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