Evidence, Challenges and
Solutions: Preventing and
Managing ChemotherapyInduced Nausea and Vomiting
Scott Edwards, Pharm D
Clinical Oncology Pharmacist
Eastern Health, St. John’s, NL
NOPS 2008
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
Adapted from:
1Coates A et al. Eur J Cancer Clin Oncol. 1983;19:203-8.
2Griffin AM et al. Ann Oncol. 1996;7:189-95.
3De Boer-Dennert M et al. Br J Cancer. 1997;76:1055-61.
4 Lindley C et al. Cancer Pract 1999;7:59-65.
CINV - Definitions

Acute – within a few minutes to several hours after drug
administration and commonly resolves within 24 hours.

Delayed – develops in patients more than 24 hours after
chemotherapy administration.
 May last up to 6 days
 It commonly occurs with cisplatin, carboplatin,
cyclophosphamide and/or anthracyclines.

Anticipatory – nausea and/or vomiting before patients receive their
chemotherapy, after a prior negative experience with chemotherapy

Breakthrough – occurs despite prophylactic treatment and/or
requires rescue.

Refractory – nausea and emesis during subsequent cycles when
antiemetic prophylaxis and/or rescue have failed in earlier cycles
Adapted from:
1. ASHP Am J Health Syst Pharm 1999;56:729-764
2. NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis
Rates of CINV
Adapted from:
1. Hickok JT, et al. Cancer. 2003;97:2880-6.
2.http://www.ashpadvantage.com/previous_meetings/mcm_2005/cemornings2005/CEM_CINV_handout.pdf
Chemotherapy-Induced Emesis
Risk Factors

Patient-related risk factors include:
 Younger age
 Female gender
 No/minimal prior history of alcohol use
 Prior CINV
 Anxiety
 High pretreatment expectation of severe
nausea
Adapted from:
1.Gregory RE et al. Drugs. 1998.; 2. Hesketh PJ et al. J Clin Oncol. 1997.
2.Roscoe JA, Bushunnow P, Morrow GR, et al. Patient experience is a strong predictor of severe nausea after
chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast
carcinoma. Cancer 2004;101:2701-2708
Influence of Patient Expectations on CINV

Expectancy of nausea assessed before patients
received their first doxorubicin-based chemotherapy
treatment was found to be a strong predictor of
subsequent nausea.
Adapted from Roscoe et al. Cancer. 2004 101(11):2701-8.
Chemotherapy-Induced Emesis Risk Factors

Treatment-related risk factors include:
 High drug dose
 High emetogenicity of chemotherapy drugs

Of all the known predictive factors, the emetogenicity of
a given chemotherapeutic agent is the predominant
factor.
Adapted from ASHP Am J Health Syst Pharm 1999;56:729-64.
Causes of CINV
In addition to emesis induced by chemotherapy, CINV
can be caused by:







Partial or complete bowel obstruction
Vestibular Dysfunction
Brain Metastases
Electrolyte imbalance: hypercalcemia, hyperglycemia,
hyponatremia, uremia
Concomitant drugs, including opiates
Gastroparesis induced by a tumor or chemotherapy
(such as vincristine)
Psychophysiologic factors, including anxiety as well as
anticipatory nausea and vomiting
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.
Consequence of Unresolved CINV
Adverse sequelae of nausea and vomiting in the cancer
patient.







Discontinuation of therapy
Serious metabolic derangements
Nutritional depletion and anorexia
Esophageal tears
Wound dehiscence
Deterioration of patients’ physical and mental status
Degeneration of self-care and functional ability
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.
Poll of the audience
As Health care professionals we often :
A. Accurately recognize the incidence of acute and delayed CINV in our
own practices.
B. Underestimate the incidence of acute and delayed CINV in our own
practices.
Anti Nausea Chemotherapy Registry
(ANCHOR) study

The authors determined the incidence of acute and
delayed CINV after modern antiemetics.

Then they compared the actual incidences of CINV to
the predictions made by physicians and nurses
regarding these patients.
Adapted from Grunberg SM et al. Cancer 2004;100:2261-8.
Anchor Study Perception vs Reality
Moderately Emetogenic Chemotherapy
Adapted from Grunberg et al. Cancer 2004;100:2261-8.
Toxicity Assessments
Dr. H. Bliss Murphy Cancer Center,
St. John’s Newfoundland

Grade common toxicity effects of adjuvant breast cancer
patients.

Patients are assessed the day of chemotherapy and
again 2-3 days post chemotherapy.

Patients also have a number to call back if they
experience any toxicities.
Rates of CINV in
Dr. H. Bliss Murphy Cancer Center,
St. John’s Newfoundland
N=26
Rate of CINV
at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland in
comparison to the Grunberg data
N=231
Adapted from Cancer 2004;100:2261-8.
Health Care Professionals Perception of CINV
at the Dr. H. Bliss Murphy Cancer Center,
St. John’s Newfoundland
Adapted from Cancer 2004;100:2261-8.
CINV—Decreased Quality of Life

CINV adversely impact patients' quality of life.

Ovarian cancer patients in a recent study included
complete to almost complete control from CINV among
the most favorable health states, just below perfect
health and clinical remission.
Adapted from Support Care Cancer 2005;13:219-27.
CINV—Decreased Quality of Life
Adapted from Support Care Cancer 2005;13:219-27.
CINV—Decreased Quality of Life





FLIE Questionnaire
HEC-FLIE > MEC-FLIE P=0.0049
FLIE-nausea > FLIE-Vomiting P=0.0097
There is a greater negative impact on
QOL from nausea than there is from vomiting
There is a greater negative impact on
QOL from HEC than there is from MEC
FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately
emetogenic chemotherapy.
Adapted from Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472.
Summary of the Importance of
Prevention and Treatment of CINV

There still is a high level of anguish for CINV
experienced by our patients.

As health care professionals, we may not be accurately
predicting the level of CINV experienced by our patients.

CINV has a enormous impact on our patients quality of
life.
Mechanisms of CINV

Central mechanism:
 Chemotherapeutic agent activates the chemoreceptor
trigger zone (CTZ).
 Activated CTZ invokes release of various
neurotransmitters, which stimulate vomiting center.

Peripheral mechanism:
 Chemotherapeutic agent causes irritation and damage
to gastrointestinal (GI) mucosa, resulting in the release
of neurotransmitters.
 Activated receptors send signals to vomiting center via
vagal afferents.
Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology.
6th ed. Lippincott Williams & Wilkins; 2001:2869–2880.
Adapted from N Engl J Med 2008;358:2482-94.
Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dose metoclopramide.

Development of 5-HT3 antagonists has had dramatic
impact:
 Highly effective in acute vomiting, less effective for
delayed events.
 Optimal use is with dexamethasone.

Primary mechanism of action appears to be peripheral.
Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins;
2001:2869-80. Gralla RJ et al J Clin Oncol 1999;17:2971-94. Antiemetic Subcommittee of the Multinational Association of
Supportive Care in Cancer. Ann Oncol 1998;9:811-19. Endo T et al Toxicology 2000;153:189-201.
Hesketh PJ et al Eur J Cancer 2003;39:1074-80.
Substance P and Neurokinin1 (NK1)
Receptor Pathway

High density of substance P/NK1 receptors located in
brain regions implicated in the emetic reflex.

Primary mechanism of NK1 receptor blockade action
appears to be central.


Effective for both acute and delayed events.
Augments antiemetic activity of a 5-HT3 receptor
antagonist and corticosteroid.
Adapted from: Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18-24.
Saria A Eur J Pharmacol 1999;375:51-60. Hesketh PJ Support Care Cancer 2001;9:350-54.
Conceptual Model of Acute & Delayed CINV
Intensity of emesis
5-HT3-sensitive phase
Prokinetic-sensitive phase
NK1-sensitive phase
Steroid-sensitive phase
5HT
Disrupted gut motility
Cell breakdown products
0
1
2
Time (days)
3
Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds).
Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147.
4
5
Pharmacogenomics

Quest for individualized therapy.

Identification and characterization of a large number of
genetic polymorphisms(biomarkers) in drug metabolizing
enzymes and drug transporters may provide substantial
knowledge about the mechanisms of inter-individual
differences in drug response.
Pharmacogenomics

Pharmacogenomics - the study of the relationship
between specific DNA sequence variations and the
actual effect of a drug.

CYP2D6 is involved in the metabolism of all of the most
commonly available serotonin antagonists, except
granisetron, and their efficacy and side effects may
therefore be affected by the CYP2D6 polymorphism. As
this enzyme is polymorphic, several different alleles may
be present in different individuals.
Pharmacogenomics Polymorphic Distribution
 CYP2D6 mutations or deletions, poor metabolizer (PM), occur in
10% of the general population
 (UM) Ultrarapid metabolizer phenotype is observed in 2% of the
general population.
Number of Subjects
 EM (extensive metabolizer), which is the normal or usual phenotype.
PM
EM
Increasing Metabolic Capacity
URM
Pharmacogenomics in CINV

Kaiser studied the impact of patient genotype for 2D6
(CYP2D6) on efficacy of ondansetron and tropisetron for
CINV.

The ultrarapid metabolizer patients experienced
significantly more nausea and vomiting after
chemotherapy.

The impact of genotype on vomiting incidence was
observed during both early (hours 0 to 4) and late (hours
5 to 24) observation periods, although delayed nausea
and vomiting was not evaluated in this study.
Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment
with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.
J Clin Oncol 20: 2805-11, 2002.
Pharmacogenomics in CINV
Figure 2. Mean number of episodes of vomiting ({+/-} standard deviation) experienced 5-24 hours after
chemotherapy as a function of the number of active cytochrome P450 CYP2D6 enzyme genes in patients
receiving tropisetron, 5 mg once a day (A), and ondansetron, 8 mg twice a day (B)
Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with
5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.
J Clin Oncol 20:2805-11, 2002.
ANTIEMETIC GUIDELINE CONSENSUS
- Official Process Subscribed to by 9 International Oncology Groups -
International:
MASCC
North America:
- U.S.
- Canada
ASCO, NCCN
CCO
Europe:
Africa:
Australia:
ESMO, EONS
SASMO
COSA
Adapted from MASCC Antiemetic March 2008 Guideline Update.
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
ANTIEMETIC TREATMENT GUIDELINES
- The Four Emetic Risk Groups HIGH
Risk in nearly all patients (> 90%)
MODERATE
Risk in 30% to 90% of patients
LOW
Risk in 10% to 30% of patients
MINIMAL
Fewer than 10% at risk
Adapted from MASCC Antiemetic March 2008 Guideline Update.
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
- Emetic Risk Groups - Single IV Agents -
HIGH
Cisplatin
Mechlorethamine
Streptozocin
Cyclophosphamide > 1500 mg/m2
Carmustine
Dacarbazine
MODERATE
Oxaliplatin
Cytarabine >1 gm/m2
Carboplatin
Ifosfamide
Cyclophosphamide <1500 mg/m2
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Irinotecan
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
- Committee I (3/5): Emetic Risk Groups - Single IV Agents
LOW
Paclitaxel
Docetaxel
Mitoxantrone
Topotecan
Etoposide
Pemetrexed
Methotrexate
Doxorubicin HCL liposome injection
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Mitomycin
Gemcitabine
Cytarabine <100 mg/m2
5-Fluorouracil
Bortezomib
Cetuximab
Trastuzumab
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
ANTIEMETIC TREATMENT GUIDELINES
- Committee I (5/5): Emetic Risk Groups - Single Oral Agents HIGH
Hexamethylmelamine
Procarbazine
MODERATE
Cyclophosphamide
Etoposide
Temozolomide
LOW
Capecitabine
Tegafur uracil
MINIMAL
Chlorambucil
Hydroxyurea
L-Phenylalanine mustard
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Vinorelbine
Imatinib
6-Thioguanine
Methotrexate
Gefitinib
Principles of Care for Acute Highly and
Moderately Emetic Settings
UNANIMOUS CONSENSUS: CATEGORY 1 EVIDENCE
-
-
-
-
Use the lowest tested fully effective dose.
No schedule is better than a single dose given before
chemotherapy.
The antiemetic efficacy and adverse effects of serotonin
antagonist agents are comparable in controlled trials.
Intravenous and oral formulations are equally effective and
safe.
Always give dexamethasone with a 5-HT3 antagonist before
chemotherapy.
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Guideline for the Prevention of Acute Nausea and
Vomiting Following Chemotherapy of High Emetic Risk:
To prevent acute vomiting and nausea following chemotherapy
of high emetic risk, a three-drug regimen is recommended
including single doses of:



5-HT3 antagonist
Dexamethasone
Aprepitant (or fosaprepitant)
given before chemotherapy is recommended.
MASCC Level of confidence : High
MASCC Level of consensus: High
ASCO Level of evidence: I
ASCO Grade of recommendation: A
Adapted from slide from MASCC Antiemetic March 2008 Guideline Update.
Guideline for the Prevention of Acute Nausea and Vomiting
Following Chemotherapy of Moderate Emetic Risk (MEC):
Example - Women receiving a combination of anthracycline +
cyclophosphamide represent a situation with a particularly
great risk of vomiting and nausea. To prevent acute vomiting
and nausea in these women, a three-drug regimen including
single doses of:
5-HT3 antagonist
 Dexamethasone
 Aprepitant (or fosaprepitant)

given before chemotherapy is recommended.
MASCC Level of confidence: Moderate
MASCC Level of consensus: High
ASCO Level of evidence: II
ASCO Grade of recommendation: A
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Guideline for the Prevention of Acute Nausea and Vomiting
Following Chemotherapy of Moderate Emetic Risk (MEC):
In patients who receive MEC, not including a combination of
anthracycline plus cyclophosphamide:
5-HT3 receptor antagonist +
 Dexamethasone

is recommended for prophylaxis of acute nausea and vomiting
in the first course.
MASCC level of confidence: High
MASCC level of consensus: High
ASCO level of evidence: I
ASCO grade of recommendation: A
Adapted from MASCC Antiemetic March 2008 Guideline Update.
B.C. Cancer Agency Antiemetic regimens
Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults.
Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E325B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf
ONS Putting Evidence into Practice
Adapted from ONS PEP Nausea Retrieved July 21, 2008 from
http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf
ONS Putting Evidence into Practice – Cont’d
Adapted from ONS PEP Nausea Retrieved July 21, 2008 from
http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf
Cancer Care Ontario - Telephone Nursing Practice
- and Symptom Management Guidelines
Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from
http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf
Cancer Care Ontario - Telephone Nursing Practice
and Symptom Management Guidelines
Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from
http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf
Common CINV Challenges

Challenges in multiple-day chemotherapy regimens

Breakthrough CINV

Anticipatory CINV

Delayed CINV
Multiple-Day Chemotherapy Regimens

Challenge – Patients receiving multi-day chemotherapy
(chemotherapy administered over several days per
cycle) are at risk for both acute and delayed nausea and
vomiting.

It is difficult to recommend appropriate antiemetics for
each day since acute and delayed may overlap after the
initial day of chemotherapy.

The period of risk for delayed nausea and vomiting also
depends on the emetogenic potential of the last
chemotherapy agent administered in the regimen.
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Multi-Day Chemotherapy Regimens (continued)

A 5-HT3 receptor antagonist should be administered
prior to each days 1st dose of moderately or highlyemetogenic chemotherapy.

Dexamethasone should be administered once daily
either orally or IV for every day of chemotherapy and for
2-3 days post chemotherapy.

Aprepitant may be used for multi-day chemotherapy.
Aprepitant 125 mg on day 1, then aprepitant 80 mg daily
on days 2 and 3 along with dexamethasone. Based on
Phase II data, aprepitant may be safely administered on
days 4 and 5 after chemotherapy.
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Breakthrough CINV

Breakthrough emesis refers to vomiting that occurs
despite prophylactic treatment and/or requires rescue.

Refractory emesis refers to emesis that occurs during
subsequent treatment cycles when antiemetic prophylaxis
and/or rescue have failed in earlier cycles.

Challenge - Breakthrough nausea and vomiting
represents a difficult situation as ongoing refractory
nausea is hard to reverse.
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Breakthrough CINV (continued)

Management Strategies -Give around the clock
administration versus prn.

Additional agents should be from a different drug class
than initial therapy. No one treatment is better than the
other.
 Possibilities include: dopamine antagonists,
metoclopramide, haloperidol, cannabinoids,
corticosteroids, or agents such as lorazepam

If patient has dyspepsia, consider antacid therapy (H2
blocker or Proton Pump Inhibitor).
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Breakthrough CINV – Cont’d
Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults.
Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E325B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf
Anticipatory CINV

Anticipatory nausea and/or vomiting is the occurrence of
nausea and/or vomiting before patients receive their
chemotherapy treatment. Because it is a conditioned
response, it can only occur after a negative past
experience with chemotherapy.

Challenge - Anticipatory nausea and/or vomiting occurs in
18% to 57% of chemotherapy patients.

Younger patients may be more susceptible as they
generally receive more aggressive therapy and have
poorer emesis control than older patients.
Adapted from: 1. Roscoe JA, et al. J Pain Symptom Manage 2000;20:113.
2. Morrow GR, et al. Support Care Cancer 1998;6:244.
Anticipatory CINV (continued)

The most effective way to treat is to prevent CINV by
using optimal antiemetics during every cycle of therapy.

Either:
 Alprazolam PO 0.25 to 0.5 mg t.i.d. beginning on the
night before treatment OR;
 Lorazepam 0.5-2 mg PO on the night before and the
morning of treatment.

Behavioral therapy

Systemic densensitization
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Delayed CINV

Challenge - Delayed emesis is 2.5 times more prevalent
than acute emesis.

For moderately emetogenic chemotherapy:
 Delayed nausea exceeds acute nausea by 16%.
 Delayed emesis exceeds acute emesis by 15%.

For highly emetogenic chemotherapy:
 Delayed nausea exceeds acute nausea by 27%.
 Delayed emesis exceeds acute emesis by 38%.
Adapted from Grunberg et al. Cancer 2004;100:2261.
Prognostic Factors for Delayed CINV

Strongest predictor of delayed nausea and vomiting was
the occurrence of acute nausea and vomiting.

Patients aged 52 years or younger and women were
more likely to have delayed nausea than were those
older than 52 years and men.

A high expectation of nausea was a significant predictor
of more severe nausea.
Adapted from The Lancet Oncology October 2005;Vol(6):Issue(10):765-72.
Case 1
Initial Presentation

Mary T. is a 56-year-old female who was completely
asymptomatic when a routine mammogram showed two
lesions. She underwent diagnostic testing and had a
mastectomy and auxiliary lymph node dissection.

Diagnosis – T3 (more than 5 cm) N0(0/6 lymph nodes)
M0. poorly differentiated invasive ductal carcinoma of
right breast, ER/PR positive and HER-2/neu negative.
Initial Presentation

PAST MEDICAL HISTORY: Unremarkable.

SOCIAL HISTORY: School teacher, married, mother of
two grown children living away, non smoker, occasional
drink on the weekends.

MEDICATIONS: Ranitidine 150 mg b.i.d.,
Lorazepam 1 mg prn

SYSTEM INQUIRY: Unremarkable.

Allergies : NKA (drugs, food, environmental allergens)
First Cycle of Chemotherapy (FEC)

The patient is prescribed FEC (Fluorouracil, Epirubicin,
Cyclophosphamide) – for 3 cycles followed by Taxotere
for 3 cycles.

She was given Ondansetron 8 mg and Dexamethasone
8 mg prior to her first cycle of chemotherapy.

She was given a prescription for Ondansetron 8 mg and
Dexamethasone 4 mg po b.i.d. x 2 days post
chemotherapy as well as Metoclopramide 10 mg po
q6hprn to be taken post chemotherapy.
Nausea post Cycle 1

When she returned for cycle two she informed the
pharmacist that she had vomited on day 2 and that she
had experienced nausea for days 2-5 post
chemotherapy.

She rates this nausea as a 8/10 for days 2-4 and 6/10 for
day 5.
Case 1: Question 1

What anti-emetics would you recommend to be given
prior to chemotherapy for her second cycle of FEC?
A.
Metoclopramide 10 mg
B.
Ondansetron 8 mg, Dexamethasone 8 mg and
Aprepitant 125 mg
A.
Ondansetron 8 mg and Dexamethasone 8 mg
Answer Question 1 = B
Guideline for the Prevention of Acute Nausea and Vomiting
Following Chemotherapy of Moderate Emetic Risk (MEC):
Women receiving a combination of anthracycline +
cyclophosphamide represent a situation with a particularly
great risk of vomiting and nausea. To prevent acute vomiting
and nausea in these women, a three-drug regimen including
single doses of:

5-HT3 antagonist

Dexamethasone

Aprepitant (or fosaprepitant)
given before chemotherapy is recommended.
Adapted from MASCC Antiemetic March 2008 Guideline Update.
Case 1: Question 2

What anti-emetics would be offered to this patient as an antinausea take home prescription for the FEC (cycle 2)
regimen?
A. Dexamethasone 8 mg bid x 3 days and Metoclopramide 10
mg q6hprn.
B. Metoclopramide 10 mg q6hprn.
C. Aprepitant 80 mg on days 2 and 3, Ondansetron 8 mg and
Dexamethasone 4 mg bid x 2 days and Metoclopramide 10
mg q6hprn.
Answer Question 2
Adapted from http://www.bccancer.bc.ca.
Case 1: Question 3

What other actions can the pharmacist take to
help M.T. control her CINV?
Answer Question 3







Explore patient adherence with anti-emetics.
Assess effectiveness/ineffectiveness of anti-emetic
plan.
Follow up toxicity assessments (use CCO telephone
toxicity guidelines).
CINV education.
Communication with her other health care providers.
Patient nausea diary (CANO patient education for
CINV).
Promote patient involvement through patient resources:
►
►
Chemotherapy and You: A Guide to Self-Help During Cancer
Treatment, http://www.nci.nih.gov/cancerinfo/chemotherapyand-you
http://www.cancernausea.com
Case 1: Question 4

The pharmacist asks the patient what medications she is
currently taking.

She informs the nurse she is taking Warfarin, Metoprolol
and ASA.
Should she be concerned about a drug interaction with
Warfarin and Aprepitant?
Case 1: Question 5
Which of the following may occur with the addition of
aprepitant to M.T’s regimen?
A. INR may decline
B. INR may increase
C. Warfarin levels may rise
Answer Question 4 and 5
Warfarin Aprepitant Interaction


Aprepitant is a CYP3A4 substrate, a 3A4 inhibitor and
inducer, and a 2C9 inducer.
INR may decline.
Adapted from Aprepitant Monograph. Retrieved July 22, 2008 from
http://www.cancercare.on.ca/pdfdrugs/aprepitant.pdf
Importance of Medication Reconciliation

Pilot Project of Medication Reconciliation in St. John’s,
Newfoundland Cancer Center

Summer project

Pharmacy Students

Obtaining an accurate medication history for
chemotherapy patients
Total Number of Medications vs.
Total Number of Inaccuracies or Omissions
Cancer Care Program
Identification of the number of patients with
inaccuracies or omissions as well as the
number of drug related problems identified
Cancer Care Program
Identification of the number of patients with
inaccuracies or omissions as well as the
number of patients taking OTC/Herbals
Cancer Care Program
Starting Docetaxel after FEC

M.T. completed her three cycles of FEC as part of the
FEC-D regimen. Since the addition of Aprepitant, her
nausea control has been much better.

Since she is starting Docetaxel, she needs to take
Dexamethasone 8 mg po b.i.d. for 3 days, starting 24
hours prior to chemotherapy.

The medical oncology team would like to keep M.T. on
Aprepitant due to her improved response.
Case 1: Question 6
As the oncology pharmacist, you tell the team that they need to
be concerned about Aprepitant drug interactions.
Which of the following would be correct to tell the team about
Aprepitant:
A. Aprepitant is a Substrate for CYP3A4,and Moderate
Inhibitor of CYP3A4.
B. Aprepitant is a Weak Inducer of CYP3A4 and CYP2C9.
C. Both A and B are correct.
Answer Question 6 - Aprepitant and P450

Substrate for CYP3A4, CYP2C19 and CYP1A2

Weak Inducer of CYP3A4 and CYP2C9

Moderate Inhibitor of CYP3A4

Weak inhibitor of CYP2C9 and CYP2C19
Case 1: Question 7
The general recommendations for dosing dexamethasone when
combined with Aprepitant is:
A. Reduce the dose of dexamethasone by 50%
B. Increase the dose of dexamethasone by 50%
C. Do not adjust the dose of dexamethasone
Answer Question 7

Aprepitant increases the AUC of dexamethasone when
the two are administered concomitantly.

Reduce dexamethasone dose by 50%.
Case 1: Question 8
What would be your recommendations for dosing
dexamethasone for Docetaxel premedication when combined
with Aprepitant for M.T. :
A. Reduce the dose of dexamethasone by 50%
B. Increase the dose of dexamethasone by 50%
C. Do not adjust the dose of dexamethasone
Case 2
 Jimmy
T. is a A 27 year old with a history of T2N2M1a,
Stage III non-seminoma testicular cancer. He had surgery
for this and in follow up was found to have metastatic
disease. He had at least two lung lesions as well as some
mediastinal adenopathy and retroperitoneal adenopathy.
Initial Presentation

PAST MEDICAL HISTORY: Unremarkable.

SOCIAL HISTORY: He lives with his common law
girlfriend,
Occasional drink on weekends, non smoker

MEDICATIONS: Acetaminophen prn

SYSTEM INQUIRY: Unremarkable.

Allergies : NKA (drugs, food, environmental allergens)a
First cycle of chemotherapy (BEP)
The patient is prescribed BEP (BLEOMYCIN-ETOPOSIDECISPLATIN) Chemotherapy for 4 cycles.
Case 2 : Question 1
What anti-emetics would you recommend to be given prior to
chemotherapy for his first cycle of BEP?
Metoclopramide 10 mg pre chemotherapy for 5 days
B. Ondansetron 8 mg, Dexamethasone 8 mg and Aprepitant
125 mg on day 1 pre chemotherapy and Ondansetron 8 mg,
Dexamethasone 4 mg and Aprepitant 80 mg on days 2-5
pre chemotherapy
C. Ondansetron 8 mg and Dexamethasone 8 mg pre
chemotherapy on days 1-5
A.
Answer Question 1
Multiple Day Chemotherapy



A 5-HT3 receptor antagonist should be administered
prior to each days 1st dose of moderately or highlyemetogenic chemotherapy.
Dexamethasone should be administered once daily
either orally or iv for every day of chemotherapy and for
2-3 days post chemotherapy.
Aprepitant may be used for multi-day chemotherapy.
Aprepitant 125 mg on day 1, then aprepitant 80 mg daily
on days 2 and 3 along with dexamethasone. Based on
Phase II data, aprepitant may be safely administered on
days 4 and 5 after chemotherapy.
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Case 2: Question 2
The oncology pharmacist performs a toxicity assessment on
Jimmy T. 3 days (Monday afternoon) post chemotherapy. The
patient complains of significant nausea that started on Sunday
evening. He vomited x 1 on Monday morning. He rates the
nausea as 8 out of 10.
He states he was given a prescription for Ondansetron 8 and
Dexamethasone 4 mg po bid x 2 days as well as
Metoclopramide 10 mg po q6hprn. The Dexamethasone and
Ondansetron were completed on Sunday morning. He did not
take the Metoclopramide as he wasn’t sure if he should.
What should the oncology pharmacist do for this patient?
Answer Question 2 - Breakthrough CINV



Management Strategies -Give around the clock
administration versus prn .
Additional agents should be from a different drug class
than initial therapy. No one treatment is better than the
other.
 Possibilities include: metoclopramide, haloperidol,
prochlorperazine, cannabinoids, corticosteroids, or
agents such as lorazepam.
If patient has dyspepsia, consider antacid therapy
(H2 blocker or Proton Pump Inhibitor).
Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,
Case 2: Question 3
Which of the following consequence of unresolved CINV do
you consider the most important for this patient?
A. Nutritional depletion and anorexia
B. Discontinuation of therapy
C. Esophageal tears
Unresolved issues in CINV?

Role of risk factor assessment in tailoring antiemetics to
the individual at the onset of chemotherapy.

Need to develop a better understanding of the
pathophysiology of delayed CINV.

Increase awareness of CINV for oncology professionals.

Newer agents/ formulations
 Olanzapine
 New NK-1 antagonists
 New formulations of 5HT3 antagonists eg transdermal
patches, oral sprays, longer acting SC injections
Emend Coverage

NL Coverage
Conclusion

Chemotherapy-induced nausea/vomiting (CINV) is a
common side effect despite antiemetic therapy.

Health care professionals need to ensure patients are
being treated according to current antiemetic guidelines.

‘It is always better and easier to PREVENT than to treat
nausea/vomiting associated with chemotherapy.’
Acknowledgements



Katrina Mulherin, Pharm D Student
Barbara Wilson, RN, BN, MS, CON(C)
Staff (nurses, physicians, pharmacists) at St. John’s
Cancer Center