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Title: Evidence, Challenges


1
Evidence, Challenges and Solutions  Preventing
and Managing Chemotherapy-Induced Nausea and
Vomiting
Scott Edwards, Pharm D Clinical Oncology
Pharmacist Eastern Health, St. Johns, NL NOPS
2008
2
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. 198319203-8. 2Griffin AM et al. Ann
Oncol. 19967189-95. 3De Boer-Dennert M et al.
Br J Cancer. 1997761055-61. 4 Lindley C et al.
Cancer Pract 1999759-65.
3
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
  • ASHP Am J Health Syst Pharm 199956729-764
  • NCCN Practice Guidelines in OncologyVersion 3.
    2008. Antiemesis

4
Rates of CINV
Adapted from 1. Hickok JT, et al. Cancer.
2003972880-6. 2.http//www.ashpadvantage.com/pre
vious_meetings/mcm_2005/cemornings2005/CEM_CINV_ha
ndout.pdf
5
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
  • Gregory RE et al. Drugs. 1998. 2. Hesketh PJ et
    al. J Clin Oncol. 1997.
  • 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
    20041012701-2708

6
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.
7
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
199956729-64.
8
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
OncologyVersion 3. 2008. Antiemesis.
9
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
OncologyVersion 3. 2008. Antiemesis.
10
Poll of the audienceAs 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.

11
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
20041002261-8.
12
Anchor Study Perception vs Reality Moderately
Emetogenic Chemotherapy
Adapted from Grunberg et al. Cancer
20041002261-8.
13
Toxicity Assessments
Dr. H. Bliss Murphy Cancer Center, St. Johns
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.

14
Rates of CINV in
Dr. H. Bliss Murphy Cancer Center, St. Johns
Newfoundland
N26
15
Rate of CINV
at the Dr. H. Bliss Murphy Cancer Center, St.
Johns Newfoundland in comparison to the Grunberg
data
N231
Adapted from Cancer 20041002261-8.
16
Health Care Professionals Perception of CINV at
the Dr. H. Bliss Murphy Cancer Center, St.
Johns Newfoundland
Adapted from Cancer 20041002261-8.
17
CINVDecreased 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 200513219-27.
18
CINVDecreased Quality of Life
Adapted from Support Care Cancer 200513219-27.
19
CINVDecreased Quality of Life
  • FLIE Questionnaire
  • HEC-FLIE gt MEC-FLIE P0.0049
  • FLIE-nausea gt FLIE-Vomiting P0.0097
  • There is a greater negative impact onQOL from
    nausea than there is from vomiting
  • There is a greater negative impact onQOL 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.
2006244472.
20
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.

21
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 200128692880.
22
Adapted from N Engl J Med 20083582482-94.
23
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 20012869-80.
Gralla RJ et al J Clin Oncol 1999172971-94.
Antiemetic Subcommittee of the Multinational
Association of Supportive Care in Cancer. Ann
Oncol 19989811-19. Endo T et al Toxicology
2000153189-201. Hesketh PJ et al Eur J Cancer
2003391074-80.
24
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
200263(suppl 11)18-24. Saria A Eur J Pharmacol
199937551-60. Hesketh PJ Support Care Cancer
20019350-54.
25
Conceptual Model of Acute Delayed CINV
5-HT3-sensitive phase
Prokinetic-sensitive phase
NK1-sensitive phase
Intensity of emesis
Steroid-sensitive phase
Disrupted gut motility
5HT
Cell breakdown products
0
2
1
3
4
5
Time (days)
Adapted from Andrews Davis. In Andrews PLR
Sanger GJ (Eds). Emesis in Anti-Cancer Therapy
Mechanisms and Treatment. London Arnold
1993147.
26
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.

27
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.

28
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.
  • EM (extensive metabolizer), which is the normal
    or usual phenotype.

Number of Subjects
PM
EM
URM
Increasing Metabolic Capacity
29
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.
30
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 202805-11, 2002.
31
ANTIEMETIC GUIDELINE CONSENSUS
- Official Process Subscribed to by 9
International Oncology Groups -
International MASCC

North America
- U.S. ASCO, NCCN
- Canada CCO

Europe ESMO, EONS
Africa SASMO
Australia COSA
Adapted from MASCC Antiemetic March 2008
Guideline Update.
32
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
ANTIEMETIC TREATMENT GUIDELINES - The Four
Emetic Risk Groups -
HIGH Risk in nearly all patients (gt 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.
33
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
- Emetic Risk Groups - Single IV Agents -
HIGH Cisplatin Mechlorethamine Streptozocin Cyclophosphamide gt 1500 mg/m2 Carmustine Dacarbazine Cisplatin Mechlorethamine Streptozocin Cyclophosphamide gt 1500 mg/m2 Carmustine Dacarbazine
MODERATE Oxaliplatin Cytarabine gt1 gm/m2 Carboplatin Ifosfamide Cyclophosphamide lt1500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan
Adapted from MASCC Antiemetic March 2008
Guideline Update.
34
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
- Committee I (3/5) Emetic Risk Groups - Single
IV Agents
LOW Paclitaxel Docetaxel Mitoxantrone Topotecan Etoposide Pemetrexed MethotrexateDoxorubicin HCL liposome injection Mitomycin Gemcitabine Cytarabine lt100 mg/m2 5-Fluorouracil Bortezomib Cetuximab Trastuzumab
Adapted from MASCC Antiemetic March 2008
Guideline Update.
35
MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES
ANTIEMETIC TREATMENT GUIDELINES - Committee I
(5/5) Emetic Risk Groups - Single Oral Agents -
HIGH Hexamethylmelamine Procarbazine Hexamethylmelamine Procarbazine
MODERATE Cyclophosphamide Etoposide Temozolomide Vinorelbine Imatinib
LOW CapecitabineTegafur uracil CapecitabineTegafur uracil
MINIMAL Chlorambucil Hydroxyurea L-Phenylalanine mustard 6-Thioguanine Methotrexate Gefitinib
Adapted from MASCC Antiemetic March 2008
Guideline Update.
36
Principles of Care for Acute Highly
andModerately 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.
37
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.
38
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.
39
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.
40
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-3F
12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pd
f
41
ONS Putting Evidence into Practice
Adapted from ONS PEP Nausea Retrieved July 21,
2008 from http//www.ons.org/outcomes/volume1/naus
ea/pdf/nauseaPEPCard.pdf
42
ONS Putting Evidence into Practice Contd
Adapted from ONS PEP Nausea Retrieved July 21,
2008 from http//www.ons.org/outcomes/volume1/naus
ea/pdf/nauseaPEPCard.pdf
43
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/doc
uments/NursingTelephonePracticeGuidelines.pdf
44
Cancer Care Ontario - Telephone Nursing
Practiceand Symptom Management Guidelines
Adapted from CCO Telephone Assessments. Retrieved
July 21, 2008 from http//www.cancercare.on.ca/doc
uments/NursingTelephonePracticeGuidelines.pdf
45
Common CINV Challenges
  • Challenges in multiple-day chemotherapy regimens
  • Breakthrough CINV
  • Anticipatory CINV
  • Delayed CINV

46
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
OncologyVersion 3. 2008. Antiemesis,
47
Multi-Day Chemotherapy Regimens (continued)
  • A 5-HT3 receptor antagonist should be
    administered prior to each days 1st dose of
    moderately or highly-emetogenic 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
OncologyVersion 3. 2008. Antiemesis,
48
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
OncologyVersion 3. 2008. Antiemesis,
49
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
OncologyVersion 3. 2008. Antiemesis,
50
Breakthrough CINV Contd
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-3F
12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pd
f
51
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 200020113.
  • 2. Morrow GR, et al. Support Care Cancer
    19986244.

52
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
OncologyVersion 3. 2008. Antiemesis,
53
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 20041002261.
54
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
2005Vol(6)Issue(10)765-72.
55
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.

56
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)

57
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.

58
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.

59
Case 1 Question 1
  • What anti-emetics would you recommend to be given
    prior to chemotherapy for her second cycle of
    FEC?
  • Metoclopramide 10 mg
  • Ondansetron 8 mg, Dexamethasone 8 mg and
  • Aprepitant 125 mg
  • Ondansetron 8 mg and Dexamethasone 8 mg

60
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.
61
Case 1 Question 2
  • What anti-emetics would be offered to this
    patient as an anti-nausea 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.

62
Answer Question 2
Adapted from http//www.bccancer.bc.ca.
63
Case 1 Question 3
  • What other actions can the pharmacist take to
    help M.T. control her CINV?

64
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/cancerinf
    o/chemotherapy-and-you
  • http//www.cancernausea.com

65
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?

66
Case 1 Question 5
  • Which of the following may occur with the
    addition of aprepitant to M.Ts regimen?
  • A. INR may decline
  • B. INR may increase
  • C. Warfarin levels may rise

67
Answer Question 4 and 5Warfarin 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
68
Importance of Medication Reconciliation
  • Pilot Project of Medication Reconciliation in St.
    Johns, Newfoundland Cancer Center
  • Summer project
  • Pharmacy Students
  • Obtaining an accurate medication history for
    chemotherapy patients

69
Total Number of Medications vs. Total Number of
Inaccuracies or Omissions
Cancer Care Program
70
Identification of the number of patients with
inaccuracies or omissions as well as the number
of drug related problems identified
Cancer Care Program
71
Identification of the number of patients with
inaccuracies or omissions as well as the number
of patients taking OTC/Herbals
Cancer Care Program
72
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.

73
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.

74
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

75
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

76
Answer Question 7
  • Aprepitant increases the AUC of dexamethasone
    when the two are administered concomitantly.
  • Reduce dexamethasone dose by 50.

77
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

78
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.

79
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

80
First cycle of chemotherapy (BEP)
  • The patient is prescribed BEP (BLEOMYCIN-ETOPOSIDE
    -CISPLATIN) Chemotherapy for 4 cycles.

81
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
  • 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
  • Ondansetron 8 mg and Dexamethasone 8 mg pre
    chemotherapy on days 1-5

82
Answer Question 1Multiple Day Chemotherapy
  • A 5-HT3 receptor antagonist should be
    administered prior to each days 1st dose of
    moderately or highly-emetogenic 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
OncologyVersion 3. 2008. Antiemesis,
83
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 wasnt sure if he should.
  • What should the oncology pharmacist do for this
    patient?

84
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
OncologyVersion 3. 2008. Antiemesis,
85
Case 2 Question 3
  • Which of the following consequence of unresolved
    CINV do you consider the most important for this
    patient?
  • Nutritional depletion and anorexia
  • Discontinuation of therapy
  • Esophageal tears

86
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

87
Emend Coverage
  • NL Coverage

88
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.

89
Acknowledgements
  • Katrina Mulherin, Pharm D Student
  • Barbara Wilson, RN, BN, MS, CON(C)
  • Staff (nurses, physicians, pharmacists) at St.
    Johns Cancer Center
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