the
fosnetupitant inhibit CYP3A4; therefore, caution should be used with
prevention of nausea and vomiting in patients receiving HEC and MEC
drugs that are metabolized by CYP3A4 to avoid drug interactions (see
based on several phase 3 randomized trials.140,141 In the phase 3 trials
prescribing information). Concomitant use with certain agents that are
assessing a prophylactic oral rolapitant-containing regimen for HEC,
strong inducers (eg, rifampin) of CYP3A4 is contraindicated.
patients received 180 mg of oral rolapitant on day 1 only; all patients
A randomized trial in patients receiving HEC assessed dexamethasone received granisetron (10 mcg/kg intravenously) and dexamethasone (20
plus 3 varying dose levels of prophylactic oral NEPA compared with oral mg orally) on day 1, and dexamethasone (8 mg orally) BID on days 2 to
palonosetron plus dexamethasone.134 The data show that the oral 4.141 More patients receiving the oral rolapitant-containing regimen had
NEPA fixed-dose combination of 300 mg of netupitant decreased CRs for prevention of delayed emesis when compared with those
nausea and vomiting in the acute, delayed, and overall phases when receiving granisetron/dexamethasone alone (pooled studies: 382 [71%]
compared with palonosetron alone. The CR for the NEPA300 arm was vs. 322 [60%]; odds ratio [OR], 1.6; 95% CI, 1.3-2.1; P = .0001). For
89.6% versus 76.5% for the palonosetron arm (P < .050). A phase 3 patients receiving HEC, the NCCN Panel recommends several

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prophylactic antiemetic regimens (category 1); a 5-HT3 antagonist, compared with the other NK1 RAs (ie, aprepitant, fosaprepitant,
dexamethasone, and rolapitant regimen is recommended for acute and netupitant, fosnetupitant).
delayed emesis prevention based on the FDA approvals and the phase
3 randomized trial.141 Other Antiemetics
Before the advent of the 5-HT3 antagonists and NK1 RAs, the available
A phase 3 trial assessed a prophylactic oral rolapitant-containing antiemetic agents included phenothiazines,142 substituted
regimen for anticancer regimens previously considered to be MEC, benzamides,143,144 antihistamines,145 butyrophenones,146
which are now categorized as HEC by the NCCN Panel (ie, AC corticosteroids,147-149 benzodiazepines,150,151 and cannabinoids.152,153
regimens and regimens containing carboplatin with an AUC of 4 or Based on clinical trial data, the NCCN Panel added
more). With the revised definition of HEC regimens, this trial actually olanzapine-containing regimens as another antiemetic option.
contained mostly HEC and only some MEC regimens (18% and 14% of Combination antiemetic therapy is generally more effective than
patients had non-AC regimens and non-carboplatin regimens).91,140 Most single-agent therapy. Other agents such as gabapentin have also been
patients also received granisetron (2 mg orally) and dexamethasone (20 evaluated as part of antiemetic regimens.
mg orally) on day 1 followed by granisetron (2 mg orally) on days 2 to
3.140 Significantly more patients receiving the oral rolapitant-containing Dexamethasone
regimen had CRs in the delayed phase than did those receiving Before the mid-1990s, studies assessing dexamethasone as an
granisetron/dexamethasone alone (475 [71%] vs. 410 [62%]; OR, 1.6; antiemetic agent were characterized by small sample size and
95% CI, 1.2-2.0; P = .0002). For patients receiving MEC, the NCCN variations in efficacy outcomes between the studies. A meta-analysis of
Panel recommends several prophylactic antiemetic regimens (category 32 studies (published from 1966-1999) was done in 5613 patients; the
1); a 5-HT3 antagonist/dexamethasone (category 1) with (or without) day 1 dose range of dexamethasone was 8 to 100 mg, and the mean
oral rolapitant is recommended for acute and delayed emesis total dose (acute and delayed) was 56 mg.154 The authors concluded
prevention based on the FDA approvals and phase 3 randomized dexamethasone offered a clear advantage over placebo for protection
trial.140 against chemotherapy-induced emesis in both acute and delayed
phases. There was incremental benefit when adding dexamethasone to
Rolapitant has an extended half-life and should not be administered at both 5-HT3 antagonist-containing regimens and non-5-HT3 antagonist
less than 2-week intervals. If oral rolapitant is given on day 1 for either regimens. Although data suggested that dexamethasone was superior
HEC or MEC, no further NK1 RA is needed on days 2 and 3. Similar to to 5-HT3 antagonists for protection against delayed emesis, there was a
the other NK1 RAs, rolapitant improves control for delayed emesis lack of a strong dose/response relationship. The authors could not rule
when compared with traditional antiemetic regimens. Rolapitant does out a subtle dose/response relationship for total doses less than 20 mg
not inhibit or induce CYP3A4; therefore, the dexamethasone dose does of dexamethasone, but even low doses showed clear efficacy.
not need to be adjusted (see Dexamethasone in this Discussion). In
addition, there are fewer drug interactions with rolapitant when

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The Italian Group for Antiemetic Research conducted 2 randomized, every 6 hours for 4 doses, starting at the same time of the
double-blinded, multicenter trials to determine the dose of chemotherapy; 2) for arm B, 24 mg of intravenous single-dose
dexamethasone to be given on day 1 of an antiemetic regimen.155,156 dexamethasone before chemotherapy; or 3) for arm C, 8 mg of
The first trial was conducted in chemo-naive patients receiving 50 intravenous single-dose dexamethasone before chemotherapy. All
mg/m2 or more of cisplatin, which is considered HEC.155 Intravenous patients received oral dexamethasone 4 mg BID on days 2 to 5.
dexamethasone day 1 doses were 4, 8, 12, and 20 mg (approximately Complete protection from acute vomiting and nausea was 84.6% and
130 patients/arm). All patients received the following: 1) ondansetron 8 66.7%, 83.6% and 56.9%, and 89.2% and 61.0% for arms A, B, and C,
mg intravenous on day 1; 2) metoclopramide 20 mg oral every 6 hours respectively. Side effects and control of delayed vomiting and nausea
on days 2 to 4; and 3) dexamethasone 8 mg oral BID on days 2 and 3, were not significantly different among the 3 groups. The authors
followed by 4 mg oral BID on day 4. Complete protection from emesis concluded that 8 mg of intravenous dexamethasone is the best dose
and nausea was 69.2% and 60.9%; 69.1% and 61.0%; 78.5% and when using dexamethasone in antiemetic regimens for patients
66.9%; and 83.2% and 71.0% for the 4-, 8-, 12-, and 20-mg receiving chemotherapy with these agents. Of note, 95% of the patients
dexamethasone doses, respectively. For protection against acute were being treated for breast cancer; thus, most patients were women.
emesis, the 20-mg dose of dexamethasone was statistically significant
when compared to the 4- and 8-mg doses. However, the 20-mg and the Information from early studies with oral aprepitant-containing regimens
12-mg doses of dexamethasone were equivalent for protection against suggested that the dose of dexamethasone should be decreased from
acute emesis. The 20-mg dose of dexamethasone was not significantly 20 mg to 12 mg because of a near doubling in the AUC of
different from the other doses for protection against acute nausea. dexamethasone, presumably due to CYP3A4 inhibition (see Drug
Adverse effects and control of delayed emesis and nausea were similar Interactions in this Discussion). This information, along with the
among the 4 groups. previous data showing a lack of a dose/response correlation, was the
basis of the NCCN Panel’s recommendation of 12 mg of
The second study compared 3 dosing regimens of dexamethasone on dexamethasone as the day 1 dose for all emetic categories when using
day 1 in patients receiving anthracyclines, cyclophosphamide, or NK1 RAs. The studies by the Italian Group were done before the NK1
carboplatin, either alone or in combination with other chemotherapy RAs were available, and dose-finding studies for dexamethasone on
agents, which previously were considered to be MEC.156 Note that AC day 1 in combination with NK1 RAs and 5-HT3 antagonists have not
regimens are now considered to be HEC by the NCCN Panel; likewise, been done.155,156
carboplatin with an AUC of 4 or more is now considered to be HEC. For
the prevention of acute emesis, during the first 24 hours, one of the The doses and schedules for dexamethasone in the NCCN Guidelines
following dexamethasone regimens was used in combination with 8 mg are mainly based on the doses and schedules used in the clinical trials
of intravenous ondansetron: 1) for arm A, 8 mg of intravenous for each regimen. However, the NCCN Panel feels that dexamethasone
dexamethasone before chemotherapy plus 4 mg oral dexamethasone doses may be individualized; lower doses, frequency, or even
elimination of dexamethasone on subsequent days may be acceptable

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based on patient characteristics (category 2B) (see the algorithm). postchemotherapy; 88.6% vs. 84.3%; P = .262) and delayed phases
Dexamethasone-sparing strategies may be appropriate for patients (days 2-5; 68.7% vs. 77.7%; P = .116).158
receiving MEC or non-cisplatin HEC; limiting dexamethasone to day 1
only in these patients may be especially appropriate for patients with Olanzapine
few identifiable risk factors for CINV or for those intolerant to steroids Olanzapine is an atypical antipsychotic agent that is also useful as an
(see the NCCN Guidelines for Antiemesis).106,157-159 Dexamethasone is antiemetic agent; it is an antagonist of multiple receptors involved in
associated with side effects, such as insomnia. For the 2018 update, CINV including dopamine, serotonin, histamine, and
the NCCN Panel simplified the dosing for dexamethasone for the acetylcholine-muscarine.20 An olanzapine-containing antiemetic 3-drug
intravenous HEC and MEC regimens. For the regimen with dexamethasone and palonosetron is effective for
olanzapine/palonosetron/dexamethasone regimen for HEC and MEC, preventing acute and delayed emesis as described in the following
the dose of dexamethasone was decreased to 12 mg PO/IV for day 1, sections.20,160-168 An olanzapine-containing 4-drug antiemetic regimen is
because all the other antiemetic regimens use this dexamethasone also effective for preventing acute and delayed emesis.169 The NCCN
dose on day 1. Previously, the panel had recommended a Panel recommends (category 1) olanzapine-containing 3-drug or 4-drug
dexamethasone dose of 20 mg PO/IV on day 1 in the 3-drug olanzapine regimens for both HEC and MEC based on the clinical trial data as
regimen. For all the HEC regimens, the panel also simplified the dosing described in the following sections.36 For the 2018 update, the NCCN
for delayed dexamethasone to 8 mg PO/IV daily on days 2 to 4 Panel added a caveat that olanzapine can be substituted for
(previously, some of the HEC regimens had used twice-daily dosing of dexamethasone if patients cannot tolerate dexamethasone (eg,
dexamethasone). For the 2018 update, the NCCN Panel feels that if diabetics).
patients cannot tolerate dexamethasone, it can be replaced with
Common side effects with olanzapine include fatigue, drowsiness, and
olanzapine.
sleep disturbances. Olanzapine should be used with caution in elderly
When dexamethasone is used with palonosetron for MEC, a patients (see boxed warning/label indication regarding death in patients
randomized trial suggests that the dose of dexamethasone can be with dementia-related psychosis and additional warnings and
decreased to 8 mg on day 1 and also eliminated on days 2 to 3.106 A precautions about type II diabetes and hyperglycemia).170 Data suggest
similar phase 3 trial assessed palonosetron with dexamethasone on day that a 5-mg dose of olanzapine may be considered in elderly or
1 only versus palonosetron (day 1) with dexamethasone on days 1 to 3 over-sedated patients.171-173 Parenteral olanzapine use combined with
in women receiving MEC regimens.158 For women receiving parenteral benzodiazepine use is contraindicated to avoid excessive
dexamethasone on day 1 only (n = 166), the overall CR rates were sedation, hypotension, and decreased respiration; toxicity may occur
67.5% versus 71.1% for those receiving dexamethasone on days 1 to 3 with this combination regardless of the routes of administration.174 To
(n = 166; difference -3.6% [95% CI, -13.5-6.3]). There was no difference avoid excessive dopamine blockade, caution is recommended when
in CR rates between the 2 regimens during the acute (0-24 hours giving olanzapine concurrently with metoclopramide or haloperidol.

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Three-Drug Regimen dexamethasone dose of 20 mg PO/IV on day 1 in the 3-drug olanzapine

An olanzapine-containing antiemetic 3-drug regimen with regimen based on the clinical trial data.167 The panel also agreed that
dexamethasone and palonosetron is effective for preventing acute and palonosetron should be used in the 3-drug olanzapine regimen; no data
delayed emesis based on phase 3 trials, phase 2 trials, and a are available to support substituting any of the other 5-HT3 antagonists.
meta-analysis.20,160-168 A randomized phase 3 trial evaluated the
effectiveness of an olanzapine (10 mg oral days 1-4) regimen versus an Four-Drug Regimen
oral aprepitant (125 mg oral day 1, 80 mg oral days 2, 3) regimen with A recent phase 3 randomized trial assessed adding olanzapine or
dexamethasone 8 mg on days 2 to 4 for preventing acute and delayed placebo to an antiemetic regimen of oral aprepitant or fosaprepitant, a
emesis in patients (N = 251) receiving HEC (cisplatin, or AC regimens); 5-HT3 antagonist, and dexamethasone for patients receiving HEC.169
both treatment arms included palonosetron (0.25 mg intravenous) and The data showed that the 4-drug regimen with olanzapine increased the
dexamethasone administered on day 1.167 The CR (no emesis, no CR rate (no emesis, no rescue) when compared with placebo during 3
rescue) rate was similar between the olanzapine and oral aprepitant time periods (<24 hours after chemotherapy, 25-120 hours, and the
regimens, both during the acute (97% vs. 87%) and delayed (77% vs. overall 120 hours: 86% vs. 65% [P < .001], 67% vs. 52% [P = .007], and
73%) periods. The proportion of patients without nausea was similar for 64% vs. 41% [P < .001], respectively). In addition, more patients
the acute period (87% in each study arm), but the olanzapine regimen receiving the 4-drug olanzapine regimen had no chemotherapy-induced
was associated with a higher rate of nausea control during the delayed nausea when compared with placebo during the 3 time periods (<24
period (69% vs. 38%) compared with the oral aprepitant regimen.167 A hours after chemotherapy, 25-120 hours, and 120 hours: 74% vs. 45%
systematic review summarized the phase 1 and 2 studies of olanzapine [P = .002], 42% vs. 25% [P = .002], and 37% vs. 22% [P = .002],
for preventing acute and delayed emesis.20 Across 4 studies (201 respectively). Based on this trial, the NCCN Panel recommends
patients), the CR rate was 97.2%, 83.1%, and 82.8 % for the acute, (category 1) the 4-drug olanzapine regimen as a first-line regimen. In
delayed, and overall phases, respectively. Other studies have also addition, clinicians can consider switching patients to the 4-drug
showed the value of olanzapine for delayed, refractory, and olanzapine regimen if patients have significant emesis after the first
breakthrough emesis and nausea.162-165,172 cycle of HEC when receiving other antiemetic regimens such as 1) NK1
RA-containing regimens; or 2) the 3-drug olanzapine regimen
The NCCN Panel recommends (category 1) an olanzapine-containing (olanzapine/dexamethasone/palonosetron).36 For the 2018 update, the
3-drug regimen for both HEC and MEC based on the phase 3 and panel agreed that any NK1 RA (ie, not just fosaprepitant or oral
phase 2 trials. As previously mentioned, the NCCN Panel decided to aprepitant) could be used in the 4-drug HEC regimen on day 1
decrease the dose of dexamethasone to 12 mg PO/IV on day 1 for the (olanzapine/ NK1 RA/5-HT3/dexamethasone), because all of the NK1
3-drug regimen with olanzapine/palonosetron/dexamethasone, because RAs are effective if the appropriate dose is used. Thus, aprepitant
all the other antiemetic regimens use a dexamethasone dose of 12 mg injectable emulsion, oral rolapitant, or NEPA may be used in the 4-drug
PO/IV on day 1. Previously, the panel had recommended a

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olanzapine regimen on day 1; however, none of these agents is Cancer Treatment from the National Cancer Institute).175 Suggestions
continued on days 2 to 4. include eating small frequent meals, food that is easy on the stomach,
full liquid foods, and food at room temperature; patients can also avoid
Treatment Issues foods that make them feel nauseated.
As new data on the use of antiemetics in patients receiving anticancer
therapy become available, clinicians should consider these data when Prevention of Acute and Delayed Emesis
caring for such patients. In contrast to other NCCN Guidelines in which To prevent acute emesis, antiemetic therapy should start before the
most of the recommendations are category 2A, many of the administration of chemotherapy and then should cover the first 24
recommendations for antiemetic management are classified as category hours. In the NCCN Guidelines for Antiemesis, the specific antiemetic
1, reflecting the large number of randomized controlled trials that have regimens are described for patients receiving highly emetogenic
focused on antiemetic management. These NCCN Guidelines include a intravenous drugs, moderately emetogenic intravenous drugs, low
section on pharmacologic considerations for the different antiemetics emetogenic intravenous drugs, and minimally emetogenic intravenous
describing: 1) the major classes of antiemetic agents; 2) clinical pearls drugs. Emesis prevention for oral chemotherapeutic agents is also
associated with the different types of agents; and 3) possible drug-drug described in the NCCN Guidelines. This section discusses
or drug-disease interactions among the different antiemetic agents (see prechemotherapy and postchemotherapy emesis prevention rather than
Pharmacologic Considerations for Antiemetic Prescribing in the NCCN primary treatment.
Guidelines for Antiemesis).
Prechemotherapy Emesis Prevention
Principles of Emesis Control The NCCN Guidelines specify different prophylactic antiemetic
These principles are described in the algorithm and are summarized regimens for cancer patients receiving anticancer therapy of different
here (see Principles of Emesis Control for the Cancer Patient in the emetogenic potential (ie, high, moderate, low, minimal). Prophylactic
NCCN Guidelines for Antiemesis). The goal of emesis control is to antiemetics should be administered before anticancer therapy. The
prevent nausea and/or vomiting. Antiemetic regimens should be chosen recommendations for prophylactic antiemetic treatment include drug
based on the drug with the highest emetic risk in the chemotherapy dosages. The guidelines reflect accumulating experience with the
regimen, previous experience with antiemetics, and patient-specific risk 5-HT3 antagonists, demonstrating their effectiveness in a range of
factors.11 Patients need to be protected throughout the entire period of doses. Unless indicated, the order of listed antiemetics in the NCCN
risk, which lasts for at least 3 days for high emetic risk agents and 2 Guidelines does not reflect preference.
days for moderate emetic risk agents after the last dose of anticancer Highly emetogenic intravenous drugs in the NCCN Guidelines include
therapy. In addition to using antiemetic regimens, patients can adjust
carboplatin (AUC ≥ 4), carmustine (>250 mg/m2), cisplatin (any dose),
their eating habits and adopt other lifestyle measures that may alleviate cyclophosphamide (>1500 mg/m2), dacarbazine (any dose), doxorubicin
nausea and vomiting (see Eating Hints: Before, During, and After (≥ 60 mg/m2), epirubicin (> 90 mg/m2), ifosfamide (≥ 2 g/m2 per dose),

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mechlorethamine (any dose), streptozocin (any dose), or AC Several drugs listed as moderately emetogenic in the NCCN Guidelines
combination regimens at any dose (eg, doxorubicin or epirubicin with may be highly emetogenic in certain patients (eg, carboplatin [AUC < 4],
cyclophosphamide). Most of these drugs are also considered highly carmustine [≤250 mg/m2], dactinomycin, daunorubicin, doxorubicin [<60
emetogenic by the Multinational Association of Supportive Care in mg/m2], epirubicin [≤90 mg/m2], ifosfamide [<2 g/m2], irinotecan,
Cancer/European Society for Medical Oncology (MASCC/ESMO) methotrexate [≥250 mg/m2], oxaliplatin, trabectedin). AC-based
guidelines.9,176 The NCCN Guidelines for highly, moderately, low, and regimens were reclassified in 2011 as highly emetogenic in the ASCO
minimally emetogenic agents differ slightly from the MASCC/ESMO antiemetic guidelines.91
guidelines based on the experience and expertise of the panel
members.177-180 The NCCN Guidelines recommend several different antiemetic regimen
options for patients receiving highly emetogenic agents. Recommended
The NCCN Panel recently changed the emetogenic classification for antiemetic regimens contain 5-HT3 antagonists, dexamethasone, NK1
carboplatin. When dosed at an AUC of 4 or more, carboplatin is now RAs (such as aprepitant [or fosaprepitant] and rolapitant), and
considered highly emetogenic; carboplatin at an AUC of less than 4 is olanzapine. If needed, lorazepam, an H2 blocker, or a proton pump
now considered moderately emetogenic. The NCCN Panel revised the inhibitor may also be added (alone or in any combination) to all of these
classification of carboplatin based on published data suggesting that regimens.34,39,120 Regimens for day 1 therapy (all are category 1) include
carboplatin, while less emetogenic than cisplatin, is perhaps on the those containing dexamethasone, a 5-HT3 antagonist, and one of the
higher end of emetogenic potential within the MEC classification.181 following: aprepitant, fosaprepitant, or rolapitant. Other antiemetic
Several trials and a subset analysis have shown benefit, in terms of CR regimens (category 1) for highly emetogenic agents on day 1 include: 1)
in the overall and delayed phases, of adding an NK1 RA to the 2-drug NEPA and dexamethasone; 2) olanzapine, palonosetron, and
regimen of 5-HT3 antagonist and dexamethasone for the prevention of dexamethasone; or 3) olanzapine, aprepitant or fosaprepitant,
CINV associated with carboplatin-based regimens.140,181-183 All of the palonosetron, and dexamethasone (see Olanzapine in this Discussion).
commercially available NK1 RAs have an FDA-approved indication for Note that the regimens and doses are often modified on days 2 to 4
MEC, but previous NCCN Guidelines have supported the addition of an after anticancer therapy.
NK1 RA only for select patients receiving MEC with additional CINV risk
factors or for those who had failed previous therapy with a steroid and Although it is not recommended as a single agent, lorazepam is a useful
5-HT3 antagonist alone. The panel did not want to create a “carboplatin adjuvant because it decreases anxiety.39,151 Lorazepam is also
subset” within the MEC classification; therefore, carboplatin at an AUC recommended for patients who are at risk for anticipatory nausea and/or
of 4 or more was escalated to the HEC classification, where a vomiting (see Anticipatory Emesis Prevention/Treatment in the
triple-drug regimen (NK1 RA plus 5-HT3 antagonist plus steroid) would algorithm). Antacid therapy (eg, proton pump inhibitors, H2 blockers)
be preferred for all patients. should be considered if patients have dyspepsia, because patients
sometimes have difficulty discriminating heartburn from nausea. If
appropriate, lorazepam (0.5-2 mg every 6 hours on days 1-4; either

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oral, intravenous, or sublingual) may be used with each of these fosnetupitant, or rolapitant; or 2) olanzapine, palonosetron, and
regimens. dexamethasone. If needed, lorazepam, an H2 blocker, or a proton
pump inhibitor may be added (alone or in any combination) to these
For intravenous regimens with high emetogenic potential, aprepitant is regimens.6 Netupitant (or fosnetupitant) is only available combined with
used at an oral dosage of 125 mg on day 1 and then 80 mg on days 2 palonosetron (NEPA) and not as a single agent. As per high emetic risk
and 3. When given with aprepitant, dexamethasone is used at a dosage prevention, an NK1 RA should be added (to dexamethasone and a
of 12 mg on day 1; the dexamethasone dose can be oral or 5-HT3 antagonist regimen) for select patients with additional risk factors
intravenous. Note that aprepitant injectable emulsion or intravenous or failure of previous therapy with a steroid and 5-HT3 antagonist alone.
fosaprepitant may be substituted for oral aprepitant on day 1 only. As Intravenous fosaprepitant or aprepitant injectable emulsion may be
previously discussed, a phase 3 randomized trial suggested that substituted for oral aprepitant on day 1 only. The NCCN Guidelines
palonosetron is preferred over granisetron in combination with recommend the use of 5-HT3 antagonists as one of several options to
dexamethasone for HEC.71 This trial has been criticized because: 1) the prevent delayed emesis for MEC. Any one of the 5-HT3 antagonists can
control arm was not adequately dosed; thus, the trial “stacked the deck” be used in the first regimen for day 1; however, preferred 5-HT3s
in favor of palonosetron; 2) a larger non-FDA-approved dose of include palonosetron or subcutaneous granisetron extended-release
palonosetron was used (ie, 0.75 mg intravenous); and 3) aprepitant was injection when an NK1 RA is not included, as previously mentioned.71,92
not used in this study. Therefore, the NCCN Guidelines do not
recommend palonosetron as the preferred 5-HT3 antagonist for HEC. The antiemetic regimen for low emetogenic intravenous drugs includes
As previously noted, an alternative antiemetic regimen in the setting of dexamethasone, prochlorperazine, metoclopramide, or orally
intravenous HEC includes olanzapine (10 mg oral days 1-4), administered 5-HT3 antagonists (see the algorithm). Lorazepam, an H2
palonosetron (0.25 mg intravenous day 1 only), and dexamethasone blocker, or a proton pump inhibitor may also be added (alone or in any
(20 mg intravenous day 1 only).167 combination) to all of these agents. When using prochlorperazine or
metoclopramide, patients should be monitored for dystonic
A Canadian meta-analysis suggested that the use of 5-HT3 antagonists reactions.185-187 Diphenhydramine can be used for the treatment of
(ie, ondansetron) on days 2 to 4 to prevent delayed emesis was not cost dystonic reactions.188,189 Benztropine may be used in patients who are
effective; however, ondansetron (when used alone) did protect against allergic to diphenhydramine.186
delayed emesis in this meta-analysis.184 Palonosetron was not
assessed in these studies. The NCCN Guidelines do not recommend a The emetogenic potential of oral anticancer agents is shown in the
5-HT3 antagonist for the prevention of CINV on days 2 to 4 for HEC. NCCN Guidelines. Oral antiemetic prophylaxis is recommended for the
following oral agents, which are of high or moderate emetic risk:
The NCCN Guidelines recommend several antiemetic regimens for altretamine, busulfan (≥4 mg/d), ceritinib, crizotinib, cyclophosphamide
intravenous MEC, including: 1) dexamethasone and a 5-HT3 antagonist (≥100 mg/m2/d), enasidenib, estramustine, etoposide, lenvatinib,
with or without NK1 RAs such as aprepitant, fosaprepitant, netupitant, lomustine (single day), midostaurin, mitotane, niraparib, olaparib,

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panobinostat, procarbazine, rucaparib, temozolomide (>75 mg/m2/d or chemotherapy-induced nausea when compared with placebo during the
≤75 mg/m2/d with concurrent radiotherapy), and trifluridine/tipiracil. For delayed time period (ie, 25-120 hours, 42% vs. 25% [P = .002]). Nausea
high or moderate emetic risk oral anticancer agents, recommended was also reduced with the 4-drug regimen with olanzapine during the
prophylaxis includes single-agent antiemetic therapy with an oral 5-HT3 acute phase and the overall time period when compared with placebo.
antagonist (such as granisetron, ondansetron, or dolasetron). For low or The data showed that the 4-drug regimen with olanzapine increased the
minimal emetic risk oral anticancer agents, recommended oral agents CR rate (no emesis, no rescue) during the delayed time period when
are given on an as-needed basis only (ie, PRN) and include oral 5-HT3 compared with placebo (67% vs. 52% (P = .007).
antagonists, metoclopramide, or prochlorperazine; the NCCN Panel
recently deleted haloperidol. Lorazepam, an H2 blocker, or a proton Delayed Emesis
pump inhibitor may also be added (alone or in any combination) if The best management for delayed emesis is prevention.190 A recent
needed to all of these high/moderate or low/minimal emetic risk survey among oncology nurses found that there is low adherence (only
regimens. Some patients receiving oral anticancer therapy of 25%) to antiemetic guidelines for preventing delayed emesis.191 For
low/minimal emetogenicity may experience nausea/vomiting; these HEC, the prophylactic treatment on days 2 to 4 depends on which
patients should be escalated to the next higher level of antiemetic antiemetics were used before anticancer therapy. Fosaprepitant,
therapy in future cycles of anticancer therapy. aprepitant injectable emulsion, oral rolapitant, granisetron
extended-release injection, granisetron transdermal patch,
Postchemotherapy/Delayed Emesis Prevention palonosetron, or NEPA are used on day 1 only, because they are
effective for an extended period of time. For the 2018 update, the
Delayed Nausea
NCCN Panel deleted a footnote that previously stated that some NCCN
Many antiemetic regimens are very useful for decreasing vomiting but
Member Institutions used a 5-HT3 RA on days 2 to 4 in addition to a
are less useful for decreasing delayed nausea that many patients
steroid and NK1 antagonist therapy. The option of adding an 5-HT3 RA
experience when taking emetogenic chemotherapy.10,21,22,26 Patients
is available for breakthrough treatment (ie, rescue).
rank nausea as more of a problem than vomiting.10 Data suggest that
rolapitant and netupitant are effective at decreasing delayed If oral aprepitant and/or olanzapine was used on day 1, then oral
nausea.134,136,140,141 Palonosetron and subcutaneous granisetron aprepitant and/or olanzapine is continued on days 2 and 3.
extended-release injection are the preferred 5-HT3 antagonists for Dexamethasone is continued on days 2 to 4 for all regimens. However,
preventing delayed nausea associated with MEC. 5-HT3 antagonists are given on day 1 only for HEC. There are several
possible HEC antiemetic regimens on days 2 to 4, including: 1) oral
A phase 3 randomized trial assessed adding olanzapine or placebo to
aprepitant (if used on day 1) with dexamethasone and with or without
an antiemetic regimen of fosaprepitant or oral aprepitant, a 5-HT3
olanzapine; or 2) olanzapine only. If needed, each of these regimens
antagonist, and dexamethasone for patients receiving HEC.169 More
may also include lorazepam, an H2 blocker, or a proton pump inhibitor
patients receiving the 4-drug regimen with olanzapine had no
(alone or in any combination). It is important to note that the doses are

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decreased when used on days 2 to 3 of oral aprepitant (80 mg oral) and algorithm). Generally, it is much easier to prevent nausea and/or
on days 2 to 4 of dexamethasone (8 mg oral or intravenous) when vomiting than to treat it. Thus, routine around-the-clock administration of
compared with the doses given on day 1. However, the dose of antiemetics should be strongly considered to prevent emesis, rather
olanzapine is not decreased on days 2 to 4. than PRN (as required) dosing. The general principle of breakthrough
treatment is to add an additional agent as needed from a different drug
The antiemetic regimens in the NCCN Guidelines include different class.34 Some patients may require several agents using different
options on days 2 to 3 for MEC.34,39,190 Postchemotherapy emetic mechanisms of action. The oral route may not be feasible because of
prevention depends on which antiemetics were used before ongoing vomiting; therefore, rectal, topical, subcutaneous, or
chemotherapy. If oral aprepitant and/or olanzapine was used on day 1, intravenous therapy is often required. Multiple concurrent agents,
then oral aprepitant and/or olanzapine is continued on days 2 and 3; perhaps in alternating schedules or by alternating routes, may be
however, granisetron extended-release injection, granisetron necessary. Another option is to consider changing from the current
transdermal patch, palonosetron, aprepitant injectable emulsion, NK1-containing regimen to an olanzapine-containing regimen, or vice
fosaprepitant, oral rolapitant, or NEPA are not given on days 2 and 3.73 versa, prior to the next cycle of anticancer therapy. Olanzapine is
Antiemetic therapy on days 2 and 3 may just be single agents. There possibly more effective than NK1-antagonist-containing regimens for
are several possible MEC antiemetic regimens on days 2 to 3, preventing nausea.20,167,168
including: 1) oral aprepitant (if used on day 1) with or without
dexamethasone; 2) dexamethasone only; 3) ondansetron, granisetron, Haloperidol, metoclopramide, olanzapine, scopolamine transdermal
or dolasetron only (if no NK1 RA, granisetron extended-release patch, corticosteroids, and agents such as lorazepam may be added for
injection, granisetron transdermal patch, or palonosetron was given on breakthrough treatment to the current antiemetic regimen. In a
day 1); or 4) olanzapine only.190 If needed, each of these regimens may randomized phase 3 trial, the effectiveness of olanzapine (10 mg/d oral
also include lorazepam, an H2 blocker, or a proton pump inhibitor for 3 days) as treatment for breakthrough emesis was compared with
(alone or in any combination). Again, the doses are decreased when metoclopramide in patients treated with HEC who developed
used on days 2 to 3 of both oral aprepitant (80 mg oral) and breakthrough emesis or nausea despite antiemetic prophylaxis
dexamethasone (8 mg oral or intravenous) when compared with the (comprising palonosetron, dexamethasone, and fosaprepitant; n = 108
doses given on day 1. However, the dose of olanzapine is not evaluable).192 Patients were observed for emesis and nausea during the
decreased on days 2 and 3. 72 hours after treatment with olanzapine or metoclopramide. During this
observation period, more patients had no emesis (70% vs. 31%; P <
Breakthrough Nausea and/or Vomiting Treatment .01) and no nausea (68% vs. 23%; P < .01) with olanzapine than with
Breakthrough nausea or emesis presents a difficult situation, because metoclopramide.192 Thus, olanzapine was more effective in controlling
refractory ongoing nausea and/or vomiting is often challenging to breakthrough emesis and nausea compared with metoclopramide in this
reverse (see Principles for Managing Breakthrough Emesis in the patient population. The MASCC/ESMO Guidelines recommend

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olanzapine for breakthrough emesis.193 The NCCN Panel recommends heartburn from nausea, addition of antacid therapy (eg, proton pump
olanzapine (category 1) for breakthrough emesis if olanzapine was not inhibitors, H2 blockers) should be considered.
used on days 1 to 4 as part of a prophylactic regimen. This category 1
recommendation is based on the magnitude of superiority of olanzapine Radiation-Induced Nausea and/or Vomiting
over metoclopramide in the randomized phase 3 trial.192 Prophylaxis for RT-induced nausea and/or vomiting is based on the site
of RT and whether it is combined with anticancer therapy.36,37,195,196
Dronabinol and nabilone (which are cannabinoids) are approved by the When RT is combined with anticancer therapy, prophylaxis is dictated
FDA for refractory nausea and vomiting when patients have not by the emetogenic potential of the chemotherapy regimen. ASCO and
responded to conventional antiemetic agents. Note that dronabinol oral MASCC/ESMO guidelines state that total body irradiation is associated
solution (5 mg/mL) and dronabinol capsules are not bioequivalent. with the highest risk for emesis and that upper abdominal RT is
Dronabinol oral solution has greater oral bioavailability than dronabinol associated with moderate risk.36,37,197 A meta-analysis suggests that
capsules (2.1 mg oral solution = 2.5 mg capsules).194 Recommended 5-HT3 antagonists are the preferred agents for preventing RT-induced
starting doses are dronabinol oral solution (4.2 mg/m2) or dronabinol vomiting.198
capsules (5 mg/m2) both given 3 to 4 times daily. Lower doses are
recommended in elderly patients. Patients undergoing RT to the upper abdomen may receive antiemetic
prophylaxis with oral ondansetron or oral granisetron, with or without
Before administering the next cycle of anticancer therapy, the patient oral dexamethasone.9,37 A randomized trial compared oral ondansetron
should be reassessed for other possible non-anticancer therapy-related with placebo in patients receiving daily fractionated radiotherapy
reasons for breakthrough emesis with the current cycle (eg, brain including the abdomen. In this study, 67% of patients given
metastases, electrolyte abnormalities, tumor infiltration of the bowel or ondansetron had complete control of emesis compared with 45% of
other GI abnormality, excessive secretions [eg, seen in patients with patients who received placebo (P < .05).199 A randomized trial showed
head and neck cancer], other comorbidities; see Principles for that the addition of oral dexamethasone (4 mg daily) to the ondansetron
Managing Breakthrough Emesis and Principles of Emesis Control for regimen decreases emesis and nausea, although the effect was
the Cancer Patient in the algorithm). Adequate hydration or fluid modest.200 Patients receiving ondansetron/dexamethasone had better
repletion should be ensured, and any possible electrolyte abnormalities complete control of emesis (23% vs. 12%; P = .02) and a lower average
should be assessed and corrected. Before the next cycle of anticancer nausea score (0.28 vs. 0.39; P = .03) when compared with those
therapy, if the antiemetic regimen (both the day 1 and post-anticancer receiving ondansetron alone. Another randomized trial in patients
therapy) did not protect the patient during the present cycle, the receiving radiotherapy to the upper abdomen found that oral granisetron
antiemetic regimen should be assessed and alternatives should be decreased emesis and nausea when compared with placebo.201
considered (see Principles for Managing Breakthrough Emesis in the
algorithm). Because patients sometimes have difficulty discriminating The NCCN Panel recommends that patients undergoing total body
irradiation or upper abdomen RT receive antiemetic prophylaxis with

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either ondansetron or granisetron; either agent can be given with or debilitating disease, and those with advanced liver disease (see
without oral dexamethasone.9,37,202 Treatment of breakthrough prescribing information). This dose may be gradually increased if
RT-induced emesis is similar to chemotherapy-induced emesis. needed. Note that the elderly are especially sensitive to the effects of
Patients who experience breakthrough nausea and/or vomiting may be benzodiazepines. The dose should be gradually reduced when
treated with a different class of agent, or with ondansetron or decreasing or discontinuing lorazepam therapy. For the 2018 update,
granisetron if they did not receive primary prophylaxis (see the NCCN Panel deleted alprazolam, because rebound anxiety is more
Breakthrough Treatment for Chemotherapy-Induced Nausea/Vomiting prevalent with alprazolam than with lorazepam. The panel added a
in the algorithm). caveat that lorazepam should be used with caution in patients receiving
scheduled opioids.
Anticipatory Nausea and/or Vomiting
About 20% of patients develop anticipatory nausea and/or vomiting.203 Multiday Emetogenic Chemotherapy Regimens
However, the rate of anticipatory nausea and/or vomiting appears to be Patients receiving multiday chemotherapy are at risk for both acute and
decreasing (when compared with older studies) with current use of delayed nausea and/or vomiting based on the emetogenic potential of
more effective antiemetic regimens.9 The most effective way to treat the individual chemotherapy agents and their sequence.34,214-218 It is
anticipatory nausea and/or vomiting is to prevent it by using optimal difficult to recommend a specific antiemetic regimen for each day,
antiemetic therapy during every cycle of treatment.34,36,204,205 The NCCN especially because acute and delayed emesis may overlap after the
Guidelines recommend that patients avoid strong smells that may initial day of chemotherapy until the last day of chemotherapy. The
precipitate symptoms. Behavioral therapy has been used in patients period of risk for delayed emesis following completion of chemotherapy
with anticipatory nausea and/or vomiting.36,206-211 For the 2018 update, also depends on the specific regimen and the emetogenic potential of
the NCCN Panel added yoga, cognitive distraction, progressive muscle the last chemotherapy agent administered in the regimen. For
relaxation, and biofeedback to the list of useful behavioral therapy multi-drug regimens, antiemetic therapy should be selected based on
options. Systematic desensitization may also be helpful.207 Hypnosis the drug with the highest emetic risk.36 General principles for managing
with guided imagery is another behavioral technique that has shown multiday emetogenic chemotherapy regimens recommended by the
some success in treating this condition.208 NCCN Panel are described in the algorithm (see Principles of Managing
Multiday Emetogenic Chemotherapy Regimens in the algorithm). For
The antianxiety agent, lorazepam has been combined with antiemetics antiemetic prophylaxis of multiday emetogenic chemotherapy regimens
for anticipatory nausea and/or vomiting.205,212,213 The usual starting dose (eg, cisplatin-containing regimens), the combination of a 5-HT3
of lorazepam for anxiety is 0.5 to 2 mg orally, beginning on the night antagonist with dexamethasone was previously recommended in the
before treatment and then repeated the next day 1 to 2 hours before 2011 MASCC/ESMO guidelines.9,34 The NCCN Guidelines and 2017
anticancer therapy begins. The usual starting dose of lorazepam is 0.5 MASCC/ESMO guidelines currently recommend a 3-drug regimen of a
mg orally for treatment of anxiety in patients who are elderly, those with 5-HT3 RA, oral aprepitant, and dexamethasone as prophylaxis for

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multiday anticancer regimens with MEC or HEC regimens.193 The The need for repeat dosing with palonosetron, either daily or less
clinical trial data to support these recommendations are described in the frequently, in the setting of multiday chemotherapy is not yet known. In
following sections. one study, patients receiving highly emetogenic multiday
cisplatin-based chemotherapy for testicular cancer (N = 41) received
Dexamethasone
multiday dosing of palonosetron (0.25 mg intravenous on days 1, 3, and
Dexamethasone should be administered once daily either orally or 5) and dexamethasone, which prevented nausea and emesis in most
intravenously for every day of MEC or HEC and continued for 2 to 3 patients on days 1 to 5 (51%) and on days 6 to 9 (83%); the most
days after chemotherapy for regimens that are likely to cause significant common adverse events were mild headache and constipation.223 A
delayed emesis. However, dexamethasone should not be added when study assessed palonosetron given for 1, 2, or 3 days in combination
the chemotherapy regimen already includes a corticosteroid. The use of with dexamethasone for patients receiving multiday high-dose
steroids as antiemetics is not recommended when using treatment chemotherapy prior to stem cell transplantation for multiple myeloma (N
regimens containing drugs that elicit an immune response such as = 73); during the 7-day emesis prevention period, about 40% to 45% of
aldesleukin, interferon, ipilimumab, nivolumab, atezolizumab, patients had no emesis (with no differences observed between
pembrolizumab, avelumab, or durvalumab.219 Dexamethasone-sparing palonosetron treatment groups), and no serious adverse events were
strategies or replacing dexamethasone with olanzapine are options for reported. However, even among the patients who received either 2 or 3
patients who cannot tolerate steroids. days of palonosetron, only 20% had a CR (ie, emesis free without
5-HT3 Antagonists
rescue medication).118 Another study found that a
For multiday chemotherapy regimens, a 5-HT3 antagonist should be palonosetron/dexamethasone regimen appeared to be more effective
administered each day before the first dose of MEC or HEC. for multiday chemotherapy than an ondansetron/dexamethasone
Intravenous palonosetron, subcutaneous granisetron or transdermal regimen; patients received a second dose of palonosetron for
granisetron may be used before the start of a 3-day chemotherapy breakthrough emesis, which was effective in 67% of patients who
regimen instead of multiple daily doses of oral or intravenous 5-HT3 experienced nausea or vomiting.220 A review also cited the value of
antagonists.220,221 Data regarding repeat dosing with subcutaneous palonosetron for patients receiving multiday chemotherapy.224 Further
granisetron for multiday regimens is unknown. Repeat dosing of studies are needed to define whether a need exists for repeat dosing of
palonosetron (0.25 mg intravenous) is likely to be safe, based on the palonosetron in the setting of multiday chemotherapy.
dose ranging phase 2 trial and the 3 phase 3 trials using palonosetron NK1 RAs
as a single fixed dose (0.75 mg intravenous).70,72,73,222 Compared to the The potential role of NK1 RAs in the antiemetic management of
approved dose of palonosetron of 0.25 mg intravenous, these higher multiday chemotherapy regimens has been investigated in several
doses were not associated with significantly different adverse events. studies.141,193,225-227 In one study, the addition of oral aprepitant to
granisetron and dexamethasone was evaluated in patients receiving
multiday HEC and MEC (N = 78). In this study, the 3-drug antiemetic

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regimen was given during chemotherapy; oral aprepitant and the overall study period was significantly higher with oral aprepitant
dexamethasone were given for an additional 2 days following compared with placebo (42% vs. 13%; P < .001). The CR rates were
chemotherapy.227 A CR (during the time period from day 1 until 5 days also higher with oral aprepitant during the acute phase (days 1-5; 47%
after chemotherapy) was observed in 58% and 73% of patients who vs. 15%; P< .001) and delayed phase (days 6-8; 63% vs. 35%; P <
received antiemetic regimens for HEC and MEC, respectively.227 In a .001).225 No statistically significant differences were observed between
multicenter phase 2 study, an extended 7-day regimen with oral treatment regimens in terms of nausea (based on patient-reported
aprepitant (125 mg oral day 1, 80 mg oral days 2-7) combined with a visual analog scale). Importantly, no increase in toxicity with oral
5-HT3 antagonist (days 1-5) and dexamethasone (8 mg oral days 1-8) aprepitant compared with placebo was reported.225
was evaluated in patients with germ cell tumors undergoing
chemotherapy cycles with 5-day cisplatin-based regimens (N = 50).226 NK1 antagonists may be used for multiday chemotherapy regimens
During cycle 1 of chemotherapy, 96% of patients had no emesis on day likely to be moderately or highly emetogenic and associated with
1 and 82% had no emesis during days 1 to 7. In addition, 71% had no significant risk for delayed nausea and emesis. As per the labeled
nausea on day 1 of cycle 1, and 27% had no nausea during days 1 to 7. indication, oral aprepitant should be administered 125 mg 1 hour prior to
More than 80% of patients had no emesis on any given day of any chemotherapy on day 1, along with a 5-HT3 antagonist and
given chemotherapy cycle. No unexpected or serious adverse events dexamethasone. Oral aprepitant 80 mg should be administered daily on
were reported.226 days 2 and 3 after the start of chemotherapy along with
dexamethasone.214 Repeated dosing of oral aprepitant over multiple
In a randomized phase 3 trial, the efficacy of adding oral aprepitant (vs. cycles of cisplatin-based chemotherapy appears to be feasible and well
placebo) to an antiemetic regimen with a 5-HT3 antagonist and tolerated; importantly, protection from emesis and from significant
dexamethasone was evaluated in patients with testicular cancer nausea was maintained during the subsequent cycles of emetogenic
undergoing 2 cycles of a 5-day cisplatin combination chemotherapy chemotherapy.214,225 Based on smaller studies, oral aprepitant 80 mg
regimen (n = 69 evaluable).225 Patients were randomized to receive oral may be safely administered beyond day 3 of initiating
aprepitant (125 mg oral day 3, 80 mg oral days 4-7) or placebo, chemotherapy.129,226 Alternatively, for HEC regimens, aprepitant
combined with a 5-HT3 antagonist (days 1-5) and dexamethasone (20 injectable emulsion 130 mg IV or fosaprepitant 150 mg intravenous with
mg days 1, 2) during the first cycle, and then crossed over to the dexamethasone may be given on day 1, with no need for oral aprepitant
opposite antiemetic regimen during the second cycle of chemotherapy. on days 2 and 3, with recommended dosing of dexamethasone on days
Thus, patients served as their own controls after receiving either oral 2 to 4. Data are not available for repeat dosing of fosaprepitant,
aprepitant or placebo for cycle 1. Palonosetron was excluded from the aprepitant injectable emulsion, NEPA, or rolapitant.
options for 5-HT3 antagonists due to its longer half-life.225 The primary
endpoint of the study was CR (no emetic episodes and no rescue
medication) during the overall study period (days 1-8). The CR rate for

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Summary because all of the NK1 RAs are effective if the appropriate dose is used.
The NCCN Guidelines for Antiemesis provide an overview of the Thus, aprepitant injectable emulsion, oral rolapitant, or NEPA may now
treatment principles for preventing anticancer therapy-induced or be used in the 4-drug olanzapine regimen on day 1; however, none of
RT-induced vomiting and nausea, and provide recommendations for these agents is continued on days 2 to 4. In the 3-drug olanzapine
prophylactic antiemetic regimens based on the emetogenic potential of regimen for HEC and MEC (olanzapine/palonosetron/dexamethasone),
anticancer agents. Prophylactic antiemetic treatment is recommended, the panel also agreed that only palonosetron should be used; no data
because it is harder to control nausea and vomiting once it has started. are available to support substituting any of the other 5-HT3 antagonists.
Although vomiting can often be prevented or substantially decreased by The panel recommends that an NK1 RA should be added to a
using prophylactic antiemetic regimens, nausea is harder to control. 5-HT3/dexamethasone regimen (2-drug antiemetic regimen) for patients
This Discussion text for antiemesis describes the algorithm in greater receiving MEC anticancer therapy who have additional risk factors or
detail, for example, by including the clinical trial data and references previous treatment failure with the 2-drug regimen. Alprazolam was
that support the NCCN Panel’s recommendations in the algorithm. deleted as anxiolytic therapy for anticipatory nausea/vomiting, because
Revisions for the 2018 update are described in this Discussion and rebound anxiety is more prevalent with alprazolam than with lorazepam.
outlined in Summary of the Guidelines Updates in the algorithm. The panel added a caveat that lorazepam should be used with caution
in patients receiving scheduled opioids.
Some of the updates for 2018 include: 1) aprepitant injectable emulsion
is a new NK-1 RA treatment option that is now recommended; and 2)
the emetogenic potential of 11 new agents was determined by the
NCCN Panel so that health care providers can select the most
appropriate antiemetic regimens for patients receiving these new
agents. The panel simplified the dosing for dexamethasone for the
intravenous HEC and MEC antiemetic regimens. On day 1, the
recommended dose of dexamethasone is now 12 mg PO/IV once. On
days 2 to 4, dexamethasone is now 8 mg PO/IV daily. The panel also
recommends that if patients cannot tolerate dexamethasone, it can be
replaced with olanzapine.
The NCCN Panel clarified the use of NK1 RAs in HEC and MEC
antiemetic regimens. The panel agreed that any NK1 RA (ie, not just
fosaprepitant or oral aprepitant) could be used in the 4-drug HEC
regimen on day 1 (olanzapine/NK1 RA/5-HT3/dexamethasone),

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines for Patients® available at www.nccn.org/patients

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

* Discussion section € Pediatric oncology

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

NCCN Antiemesis Panel Members

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

AE-5 and AE-6 concentrations. Rolapitant does not inhibit dexamethasone

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

PRINCIPLES OF EMESIS CONTROL FOR THE CANCER PATIENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

EMETOGENIC POTENTIAL OF INTRAVENOUS ANTICANCER AGENTSa

Adapted with permission from:

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

EMETOGENIC POTENTIAL OF INTRAVENOUS ANTICANCER AGENTSa

High Emetic Risk (See AE-2)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

EMETOGENIC POTENTIAL OF ORAL ANTICANCER AGENTSa

High Emetic Risk (See AE-2)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

Footnotes for pages AE-5 and AE-6

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

LOW AND MINIMAL EMETIC RISK INTRAVENOUS CHEMOTHERAPY - EMESIS PREVENTIONf,g,h,j

Start before chemotherapy (order does not imply preference) g,h,v

Minimal No routine prophylaxis

fSee Emetogenic Potential of Intravenous Antineoplastic Agents (AE-3).

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

ORAL CHEMOTHERAPY - EMESIS PREVENTIONg,h,w,x

Start before chemotherapy and continue daily

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

BREAKTHROUGH TREATMENT FOR RESPONSE SUBSEQUENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

RADIATION-INDUCED EMESIS PREVENTION/TREATMENT

Start pretreatment for each day of RT treatment

Chemotherapy and RT See emesis prevention for chemotherapy-induced nausea/vomiting

jSee Pharmacologic Considerations for Antiemetic Prescribing (AE-B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

ANTICIPATORY EMESIS PREVENTION/TREATMENT

See Principles of Emesis Control

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1

3Rolia F, Ruggeri B, Ballatori E, et al Aprepitant versus dexamethasone for

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

PHARMACOLOGIC CONSIDERATIONS FOR ANTIEMETIC PRESCRIBING

NCCN Guidelines Version 3.2018 NCCN Guidelines Index

PHARMACOLOGIC CONSIDERATIONS FOR ANTIEMETIC PRESCRIBING