Effective Management Therapies to

Improve Chemotherapy-Induced
Nausea and Vomiting (CINV)
Alison Duffy, PharmD, BCOP
Associate Professor
Department of Pharmacy Practice and Science
School of Pharmacy
University of Maryland
Oncology Clinical Pharmacy Specialist
Greenebaum Comprehensive Cancer Center
University of Maryland
Baltimore, Maryland
© 2019. All rights reserved.
No part of this report may be reproduced or distributed
without the expressed written permission of PTCE.
This activity is supported by an educational
grant from
Helsinn Therapeutics (U.S.), Inc.
Educational Objectives
• Demonstrate the value of assertively controlling CINV
• Evaluate the current role of serotonin 3 (5-HT3) receptor antagonists in managing
CINV
• Examine the efficacy and safety profiles of neurokinin-1 (NK1) receptor
antagonists
• Construct individualized emesis prophylaxis regimens
 CINV Incidence and Patient Perceptions
• Most recently approved antiemetic medications have reduced the incidence of
vomiting

•30%-60% of patients still experience either acute or delayed nausea

after chemotherapy

• Nausea remains 1st or 2nd most severe/feared adverse effect of

chemotherapy

Rao KV, et al. Am Health Drug Benefits. 2012:5(4):232-240; Cohen L, et al. Support Care Cancer. 2007;15:497-503; de Boer-Dennert M, et al. Br J Cancer.
1997;76(8):1055-1061; Griffin AM, et al. Ann Oncol. 1996;7(2):189-195; Hofman M, et al. Cancer. 2004;101(4):851-857; Lindley C, et al. Cancer Pract. 1999;7(2):59-65.
 Associated Implications of CINV
Retrospective
analysis (n=19,139)
Prospective
• 14% had CINV-
analysis (n=178)
associated visit
• 61% of
patients
o 64% inpatient
reported CINV
admission
(34% acute;
o Hospitalizations
58% delayed)
during delayed
• Nearly 40%
phase were most
reported
costly ($7500)*
impaired daily
functioning

Schnell FM. Oncologist. 2003;8(2):187-198; Burke TA, et al. Support Care

Cancer. 2011;19(1):131-140; Haiderali A, et al. Support Care Cancer.
2011;19(6):843-851. *Mean per-patient CINV-associated costs.
CINV Pathophysiology

Navari RM, Aapro M. N Engl J Med. 2016;374(14):1356-1367.

Treatment Guidelines
• Guidelines for the prevention and treatment of CINV:

• National Comprehensive Cancer Network (NCCN) 2018

• American Society of Clinical Oncology (ASCO) 2017

• Multinational Association of Supportive Care in Cancer/European Society for

Medical Oncology (MASCC/ESMO) 2016

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed
September 17, 2018; Hesketh PJ, et al. J Clin Oncol. 2017;35(28):3240-3261; Roila F, et al. Ann Oncol.
2016;27(suppl 5):v119-v133.
Emetic Potential
High emetic risk*: >90%
frequency of emesis

Moderate emetic risk*: 30%

to 90% frequency of emesis

Low emetic risk*: 10% to

30% frequency of emesis

Minimal emetic risk*: <10%

frequency of emesis
*Proportion of patients who
NCCN clinical practice guidelines experience emesis in the
in oncology, antiemesis. Version
3.2018. Published June 11, 2018. absence of effective antiemetic
Accessed September 17, 2018 prophylaxis.
Patient- and Agent-Related Risk Factors
• Patient • Chemotherapy
• Absence of alcohol use • High emetic risk of agent, moderate to
• Age high dose, more frequency, longer
• Gender duration, short infusion rate
• History of motion sickness • Radiation
• Hyperemesis with pregnancy • Increased with higher doses and amount
• Pre-chemotherapy nausea or past CINV of irradiated tissue

• Cancer
• Gastrointestinal, liver, brain
• Concomitant constipation, bowel
obstruction

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018
Emetic Risk of Chemotherapy Agents
Intravenous Agents
High Emetic Risk (HEC): >90% Frequency of Emesis
• AC (anthracycline and cyclophosphamide) • Doxorubicin ≥60 mg/m2
• Carboplatin AUC ≥4 NCCN and ASCO • Epirubicin >90 mg/m2
• Carmustine >250 mg/m2 Guideline • Ifosfamide ≥2 g/m2 per dose
• Cisplatin • Mechlorethamine
Update
• Cyclophosphamide >1500 mg/m2 • Streptozocin
• Dacarbazine
Moderate Emetic Risk (MEC): >30%-90% Frequency of Emesis
• Aldesleukin >12 to 15 million IU/m2 • Cytarabine >200 mg/m2 • Interferon alpha ≥10 million IU/m2
• Amifostine >300 mg/m2 • Dactinomycin • Irinotecan
• Arsenic trioxide • Daunorubicin • Melphalan
• Azacitidine • Dual-drug liposomal encapsulation • Methotrexate ≥250 mg/m2
• Bendamustine cytarabine/daunorubicin • Oxaliplatin
• Busulfan • Dinutuximab • Temozolomide
• Carboplatin AUC <4 • Doxorubicin <60 mg/m2 • Trabectedin
• Carmustine ≤250 mg/m2 • Epirubicin ≤90 mg/m2
• Clofarabine • Idarubicin
• Cyclophosphamide ≤1500 mg/m2 • Ifosfamide <2 mg/m2 per dose

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
Emetic Risk of Chemotherapy Agents
Oral Agents
Moderate to High Emetic Risk (≥30% Frequency of Emesis)
• Altretamine • Midostaurin
• Busulfan ≥4 mg/d • Mitotane
• Ceritinib • Niraparib
• Crizotinib • Olaparib
• Cyclophosphamide ≥100 mg/m2/d • Panobinostat
• Enasidenib • Procarbazine
• Estamustine • Rucaparib
• Etoposide • Temozolomide >75 mg/m2/d
• Lenvatinib • Trifluridine/tipiracil
• Lomustine

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018.
Classification of CINV
Anticipatory Breakthrough Refractory
Acute Delayed
emesis emesis emesis

Occurs during
Occurs despite
Occurs prior subsequent
Occurs 1-5 use of
Occurs 1 or 2 to treatment cycles when
days after prophylaxis
hours after as a antiemetic
chemotherapy and/or
chemotherapy conditioned prophylaxis
requires
(peak at 5-6 (peak at 1 or 2 response in and rescue
rescue
hours) days) patients with has not been
antiemetic
previous CINV effective in
therapy
earlier cycles

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018.
NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018.
Goals of Treatment and CINV
Approach
• Consider other causes of nausea and emesis
• Goals
• Prevention of CINV through antiemetic treatment and patient education is imperative in
optimizing chemotherapy success
• Minimize extent and duration of symptoms
• Evaluate risk factors when choosing a chemotherapy regimen
• Choose antiemetic regimen based on drug with highest emetic risk and patient-
specific risk factors
• Repeat daily for multi-day regimens

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
 Antiemetic Classes and Place in Therapy
• Triple therapy
HEC • 5-HT3 RA AND dexamethasone
AND NK1 RA
• Consider H2 blocker or proton pump
inhibitor to prevent dyspepsia, which
can mimic nausea
MEC • Doublet therapy • Nonpharmacologic measures
• 5-HT3 RA AND dexamethasone

• Monotherapy
Low • 5-HT3 RA OR dexamethasone OR
prochlorperazine/metoclopramide

Minimal • No routine prophylaxis

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published
June 11, 2018. Accessed September 17, 2018.
Literature Evaluation and Guideline
Application

• 5-HT3 RAs
Prevention of
• NK1 RAs
CINV
• Olanzapine
Breakthrough
• Olanzapine
CINV

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018.

Published June 11, 2018. Accessed October 24, 2018.
5-HT3 RA
 Focus on 5-HT3 Antagonists
Agent Formulation Half-life Other pharmacokinetics Hepatic metabolism Adverse effects Cost per dose
(hours) (AWP)
Dolasetron PO 7-8 CYP3A, CYP2D6 Dose- and route-dependent QTc $114.61
prolongation risk; (dolasetron
Ondansetron PO/IV 3-4 CYP3A, CYP2D6, $0.28-0.64
>ondansetron >granisetron
CYP1A, CYP2E1
>palonosetron)
Granisetron Extended-release 24 Extended half-life: do not administer CYP3A No differences in other class-wide $688.85
subcutaneous at <1-week intervals; not toxicities: headache, constipation,
polymer-based interchangeable with IV formulation malaise
injection (Sustol)

IV (Kytril) 5-9 $7-70

PO (Kytril) 6
Transdermal patch Time to peak: 48 hours after patch $640.26
(Sancuso) 24 application (24-168 hours)

Palonosetron IV 40 • 100-fold higher binding affinity CYP3A, CYP2D6, CYP1A $108.72

for 5-HT3 receptor
• Allosteric receptor antagonist
• Triggers receptor internalization
• Inhibits 5-HT3/NK1 receptor
“crosstalk”

Anzemet [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; 2014; Zofran (oral) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2016; Zofran (injection)
[prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2017; Sustol [prescribing information]. Redwood City, CA: Heron Therapeutics; 2016; Kytril [prescribing
information]. Nutley, NJ: Roche; 2009; Sancuso [prescribing information]. Bedminster, NJ: ProStrakan Inc; 2015; Aloxi [prescribing information]. Bloomington, MN: MGI Pharma, Inc; 2006.
 Focus on 5-HT3 RA
NCCN Treatment Algorithm: HEC
Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention
3-drug Regimens
A NK1 RA (choose one): • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Aprepitant injectable emulsion 130 mg IV once and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once
• Rolapitant 180 mg PO once Ondansetron for delayed CINV
not cost-effective unless used
5-HT3 RA (choose one) • Dolasetron 100 mg PO once alone for delayed CINV
• Granisetron 10 mg SC once, 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 once ASCO day 1 ondansetron: Dexamethasone 8 mg PO/IV daily on days 2-4
8 mg PO bid
B Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2-4
Palonosetron 0.25 mg IV once
Dexamethasone 12 mg PO/IV once
4-drug Regimen
C • Olanzapine 10 mg PO once If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Same as A and 3; dexamethasone 8 mg PO/IV daily on days 2-4; olanzapine
10 mg PO daily on days 2-4

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
 Focus on 5-HT3 RA
NCCN Treatment Algorithm: MEC
Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention
2-Drug Regimens
A 5-HT3 RA (choose one) • Dolasetron 100 mg PO once 5-HT3 monotherapy if gave: dolasetron,
• Granisetron 10 mg SC once (preferred), or 2 mg PO once, or ondansetron, granisetron PO or IV
NCCN: Preferred 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24-h transdermal
ONLY if no NK1 RA patch applied 24-48 h prior to first dose of chemotherapy
ASCO and MASCC: • Ondansetron 16-24 mg PO once, or 8-16 mg IV once OR
No Preference • Palonosetron 0.25 mg IV once (preferred)
Dexamethasone 12 mg PO once Dexamethasone 8 mg PO/IV daily on days 2
and 3

B Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2 and 3

Palonosetron 0.25 mg IV once
Dexamethasone 12 mg PO/IV once
3-Drug Regimen
C NK1 RA (choose one) PLUS same as A • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg
• Aprepitant injectable emulsion 130 mg IV once PO daily on days 2 and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once +/- dexamethasone
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once
• Rolapitant 180 mg PO once

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261; Roila F, et al. Ann Oncol. 2016;27(suppl 5):v119-v133.
 A Closer Look at 5-HT3 Antagonist Trials
Number of % Patients
Number of Emetic Risk of Dosage of Antiemetic Receiving
Reference Patients Chemotherapy Chemotherapy Comparator Agents Used Dexamethasone
Granisetron
Saito et al 1143 Cisplatin ≥50 mg/m2 or AC/EC High 100 (for 3 days)
40 mcg/kg
cisplatin ≥60 mg/m2,
cyclophosphamide >1500
Aapro et al 667 mg/m2, carmustine [BCNU] High Ondansetron 32 mg 67
>250 mg/m2, dacarbazine
[DTIC], or mechlorethamine
Doublet regimen;
69% receiving AC or cisplatin no NK1 RAs used
Moderate
Eisenberg et al 592 ≤50 mg/m2 Dolasetron 100 mg 5
Actual: High

63% cyclophosphamide <1500

mg/m2, 48% doxo >25 mg/m2, Moderate
Gralla et al 563 Ondansetron 32 mg 0
18% cisplatin <50 mg/m2 Actual: High

*Patients Aapro MS et al, 2006; Eisenberg P et al, 2003; and Gralla R et al, 2003 make up 60% of patients evaluated in Jin Y et al, 2013.
Saito M, et al. Lancet Oncol. 2009;10:115-124; Aapro MS, et al. Ann Oncol. 2006;17(9):1441-1449; Eisenberg P, et al. Cancer. 2003;98(11):2473-2482; Gralla R, et al. Ann Oncol.
2003;14(10):1570-1577; Jin Y, et al. Eur J Cancer Care (Engl). 2013;22(1):41-50.
 Palonosetron versus Granisetron in Doublet
Therapy

45%

Saito M, et al. Lancet Oncol. 2009;10:115-124.

 Clinical Controversies: 5-HT3 Agent Selection
Fraction (%) Patients with Complete
Response
Relative Risk Number Needed
Ref Palonosetron Comparator (95% CI)b to Treat (95% CI)c • Noninferiority trial; did not have adequate power to
demonstrate superiority
1 418/555 (75.3) 410/559 (73.3) 1.03 (0.96–1.10) 51 (0–183) “Stacking the deck” in favor of palonosetron
• Most patients received HEC chemotherapy (classified as
2 132/223 (59.2) 126/221 (57.0) 1.04 (0.89–1.22) 46 (0–240)
Limitations MEC in studies) with doublet antiemetics
• No NK1 RAs used
3 119/189 (63.0) 101/191 (52.9) 1.19 (1.00–1.42) 10 (0–20)
• Dexamethasone inconsistently incorporated
4 153/189 (81.0) 127/185 (68.6)A 1.18 (1.05–1.33) 8 (2–14) • Comparison of 5-HT3 antagonists as single-dose
comparison
5 86/104 (82.7) 75/104 (72.1) 1.15 (0.99–1.33) 9 (0–20)

6 105/118 (89.0) 91/118 (77.1) 1.15 (1.03–1.30) 8 (2–15) Cost • Palonosetron-based regimens: cost per quality-adjusted
life-year >$100,000 ($184/chemotherapy cycle)
7 91/128 (71.1) 90/138 (65.2) 1.09 (0.92–1.28) 17 (0–50)
Implications
8 42/44 (95.5) 42/45 (93.3) 1.02 (0.92–1.13) 47 (0–262)
Complete response= (no emetic episode and no use of rescue medication)
Overalld (75.2) (69.2) 1.09 (1.04–1.14) 17 (8–26) during the 24 hours after chemotherapy. Unless otherwise indicated, the
difference between drugs in complete-response rate was not significant.
aP=0.025;
1. Saito M, et al. Lancet Oncol. 2009;10:115-124; 2. Aapro MS, et al. Ann Oncol. 2006;17(9):1441-1449;
bRelative risk of development of CINV.
3. Eisenberg P, et al. Cancer. 2003;98(11):2473-2482; 4. Gralla R, et al. Ann Oncol. 2003;14(10):1570-1577;
cNumber needed to treat to add 1 quality-adjusted life-year; calculated from
5. Yu Z, et al. Support Care Cancer. 2009;17(1):99-102; 6. Bernardo G, et al. J Clin Oncol. 2009;27:e20573; 7.
Tian W, et al. Med Oncol. 2011;28(1):71-78; 8. Dong X, et al. Med Oncol. 2011;28:1425-1429. Kolesar JM, et fixed-effects (Mantel-Haenszel) meta-analysis model.
dPooled estimates from fixed-effects (Mantel-Haenszel) meta-analysis model
al. Am J Health Syst Pharm. 2014;71(6):507-510; Avritscher EB, et al. J Support Oncol. 2010;8(6):242-251.
with Woolf’s test for heterogeneity; P=0.285.
Palonosetron versus Granisetron in Triplet
Therapy

Hashimoto H, et al. J Clin Oncol. 2013;31:Abstract 9621.

5-HT3 RA Summary
Efficacy
• Evidence demonstrating that palonosetron is no more efficacious
than other 5-HT3 antagonists in contemporary practice
• Trials limited by use of nonstandard antiemetic regimens and by
suboptimal dosing of 5-HT3 antagonist comparators

Safety
• Palonosetron and granisetron safest if patients with cardiac
conduction abnormalities and/or treated with medications known
to prolong the QT interval
NK1 RAs
 NK1 RA Comparison
Agent Emetogenicity of Chemotherapy/Type of CINV Timing Prior to Day 1 Dosing Days 2 and 3 Dosing Pearls
Prevention Chemotherapy
Aprepitant (Emend) oral HEC and MEC: Prevention of acute and delayed 1 hour 125 mg PO 80 mg Data exist for multi-day dosing
suspension 40 mg, 125 CINV (days 1-5)
mg, capsules 125 mg, 80
mg
Fosaprepitant (Emend) HEC: Prevention of acute and delayed CINV 30 minutes 150 mg Infusion-site reactions (including
for injection 150 mg MEC: Prevention of delayed CINV thrombophlebitis, necrosis, vasculitis)
(polysorbate 80)

Aprepitant (Cinvanti)
injectable
(soy-based emulsion)
Netupitant 300 mg
/palonosetron 0.5-mg
capsule (Akynzeo)
Fosnetupitant 235 mg/
palonosetron 0.25-mg
injection (Akynzeo)
Rolapitant 90-mg
capsule (Varubi)
HEC (single-dose regimen) 30 minutes 130 mg Not interchangeable with fosaprepitant;
hypersensitivity reaction (including
MEC (3-day regimen) 100 mg Aprepitant (80 mg) anaphylaxis and anaphylactic shock)
capsules orally on
days 2 and 3
Indicated for prevention of acute and delayed 1 hour 1 capsule with
CINV, including, but not limited to HEC or without food
Indicated for prevention of acute and delayed 30 minutes 1 vial Extended half-life: CYP3A4 inhibition for
CINV of HEC (not studied with AC chemotherapy) 6 days; avoid concomitant CYP3A4
substrates for 1 week if feasible
Prevention of delayed CINV including, but not Within 2 hours 180 mg Rolapitant 90-mg injection Does not inhibit/induce CYP3A4 (no
limited to HEC (Varubi) voluntarily removed dose adjustments needed with dex)
from market due to serious Extended half-life (do not redose within
hypersensitivity reactions 2 weeks)

Emend (injection) [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018; Emend (capsules) [prescribing information]. Whitehouse Station, NJ; Merck Sharp &
Dohme Corp; 2010; Cinvanti [prescribing information]. San Diego, CA: Heron Therapeutics; 2017; Akynzeo (capsules) [prescribing information]. Iselin, NJ: Helsinn Therapeutics (US); 2015;
Akynzeo (injection) [prescribing information]. Iselin, NJ: Helsinn Therapeutics (US); 2018; Varubi [prescribing information]. Waltham, MA: Tesaro, Inc; 2018; Albany C, et al. J Clin Oncol.
2012:30(32):3998-4003.
A Closer Look at Oral NK1 RAs
• Benefits • Literature critique
• Lower pill burden • “Stacking the deck”
• Favorable safety profile • No NK1 RA in comparator group
• Patient assistance programs • Lack of delayed CINV prevention
• Literature • Pharmacoeconomic evaluation
Drug Emetogenicity Endpoints Favors Study
Drug
Limitations
• 3% difference in nausea/vomiting
NEPA HEC CR 0-120 h Yes 2-drug
response compared to aprepitant
comparator • Need to treat 33 patients at $20,000 to
MEC CR 24-120 h Yes 2-drug
comparator
prevent 1 episode of CINV or rescue
HEC/MEC Safety Equal
antiemetic use
CR 0-120 h Yes Not powered
ROLA HEC CR 24-120 h Yes 2-drug Hesketh PJ, et al. Ann Oncol. 2014;25(7):1340-1346; Aapro M, et al. Ann Oncol.
comparator 2014;25(7):1328-1333; Gralla RJ, et al. Ann Oncol. 2013;25(7):1333-1339;
Non-AC MEC CR 24-120 h Yes 2-drug Rapoport BL, et al. Lancet Oncol. 2015;16(9):1079-1089; Schwartzberg LS, et al.
comparator Lancet Oncol. 2015:16(9):1071-1078.
AC MEC
Equal
 A Closer Look at Oral NK1 RAs
• Randomized, double-blind phase 3,
noninferiority study (n=828)
• Cisplatin-based HEC regimens
• Study arms:
• NEPA on day 1 + dex days 1-4
Fair
comparison! • 3-day oral aprepitant-granisetron/dex
days 1-4
• Study conclusions:
• Noninferior: overall complete response,
no emesis, no significant nausea
• Significantly fewer NEPA patients used
rescue medications (NEPA 96.6% vs
control 93.5%; 95% CI [0.2%, 6.1%]).
Zhang L, et al. Ann Oncol. 2018;29(2):452-458.
 NCCN Treatment Algorithm: HEC Focus on NK1 RA

Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention

3-Drug Regimens
A NK1 RA (choose one): • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Aprepitant injectable emulsion 130 mg IV once and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once NCCN 2.2018 Update:
• Rolapitant 180 mg PO once Removed Rolapitant IV
5-HT3 RA (choose one) • Dolasetron 100 mg PO once
• Granisetron 10 mg SC once, 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 once ASCO and MASCC: Dexamethasone 8 mg PO/IV daily on days 2-4
20 mg on day 1 with
B Olanzapine 10 mg PO once ASCO
Olanzapine 10 mg PO daily on days 2-4 and MASCC:
rolapitant
Palonosetron 0.25 mg IV once 8 mg BID with rolapitant
Dexamethasone 12 mg PO/IV once +/- fosaprepitant
4-Drug Regimen
C • Olanzapine 10 mg PO once If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Same as A and 3; dexamethasone 8 mg PO/IV daily on days 2-4; olanzapine
10 mg PO daily on days 2-4

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
 Focus on NK1 RA
NCCN Treatment Algorithm: MEC
Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention
2-Drug Regimens
A 5-HT3 RA (choose one) • Dolasetron 100 mg PO once 5-HT3 monotherapy if gave: dolasetron,
• Granisetron 10 mg SC once (preferred), or 2 mg PO once, or ondansetron, granisetron PO or IV
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 OR
• Palonosetron 0.25 mg IV once (preferred)
Dexamethasone 12 mg PO once Dexamethasone 8 mg PO/IV daily on days 2
and 3 ASCO: May omit day 2 and 3
unless cyclophosphamide,
doxorubicin, oxaliplatin

B Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2 and 3

Palonosetron 0.25 mg IV once
Dexamethasone 12 mg PO/IV once
3-Drug Regimen
C NK1 RA (choose one) PLUS same as A • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg
• Aprepitant injectable emulsion 130 mg IV once PO daily on days 2 and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once +/- dexamethasone
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once
• Rolapitant 180 mg PO once
NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
Olanzapine Pharmacology and Dosing
• Atypical antipsychotic • Dosing
• Blocks multiple neurotransmitters • Substitute for dexamethasone if appropriate
• 5 to 10 mg PO daily
• Lower dose in sedated, elderly
Serotonin Dopamine • Only use PO lorazepam, if given concomitantly
5-HT2A,2c, 6 D1-4
• Adverse effects
• Anticholinergic effects
• Sedation
Alpha1 Histamine • Dystonic reactions
adrenergic H1
• Long-term effects
• Weight gain, diabetes
Serotonin Muscarinic
5-HT3 M1-5 Yanai T, et al. Int J Clin Oncol. 2018;23(2):382-388; Hashimoto H, et al. J Clin Oncol. 2016;34:
Abstract 10111; Mizukami N et al. J Pain Symptom Manag. 2014;47(3):542-550;
Mukhopadhyay S, et al. Support Care Cancer. 25(suppl 2): Abstract eP016; Navari RM.
Drugs. 2013;73(3):249-262.
Olanzapine for Prophylaxis (Triple Therapy)

Navari RM, et al. J Support Oncol. 2011;9(5):188-195.

Olanzapine for Prophylaxis (4-Drug Therapy)
• Definition: Complete response = no emetic episode and no use of rescue
medication
• Adding olanzapine to (fos) aprepitant and dex for HEC increased complete
response rate versus placebo at 3 time points:
• <24 hours after chemotherapy, 25-120 hours, overall 120 hours
• 86% vs 65% [P<0.001], 67% vs 52% [P=0.007], and 64% vs 41% [P<0.001], respectively
• More patients had no nausea when compared with placebo during same time
periods
• 74% vs 45% [P=0.002], 42% vs 25% [P=0.002], and 37% vs 22% [P=0.002].

Navari RM, et al. N Engl J Med. 2016;375(2):134-142.

 Focus on

NCCN Treatment Algorithm: HEC olanzapine

Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention

3-Drug Regimens
A NK1 RA (choose one): • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Aprepitant injectable emulsion 130 mg IV once and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once
• Rolapitant 180 mg PO once
5-HT3 RA (choose one) • Dolasetron 100 mg PO once
• Granisetron 10 mg SC once, 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 once Dexamethasone 8 mg PO/IV daily on days 2-4
B Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2-4
Palonosetron 0.25 mg IV once
Dexamethasone 12 mg PO/IV once
4-Drug Regimen
C • Olanzapine 10 mg PO once ASCO: Option C If aprepitant PO on day 1, aprepitant 80 mg PO daily on days 2
• Same as A and 3; dexamethasone 8 mg PO/IV daily on days 2-4; olanzapine
Preferred 10 mg PO daily on days 2-4

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
 Focus on

NCCN Treatment Algorithm: MEC olanzapine

Day 1 (Start BEFORE Chemotherapy) Delayed CINV Prevention

2-Drug Regimens
A 5-HT3 RA (choose one) • Dolasetron 100 mg PO once 5-HT3 monotherapy if gave: dolasetron,
• Granisetron 10 mg SC once (preferred), or 2 mg PO once, or ondansetron, granisetron PO or IV
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 OR
• Palonosetron 0.25 mg IV once (preferred)
Dexamethasone 12 mg PO once Dexamethasone 8 mg PO/IV daily on days 2
and 3
B Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2 and 3
Palonosetron 0.25 mg IV once
Dexamethasone 12 mg PO/IV once
3-Drug Regimen
C NK1 RA (choose one) PLUS same as A • Aprepitant 125 mg PO once If aprepitant PO on day 1, aprepitant 80 mg
• Aprepitant injectable emulsion 130 mg IV once PO daily on days 2 and 3
• Fosaprepitant 150 mg IV once
• Netupitant 300 mg/palonosetron 0.25 mg PO once +/- dexamethasone
• Fosnetupitant 235 mg/palonosetron 0.25 mg IV once
• Rolapitant 180 mg PO once
NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018; Hesketh PJ, et al. J Clin Oncol.
2017;35(28):3240-3261.
Dexamethasone Extension/Sparing
Strategies
• Dexamethasone-extension strategy
• For patients suffering from extended delayed CINV, consider extending course of
dexamethasone as appropriate, dosing in morning to minimize insomnia
• Dexamethasone-sparing strategies
• NCCN 2018 Guideline Update: dexamethasone 12 mg for MEC regimens
(from 20 mg)
• Avoid as antiemetic with immunotherapy and cellular therapies
• Dexamethasone-sparing strategies (non-cisplatin HEC and MEC)
• Limit to day 1 only in patients with few risk factors for CINV or those intolerant to steroids (or
lower doses)
• If cannot tolerate dexamethasone, consider replacing with olanzapine

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11, 2018. Accessed September 17, 2018;
Hesketh PJ, et al. J Clin Oncol. 2017;35(28):3240-3261.
Breakthrough CINV
• Best way to address is to prevent
• Give additional agent from different
NCCN and ASCO
drug class Recommendations
• Consider routine, around-the-clock
administration
• Rectal or IV is usually required
• First choice: olanzapine
• Multiple concurrent agents, alternating • Second choice: other agents
schedules or routes may be needed (dopamine antagonist,
• Ensure adequate hydration lorazepam, steroids)
• Correct electrolyte abnormalities
Olanzapine for Breakthrough CINV

Navari RM, et al. Support Care Cancer. 2013;21(6):1655-1663.

 Pharmacologic Considerations for
Antiemetic Prescribing
• Benzodiazepines
• CNS depression; use with caution in patients at risk for falls or at risk of orthostatic hypotension
• Less of a concern with lower doses
• Clinical pearl: consider for anticipatory CINV or when breakthrough CINV has an anxiety component
• Atypical antipsychotic/phenothiazines/metoclopramide/haloperidol
• Caution with other dopaminergic agents (increased risk of extrapyramidal symptoms)
• May increase risk of QT interval prolongation*
• CNS depression: caution in patients at risk for falls or for orthostatic hypotension (dose-related)
• Clinical pearl: metoclopramide increases gut motility; may be beneficial in patients with
gastroparesis

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11,
*Use caution and monitor ECG in patients with
2018. Accessed September 17, 2018. other risk factors for QT prolongation.
Pharmacologic Considerations for
Antiemetic Prescribing
• Scopolamine
• CNS depression
• Clinical pearl: consider when positional changes, movement, or excessive
secretions are CINV triggers
• Cannabinoids
• Refractory CINV; may stimulate appetite
• Dronabinol capsules 5-10 mg or dronabinol solution 2.1-4.2 mg/m2 PO 3 or 4
times daily
• Lower doses in elderly; marijuana-naïve patients
• CNS depression
NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11,
2018. Accessed September 17, 2018.
 Selecting an Appropriate Regimen
• Use guidelines as a starting point
• Therapy will be individualized based on patient
• A “value judgment” should be made considering the following relevant factors:
Clinical success Logistics Safety Cost

• Appropriate • Likelihood of • Consideration of • Per dose

selection of adherence adverse effects • Per cycle
therapy based on • Health literacy • 5-HT3 RA: QTc • Of hospitalization
patient and • Complexity of prolongation, for breakthrough
treatment risk regimen headache,
factors constipation
• Steroids:
hyperglycemia
• D2 antagonists:
drowsiness,
Guideline- extrapyramidal Patient’s
based syndrome optimal
therapy therapy
Rao KV, Faso A. Am Health Drug Benefits. 2012;5(4):232-240.
 Cycle Reassessment
Modifying Antiemetics for Next Cycle Checklist

Non–chemotherapy-related Goals of Care? Reassess Antiemetic Regimen

Breakthrough on Day 1 and Post-chemotherapy
Nausea/Vomiting?
Brain metastases? If noncurative, consider CHECK Emetic risk of regimen
Electrolyte abnormalities? switching/modifying adherence
Tumor infiltration? chemotherapy regimen
Comorbidities?
ADD 1) NK1 RA
2) Other concomitant antiemetics
(eg, dopamine antagonists)
3) Anxiolytic agent
4) Antacid if dyspepsia
COMBINE NK1 RA regimen with olanzapine
CHANGE 1) NK1 RA regimen to olanzapine-containing, or
vice-versa
2) Dose (intensity or frequency) of 5-HT3 RA
3) 5-HT3 RA

NCCN clinical practice guidelines in oncology, antiemesis. Version 3.2018. Published June 11,
2018. Accessed September 17, 2018.
 Adherence to Antiemetic Guidelines
• Adherence to guidelines significantly • Factors influencing suboptimal adherence
increased the control of chemotherapy- • Underestimation of delayed CINV
induced emesis • May be underreported
• Guideline adherence is suboptimal • Difficult to assess
• Subjective
• Study 1: overestimation of effectiveness of
• More comprehensive nausea-specific
antiemetic prophylaxis questionnaires needed
• 56% of patients did not receive any antiemetic • Lack of continuing education
agent for delayed-onset CINV
• Lack of availability of or reimbursement for
• Study 2: 61% of patients treated according to antiemetic drugs
guidelines
• Prophylaxis of delayed CINV: 89%
nonadherence
• Significant overuse of serotonin receptor
antagonists for delayed CINV prophylaxis
Navari RM, et al. N Engl J Med. 2016;374:1356-1367. Escobar Y, et al. Support Care Cancer. 2015;23(9):2833-2840; Burmeister H, et al. Support Care
Cancer. 2012;20(1):141-147; Aapro M, et al. Ann Oncol. 2012;23(8):1981-1992.
Strategies for Adherence Improvement and
the Pharmacist’s Role
• Institutional guideline and order set development and implementation
• Guideline/order set dissemination and integration + “audit-and feedback” strategy +
educational outreach visit increased guideline adherence
• Provider education
• Initial and ongoing assessment of patient’s risk factors for CINV and response to
therapy
• Assist with identifying financial issues of antiemetics prior to therapy initiation
• Pharmacist involvement can help reduce costs and efficiently promote use of
antiemetics in a clinically appropriate manner

Affronti ML, et al. Support Care Cancer. 2014;22(7):1897-1905; Roila F. Support Care Cancer. 2004;12(6):446-453; Vidall C, et al. Ecancermedicalscience.
2011;5:211; Iihara H, et al. J Eval Clin Pract. 2012;18(4):753-760; Dranitsaris G, et al. Support Care Cancer. 2001;9(8):611-618.
The Pharmacist’s Role: Patient Education
• Develop a treatment with patients, including:
• Medication access Patient Education
• Screening for concomitant medications Checklist
• Goals of therapy
• Instructions for proper use
• Adverse effect management
• Adherence assessment
• Patient education tools:
• Time to Talk CINV Toolkit: hoparx.org/patient-education/time-to-talk-cinv
• Cancer.Net ASCO Answers: Nausea and Vomiting
• Chemocare.com Managing Side Effects: Nausea and Vomiting

Grunberg SM, et al. J Natl Compr Canc Netw. 2009;7(5):601-605; NCCN clinical practice guidelines in oncology,
antiemesis. Version 3.2018. Published June 11, 2018. Accessed October 10, 2018.
Conclusion
• Risk factors for CINV can be either patient specific or treatment specific
• Treatment-specific risks include emetogenicity of the agents used, the dose and schedule
of each agent, and, if applicable, the radiation or surgery site
• Agents available to treat CINV include 5-HT3 RAs, NK1 RAs, and corticosteroids, as well as
dopamine receptor antagonists, benzodiazepines, olanzapine, and cannabinoids
• Guidelines from the NCCN and ASCO can help providers personalize the antiemetic
regimens for their patients, but these are only starting points; a “value judgment” must
also be made
• The preferred status for palonosetron was derived from data in 3 of 4 trials showing
significant benefits in the delayed setting; these trials had significant flaws in design,
leading to questioning of this “preferred” status and suggesting that all 5-HT3 receptor
antagonists are equal if used at equivalent doses and schedules
• Providers must consider clinical, logistic, safety, and cost factors when treating CINV, and
antiemetic regimens for a particular patient must be evaluated and then reevaluated at
every treatment cycle
 Thank you!

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