Prevention and Treatment of
Chemotherapy Induced
Nausea and Vomiting
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
UCSF Helen Diller Family Comprehensive Cancer Center
With thanks to Steven Grunberg and Frankie Holmes
Patient Perceptions of the Most Severe
Side Effects of Cancer Chemotherapy
Rank 19831 19932 19953 19994
1. Vomiting Nausea Nausea Nausea
2. Nausea Constantly tired Loss of hair Loss of hair
3. Loss of hair Loss of hair Vomiting Constantly tired
4. Thought of
coming for
treatment
Effect on family Constantly tired Vomiting
5. Length of time
treatment takes
Vomiting Having to have
an injection
Changes in the
way things taste
1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-208.
2. Griffin AM, et al. Ann Oncol. 1996;7:189-195.
3. De Boer-Dennert M, et al. Br J Cancer. 1997;76:1055-1061.
4. Lindley C, et al. Cancer Pract. 1999;7:59-65.
Association Between CINV and QOL (FLIE
Interference Scores) in the Community
Oncology Setting
Prospective observational study in patients receiving emetogenic chemotherapy; 82% women; mean age
51 years
FLIE = Functional Living Index – Emesis
Per
cent
of
Pat
ient
s w
ith In
terf
eren
ce
with
Dai
ly F
unct
ioni
ng
(FLI
E S
core
s
108
)
8
2 0
38
20
42
0 3
0
10
20
30
40
50
60
70
Pretreatment Day 6 Pretreatment Day 6
17
63
13
24 P>0.20
P<0.0001 P<0.0001
P=0.003
P=0.002
2
65
Pretreatment Day 6
0 2
52
69
Delayed CINV alone No CINV Acute and Delayed CINV P<0.0001
Cycle 1 (N=146) Cycle 2 (N=134) Cycle 3 (N=106)
Cohen L, et al. Support Care Cancer. 2007;15:497-503.
Other consequences of CINV: increased cost,
delayed or reduced treatment, hospitalization
Emetogenicity of Chemotherapy
Emetogenic
Classification
Incidence of
Emesis
Index Agents
High > 90% Cisplatin
Doxorubicin:
(AC or >60 mg/m2)
Moderate 30-90% Cyclophosphamide ≤1500 mg/m2
Carboplatin
Low 10-30% Eribulin
Minimal < 10% Vinorelbine
Grunberg, Support Care Cancer 13:80, 2005, NCCN guidelines 2013
1. Gregory RE, et al. Drugs. 1998;55:173-189.
2. Hesketh PJ, et al. J Clin Oncol. 1997;15:103-109.
Chemotherapy-Induced Emesis:
Risk Factors • Patient-related risk factors1:
– Younger age
– Female gender
– No/minimal prior history of alcohol use
– Prior CINV
– Anxiety
• Treatment-related risk factors1,2:
– Moderate to high emetogenicity of
chemotherapy agents or regimens
– Moderate to high drug dose
1. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999;56:729-
764. 2. Aapro MS, et al. Support Care Cancer. 2005;13:117-121. 3. Hesketh PJ. Cancer
Invest. 2000;18:163-173. 4. Lindley CM, et al. Qual Life Res. 1992;1:331-340. 5. O’Brien
BJ, et al. Can Med Assoc J. 1993;149:296-302. 6. Grunberg SM, et al. J Natl Cancer Inst.
1988;80:864-868.
Chemotherapy-Induced Emesis:
Classification
• Classification1:
– Acute (0-24 hr after chemotherapy)
– Delayed (24-120 hr after chemotherapy) • May last up to 6 days
• Incidence without treatment 20%-90%
– Anticipatory (prior to chemotherapy) • Experienced by up to 25% of patients by 4th chemotherapy
cycle2
• Potential to cause:
– Dehydration and electrolyte imbalance1,3
– Impaired health-related quality of life4,5
• Negative impact on activities of daily living
– Rehospitalization6
1. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999;56:729-764. 2. Aapro MS, et al. Support Care Cancer. 2005;13:117-121. 3. Hesketh PJ. Cancer Invest.
2000;18:163-173. 4. Lindley CM, et al. Qual Life Res. 1992;1:331-340. 5. O’Brien BJ, et al. Can Med Assoc J. 1993;149:296-302. 6. Grunberg SM, et al. J Natl Cancer Inst. 1988;80:864-868.
Principles and Goals of Therapy
• The goal is to prevent nausea and vomiting
– Be aware of toxicities/drug interactions
– Acute is generally easier to control than delayed
– Control should be maintained for at least 3 days
• IV and oral drugs overall are similar in effectiveness
• Personalize therapy for treatment and patient factors
• Consider non-chemotherapy related causes
• Consider use of an H2 blocker or PPI to prevent dyspepsia,
which can mimic nausea
• Lifestyle measures may help
– Eat small meals, choose healthful foods, eat food at room
temperature, etc
Natural History of Delayed
Nausea and Vomiting
0
10
20
30
40
50
60
70
80
Percent with
Nausea or
Vomiting
0-24 24-48 48-72 72-96 96-120
Hours after Cisplatin
Vomiting
Nausea
Kris, J Clin Oncol 3:1379, 1985
Delayed Nausea/Vomiting after Complete
Protection from Acute Nausea/Vomiting
0
5
10
15
20
25
30
35
40
Vomiting Nausea
Percent of Patients with Delayed Symptoms
IGAR, Support Care Cancer 8:229, 2000
DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists.
Emetic Reflex
Histamine
Endorphins
Acetylcholine
Dopamine/ DA RAs
Substance P/ NK-1 receptor antagonists
GABA Cannabinoids
Serotonin/ 5-HT3 receptor antagonists
Neurotransmitters / Therapies
Associated With Emesis
Three Major Classes of Anti-Emetic Drugs
• Steroids (dexamethasone)
• 5HT3 receptor antagonists
– 2nd generation: palonosetron (IV only)
• T1/2 40 hours
• Effective for both acute and delayed CINV as a single IV
infusion
– 1st generation: ondansetron, granisetron (also in
transdermal form), dolasetron (PO only)
• Primarily effective for acute CINV, also for rescue
• Neurokinin-1 antagonists
– Aprepitant (po x 3d), fosaprepitant (IV x 1)
– Effective for delayed CINV when given with a 5HT3 RA
Chemotherapy – Emesis Prevention HIGH
EMETIC RISK
MODERATE
EMETIC RISK
LOW
EMETIC RISK
MINIMAL
EMETIC RISK
Serotonin (5-HT3)
antagonist:
Dolasetron or
Granisetron or
Ondansetron or
Palonosetron (preferred)
AND
Steroid*
AND
Neurokinin (NK1)
antagonist
± Lorazepam
± H2 blocker or PPI
Serotonin (5-HT3)
antagonist:
Dolasetron or
Granisetron or
Ondansetron or
Palonosetron (preferred)
AND
Steroid*
WITH / WITHOUT
Neurokinin (NK1)
antagonist†
± Lorazepam prn
± H2 blocker or PPI
Dexamethasone
OR
Metoclopramide
OR
Prochlorperazine
± Lorazepam prn
± H2 blocker or
PPI
No routine
prophylaxis
*Use of steroids is contraindicated with drugs such as interleukin-2 (IL-2, aldesleukin) and interferon
†As per high emetic risk prevention, an NK1 antagonist should be added (to dexamethasone and a 5-HT3 antagonist regimen) for selected patients receiving other chemotherapies of moderate emetic risk (e.g. carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate)
Recent data suggests that gabapentin may help prevent CINV (Cruz et al, 2012)
PPI = proton pump inhibitor Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Antiemesis V.1.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights
reserved. The NCCN Guidelines™ and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.
Hudis CA, et al. Breast Cancer Res Treat. 2003;82(suppl 1):S153. Abstract 635.
• 100% female; mean age 52 years; 63% chemotherapy-naïve
• Majority of women receiving cyclophosphamide and/or doxorubicin combination
• Concomitant dexamethasone pretreatment received by 2.6% of patients
Palonosetron vs. Ondansetron or Dolasetron (Breast Cancer Subset) – Complete Response
p=0.063, NS
63.2 54.7
39.7 34.2
*p<0.001
58.7 *p<0.001
49.6
0
20
40
60
80
100
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
Co
mp
lete
Resp
on
se
(No
Em
esis
, N
o R
escu
e)
(% o
f P
ati
en
ts)
Palonosetron 0.25 mg IV (n=242) Ondansetron 32 mg/Dolasetron 100 mg IV
(n=234) *p<0.025 (Fisher’s exact test)
PALO-99-03/99-04 Breast Cancer Subset
Time Course of Emesis following Cisplatin
with a 5-HT3 Antagonist or Aprepitant
Patients with no emesis (%)
Time since cisplatin (hours)
0 8 24 40 60 80 100 120 0
20
40
60
80
100 Granisetron + dexamethasone d1 / placebo d2–5
Granisetron + dexamethasone + aprepitant d1 / aprepitant d2–5
Aprepitant d0 / aprepitant + dexamethasone d1 / aprepitant d2–5
Aprepitant + dexamethasone d1 / aprepitant d2–5
Hesketh, Support Care Cancer 10:365, 2002
SPECIAL TOPICS:
• Toxicity
• Patient perception
• Anticipatory emesis
• Breakthrough treatment
• Polymorphisms
Toxicity of Primary Agents
• 5HT3 receptor antagonists
– Headache
– Constipation
– Prolonged QT
• NK1 receptor antagonist
– Drug-drug interactions
• Substrate, moderate inducer and moderate
inhibitor of CYP3A4, and inducer of CYP2C9
• More with oral form than IV due to 1st pass
metabolism
• Most important: coumadin
Perception vs Reality
Highly Emetogenic Chemotherapy
0
10
20
30
40
50
60
70
Acute
Nausea
Acute
Vomiting
Delayed
Nausea
Delayed
Vomiting
Percent of patients
MD/RN Prediction Patient Experience
Grunberg, Cancer 100:2261, 2004
Anticipatory Emesis
• Prevention is critical
– Use optimal antiemetic therapy during every
cycle of treatment
• Behavioral therapy
– Relaxation/desentization
– Hypnosis/guided imagery
– Music therapy
• Acupuncture/acupressure
• Alprazolam or lorazepam the night before
and morning of treatment
Breakthrough Treatment General principle: add one agent from a different drug class sequentially
Class Agents
Benzodiazepine Lorazepam 0.5-2 mg PO or IV q 4-6h
Cannabinoid Dronabinol 5-10 mg PO q 3-6h
Nabilone 1-2 mg PO BID
Other Haloperidol 0.5-2 mg
Metoclopramide 10-40 mg PO/IV q 4-6h
Olanzapine 10 mg PO qd x 3
Scopolamine patch q 72h
Phenothiazine Prochlorperazine 25 mg supp PR q 12h or 10 mg PO/IV q 6h
Promethazine 12.5-25 mg PO/IV q 4h
Serotonin 5-HT3 RA Dolasetron 100 mg PO qd
Granisetron 1-2 mg PO qd /1 mg PO BID/ 0.01 mg/kg (max 1 mg) IV
Ondansetron 16 mg PO/IV qd
Steroid Dexamethasone 12 mg PO/IV daily
Neurokinin-1 RA Add aprepitant/fosaprepitant to subsequent cycles
Cyp3A4 Polymorphisms and Emesis:
Population Effects with Granisetron
Based Therapy
0
10
20
30
40
50
60
70
Acute
Emesis
Acute
Nausea
Delayed
Emesis
Delayed
Nausea
Chinese
Malay
Indian
Hassan, Asian Pac J Cancer Prev 12:185, 2011
Conclusions
• Antiemetic control has been a highly successful area of cancer supportive care
• Better understanding of mechanisms of action will allow identification of improved antiemetics and more effective therapy
• Nausea remains a significant problem
• The ultimate goal remains Total Control of chemotherapy-induced nausea and vomiting