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