The N Factor: Prevention & Treatment of Chemotherapy-Induced Nausea & Vomiting

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4 5T H A N N U A L G R E AT L A K E S C A N C E R N U R S I N G C O N F E R E N C E S O M E R S E T I N N , T R O Y, M I C H I G A N O C TO B E R 2 0 1 2 J O A N N E P. M C G U R N , B S P H A R M , B C O P C L I N I C A L P H A R M A C I S T M U N S O N M E D I C A L C E N T E R T R A V E R S E C I T Y, M I C H I G A N

The

“N”

Factor:

Prevention & Treatment of

(2)

Objectives

For the patient receiving chemotherapy, the

participant will be able to:

 Recognize the patient- and drug- specific risk factors

associated with chemotherapy-induced nausea and vomiting (CINV).

 Understand antiemetic drug classifications and be able to

develop a plan for adequate anti-emetic prophylaxis and breakthrough treatment.

(3)

Goal of Anti-Emetic Therapy

PREVENTION!

 Optimally, no patient should become nauseated or have

vomiting as a result of their cancer treatment

MINIMIZE

 If nausea/vomiting cannot be prevented,

the goal is to minimize the extent and duration of symptoms

RESCUE

 When a patient has been optimally

treated but still has breakthrough nausea or vomiting

(4)

Guidelines

NCCN (National Comprehensive Cancer Network)

 Revised several times each year.

 Website: http://www.nccn.org

 NCCN Guidelines – Antiemesis pocket Version 1.2012 available

ASCO (American Society of Clinical Oncology)

 Updated periodically with most recent in 2011.

MASCC (Multinational Association of Supportive Care in Cancer)  Involves nine different oncology organizations from around the world

 Updated every 6-12 months based on specific criteria. Most recent

update 2011.

 Website: http://www.mascc.org

 MAT (MASCC Antiemesis Tool)

Other contributors:

 Oncology Nursing Society (ONS), American Society of Health-System

(5)

Use of Guidelines

Use of guidelines will help to:

 Optimize patient care

 Standardize the ordering, preparation, and administration of

anti-emetic therapies

 Function as an educational tool for new staff

 Provide a systematic method of assessment and adjustment

of treatment in challenging patients

 Aid in predicting volume and containing

(6)

Definitions…

Nausea

 The inclination to vomit or a ‘feeling’ in the throat or

epigastric region alerting an individual that vomiting is imminent

 Usually involves concurrent tachycardia and

hyper-salivation

 Nausea is very subjective

 Response to drug therapy is often

(7)

Definitions…

Vomiting

 “Reverse peristalsis” – contraction of the

abdominal muscles and diaphragm result in the expulsion of gastric contents through the

mouth

 Can objectively be quantified

 In general, is responsive to drug therapy

Retching

 The labored movement of abdominal and

thoracic muscles before vomiting

 Spasmodic and abortive respiratory

movements, distinct from vomiting

 Can objectively be quantified

(8)

Definitions…

Acute emesis

 Occurs during the first 24 hours after chemotherapy

administration, with the peak seen at about 5-6 hours

 Responsive to drug therapy

Delayed emesis

 Vomiting occurring after the first 24 hours and, depending on

the offending drug, may last up to 5 days (or longer) after chemotherapy administration, with peak in 2 to 3 days

 Mechanism involves stimulation of neuroreceptors other than

serotonin

 Patients are at higher risk for developing anticipatory N/V  Variable response to drug therapy

Lohr,L., Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. J Hematol Oncol Pharm. 2011;1(4):13-21.

(9)

Definitions.

Breakthrough emesis

 Vomiting that occurs on any day of treatment despite

appropriate antiemetic prophylaxis and/or requires the use of rescue therapy

Refractory emesis

 Emesis that occurs during subsequent

treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles

Roila, F, Hesketh PJ, Herrstadt, J. Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 2006;17:20-28.

(10)

Definitions…

Anticipatory Nausea and Vomiting

 A conditioned or learned response to chemotherapy that

develops in up to 25% of patients by the 4th treatment cycle

 Triggered by sights, smells, or sounds and is

due to inadequate control of N/V in the past

 Negative expectations and emotional stress

prior to treatment can also have an impact on presence or absence of ANV

Prevention of N/V with initial cycles of

chemotherapy is the best treatment

(11)

Causes of Emesis In Cancer Patients

GIT

 Partial or complete bowel obstruction, gastric outlet

obstruction, constipation (disease or drug induced)

 Gastroparesis

 Tumor or chemotherapy (eg., vincristine) induced  Other causes (eg., diabetes)

 Liver metastases

Vestibular dysfunction

Increase ICP due to brain metastases

Metabolic imbalance

 Hypercalcemia, hyponatremia  Uremia, hyperglycemia 

Psychophysiologic

 Anxiety, pain  Anticipatory N/V

(12)

Physiology of CINV

Complex interaction between receptors in the central and

peripheral nervous systems and neurotransmitters

Two primary sources of afferent input that can initiate the

emetic reflex following chemotherapy:

Abdominal Vagal Afferents

The Area Postrema

(13)

Physiology of CINV

Abdominal Vagal Afferents

 Appear to contribute the most to

the emetic process

 Contain a variety of receptors at their

terminal ends

 5-Hydroxytryptamine3 (5-HT3)

(serotonin)

 Neurokinin-1 (NK1)

 Cholecystokinin-1

 End receptors are located in close proximity to enterochromaffin

cells in the proximal small intestine which contain local mediators such as 5-HT (serotonin), Substance P, and cholecystokinin

 In this process, 5-HT is believed to play the most important role

(14)

Physiology of CINV

Abdominal Vagal Afferents

 Chemotherapy stimulates cells in

small intestine, releasing mediators which bind to the vagal fibers

 Once bound, an afferent stimulus is

carried to the nucleus tractus

solitarius (NTS) in the dorsal brain

stem and subsequently activates the “central pattern generator”

 The dorsal vagal complex contains

many receptors of significance in the emetic process including NK1, 5-HT3 and dopamine-2 receptors

(15)

Physiology of CINV

The Area Postrema

(previously termed ‘Chemoreceptor Trigger Zone’)

 A circumventricular structure located at the caudal end of

the fourth ventricle

 Blood-brain-barrier is quite permeable in this part of the

brain and is thought to be accessible to blood and cerebrospinal fluid-borne emetic stimuli

 Opioids can induce emesis when bound to this area

 It is possible that gut-derived

peptides and chemotherapy metabolites could also cause

emesis by binding at this site

(16)

Physiology of CINV

Amygdala

 An almond-shaped mass of nuclei

located deep within the temporal lobe of the brain

 It is a limbic system structure

whose primary role is the processing of memory and emotional reactions

Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358:2482-94 Amygdala, Wikipedia.

(17)

Physiology

of CINV

Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358:2482-94.

(18)

Reflex Pathways of Vomiting

Central Pattern Generator 1. Salivatory Center 2. Vasomotor Center 3. Respiratory Center 4. Cranial Nerves

Abdominal Diaphragm Stomach Esophagus

(19)

Neurotransmitters

Four classes of neurotransmitters have been implicated

in CINV

 Dopamine

 The focus of early antiemetic studies

 5-Hydroxytryptamine (5-HT)

 The most important in acute CINV

 Substance P (a member of a group of peptides called tacykinins)

 Binds to neurokinin-1, 2, and 3 receptors

 NK1 receptors are found throughout CNS (including the dorsal vagal

complex) and in the GI tract

 Endocannabinoids

 Unlike the above which have a pro-emetic role, endogenous

cannabinoids exert an agonistic antiemetic effect.

(20)

How do you determine a

patient’s risk for CINV ?

(21)

Patient-Related Risk Factors

Patient characteristics that may increase the risk

of CINV:

 Age < 50 years  Female sex

 No/minimal history of alcohol use

 Prior experience or poor emetic

control with previous chemotherapy

 History of hyperemesis or extreme

morning sickness with pregnancy

 History of motion sickness, depression

or other psychosocial factors Adapted from multiple resources.

(22)

Treatment-Related Risk Factors

Categories of Emetic Risk

HIGH

(Level 4)  >90% frequency of emesis 

MODERATE

(Level 3)  31-90% frequency of emesis 

LOW

(Level 2)  10-30% frequency of emesis 

MINIMAL

(level 1)  <10% frequency of emesis

(23)

HIGH Risk (>90%)

Carmustine >250mg/m2

Cisplatin >50mg/m2

Cyclophosphamide >1.5g/m2

Dacarbazine

Doxorubicin >60mg/m2

Epirubicin >90mg/m2

Ifosfamide >10g/m2

Mechlorethamine

Streptozocin

AC combination

(defined as either doxorubicin or epirubicin with cyclophosphamide)

(24)

MODERATE Risk (31-90%)

 Aldesleukin >12-15 MIU/m2  Amifostine <300mg/m2  Arsenic trioxide  Azacitidine  Bendamustine  Busulfan  Carboplatin  Carmustine </=250mg/m2  Cisplatin <50mg/m2  Clofarabine  Cyclophosphamide </=1.5g/m2  Cytarabine >200mg/m2  Dactinomycin  Daunorubicin  Doxorubicin </=60mg/m2  Epirubicin </=90mg/m2  Idarubicin  Ifosfamide <10g/m2

 Interferon alfa >/=10 MIU/m2  Irinotecan

 Melphalan

 Methotrexate >/=250mg/m2  Oxaliplatin

 temozolomide

(25)

LOW Risk (10-30%)

Amifostine </=300mg/m2

Aldesleukin </=12 MIU/m2

Cabazitaxel

Cytarabine 100-200mg/m2

Docetaxel

Doxorubicin (liposomal)

Eribulin

Etoposide

5-Fluorouracil

Floxuridine

Gemcitabine

Interferon alfa >5<10

MIU/m2

Ixabepilone

Methotrexate >50mg/m2

<250mg/m2

Mitomycin

Mitoxantrone

Paclitaxel

Paclitaxel-albumin

Pemetrexed

Pentostatin

Pralatrexate

Romidepsin

Thiotepa

topotecan

(26)

MINIMAL Risk (<10%)

 Alemtuzumab  Asparaginase  Bevacizumab  Bleomycin  Bortezomib  Cetuximab  Cladribine  Cytarabine <100mg/m2  Decitabine  Denileukin diftitox  Dexrazoxane  Fludarabine

 Interferon alfa </=5 MIU/m2

 Ipilimumab  Methotrexate </=50mg/m2  Nelarabine  Ofatumumab  Panitumumab  Pegasparaginase  Peginterferon  Rituximab  Temsirolimus  Trastuzumab  Valrubicin  Vinblastine  Vincristine  Vinorelbine NCCN Guidelines. Antiemesis Version 1.2012

(27)

Rule(s) of Thumb

Combination therapy

 is usually more emetogenic than single agent regimens

Multiday regimens

 put patient at risk for both acute and delayed N/V

Emetogenicity is dose-related,

 with high-dose chemotherapy regimens (eg., stem cell transplant

conditioning regimens) being more emetogenic than lower doses 

Emetogenic potential may be different on different

days of treatment –

 antiemetics should be tailored accordingly

Antiemetic choices should be based on the drug with

(28)

Making it Real…

AJ

is a 46-year old woman who was recently diagnosed with extensive stage small cell lung cancer. She is a non-drinker who stopped smoking 12 years ago. Her past medical history is significant for depression, morning

sickness with multiple pregnancies and motion sickness. Her oncologist plans to use cisplatin 75mg/m2 (day 1) and etoposide 100mg/m2 (days 1-3) every 28 days to treat her disease.

(29)

What About AJ…

AJ

is a

46

-year old

woman

who was recently

diagnosed with extensive stage small cell lung

cancer. She is a non-drinker who stopped smoking

12 years ago. Her past medical history is significant

for depression, morning sickness with multiple

pregnancies and motion sickness. Her oncologist

plans to use cisplatin 75mg/m2 and etoposide

100mg/m2 every 28 days to treat her disease.

(30)

What About AJ…

AJ

is a 46-year old woman who was recently

diagnosed with extensive stage small cell lung

cancer. She is a

non-drinker

who stopped smoking

12 years ago. Her past medical history is significant

for depression, morning sickness with multiple

pregnancies and motion sickness. Her oncologist

plans to use cisplatin 75mg/m2 and etoposide

100mg/m2 every 28 days to treat her disease.

(31)

What About AJ…

AJ

is a 46-year old woman who was recently

diagnosed with extensive stage small cell lung

cancer. She is a non-drinker

who stopped smoking

12 years ago. Her past medical history is significant

for

depression

,

morning sickness

with multiple

pregnancies and

motion sickness

. Her oncologist

plans to use cisplatin 75mg/m2 and etoposide

(32)

What About AJ…

AJ

is a 46-year old woman who was recently

diagnosed with extensive stage small cell lung

cancer. She is a non-drinker

who stopped smoking

12 years ago. Her past medical history is significant

for depression, morning sickness with multiple

pregnancies and motion sickness. Her oncologist

plans to use

cisplatin

75mg/m2 and etoposide

100mg/m2 every 28 days to treat her disease.

(33)

What should

AJ

be given to

prevent N/V with treatment?

(34)

Considerations…

Treatment risk:

 Cisplatin (day 1) - Level of emetogenicity = HIGH  Etoposide (days 1-3) – Level of emetogenicity = LOW

Emetic Pattern:

 HIGH Risk = 3 days after last dose of chemotherapy

 MODERATE Risk = 2 days after last dose of chemotherapy

Patient should be protected throughout the full period of risk

(35)

New Ondansetron max IV = 16mg, PO = 24mg*

*Reference 12

(36)

AJ…

Treatment risk:

 Cisplatin - Level of emetogenicity = HIGH  Etoposide – Level of emetogenicity = LOW

N/V Prophylaxis:

5-HT

3

+ NK1 + corticosteroid*

 Palonosetron (Aloxi) 0.25mg IV day 1 +

 Fosaprepitant (Emend) 150mg IVPB, day 1 +

 Dexamethasone 12mg PO/IV day 1,

8mg PO day 2, 8mg PO BID, days 3-4

 Prochlorperazine (Compazine) 10mg PO

Q6hr PRN is ordered for breakthrough N/V *References 2, 3, 4

(37)

New ondansetron max IV = 16mg, PO = 24mg*

*Reference 12

New ondansetron max IV = 16mg; PO = 24mg*

(38)
(39)

Drug Classes Available for Prevention &

Treatment of CINV

Serotonin (5-HT

3

) Receptor Antagonists

Neurokinin-1 Receptor Antagonists

Corticosteroids

Dopamine Receptor Antagonists

 Phenothiazines  Butyrophenones  Metoclopramide

Benzodiazepines

Cannabinoids

(40)

Serotonin (5-HT

3

) Receptor Antagonists

Block serotonin receptors in two ways:

 Peripherally – by blocking release from enterochromaffin

cells in the GIT

 Centrally – antagonism of central receptors in the medulla

Agents

 Ondansetron (Zofran)

 Granisetron (Kytril, Sancuso)  Dolasetron (Anzemet)

(41)

Serotonin (5-HT

3

) Receptor Antagonists

Adverse effects include:

 Headache

 Constipation or diarrhea

 Transient ECG interval abnormalities (particularly QT

prolongation), often asymptomatic

 Somnolence, sedation

(42)

Serotonin (5-HT

3

) Receptor Antagonists

Role in cancer patients:

 Standard therapy for highly and moderately emetogenic

agents due to efficacy and low adverse effect profiles

 Addition of corticosteroids is synergistic (20% increase in

effectiveness)

 Not as effective as corticosteroids for delayed N/V

 All agents, when administered in equipotent doses, have

similar efficacy and safety

 Palonosetron has longer half-life and more avid receptor binding  Granisetron (Sancuso) is a patch formulation

 Current guidelines indicate that PO administration is

equivalent to IV administration in efficacy References 2,3,4.

(43)

5-HT

3

’s and QT Prolongation

September 2011, FDA released an alert concerning

an association between Zofran (ondansetron) and

prolongation of QT intervals. The FDA required a

revision of labeling as follows:

 “…to include a warning to avoid use in patients with

congenital long QT syndrome….Additionally,

recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia,

hypomagnesemia), CHF, bradyarrhythmias, or in patients

taking other medications that can lead to QT prolongation…” U.S. Food and Drug Administration. September 15, 2011.

(44)

5-HT

3

’s and QT Prolongation

In a subsequent report the FDA made the following

recommendations:

 A recently completed clinical study suggests that a 32mg single IV dose of

ondansetron may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop Torsades de Pointes.

 Ondansetron will continue to be used in the prevention and

treatment of CINV; HOWEVER, no single IV ondansetron dose should exceed 16mg.

 This does not change any of the recommended oral dosing

regimens for ondansetron (max PO dose = 24mg). U.S. Food and Drug Administration. June 29, 2012.

(45)

Neurokinin-1 (NK1) Receptor Antagonists

Inhibits the substance P/neurokinin 1 (NK1)

receptor

 Augments the antiemetic activity of 5-HT3 receptor

antagonists and corticosteroids to inhibit acute and delayed phases of CINV in both highly and moderately emetogenic regimens

 Do not use as single agent

Adverse effects may include:

 Fatigue  Hiccups

(46)

Neurokinin-1 (NK1) Receptor Antagonists

Aprepitant

is a substrate, a moderate inhibitor, and an

inducer of CYP3A4 when used as a 3-day regimen

Fosaprepitant

,

given as a single dose, is a weak inhibitor of

CYP3A4 and does not induce CYP3A4

Potential drug interactions include:

 Oral contraceptives (decreased efficacy)  Warfarin (decreased efficacy)

 Dexamethasone/methylprednisolone (increased efficacy)  Midazolam (increased efficacy)

 CYP3A4 inhibitors (increase aprepitant AUC)

 Erythromycin, itraconazole, ketoconazole, etc

 CYP3A4 inducers (decrease aprepitant AUC)

 Carbamazepine, phenytoin, rifampin

(47)

Neurokinin-1 (NK1) Receptor Antagonists

Chemotherapeutic agents known to be metabolized

by CYP3A4

 docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide,

imatinib, vinorelbine, vinblastine, vincristine

 Doses were not adjusted when used concurrently with etoposide, vinorelbine, or paclitaxel in phase III trials, but caution is

warranted

 Ifosfamide neurotoxicity

 Recent study found no association between aprepitant use and the risk of neurotoxicity in patients receiving ifosfamide-based therapy; caution is warranted

Jarkowski,A., et al. The Risk of Neurotoxicity with Concomitant Use of Aprepitant and Ifosfamide. The Oncology Pharmacist; April 2011. Product Information. Merck & Co.

(48)

Neurokinin-1 (NK1) Receptor Antagonists

Dosing

 ORAL

 Aprepitant 125mg PO day 1, 80mg PO days 2 and 3 +  5-HT3 of choice day 1

 Dexamethasone 12mg PO day 1, 8mg PO days 2, 3, 4

 IV

 Fosaprepitant 150mg IV day 1 (only)  5-HT3 of choice day 1

 Dexamethasone 12mg PO day 1, 8mg PO day 2, 8mg PO BID days 3 and 4

(49)

Fosaprepitant (Emend IV)

Important points:

 Final solution concentration 1mg/ml in NS

 Administer over at least 20-30 minutes using PVC-free tubing;

increase administration time and/or solution volume if vein irritation develops

 Incompatible with divalent cations like magnesium and

calcium; infuse through NS line only

 Incompatible with palonosetron (Aloxi) – flush pre/post with

NS

 Compatible (admix or Y-site) with ondansetron or granisetron

and dexamethasone or methylprednisolone

 May cause hypersensitivity reactions (contains the same base

as contained in docetaxel) Merck & Co., Inc. Medical Information. Nov. 2010.

(50)

Corticosteroids

General:

 Dosing:

 Dexamethasone dose ranges from 8-20mg

 Methylprednisolone dose ranges from 40-125mg

 Reduce dose when used with aprepitant/fosaprepitant

 Do not give additional steroid if present in treatment regimen

 Adverse effects from single and short courses less frequent, but

may include:

 Euphoria, anxiety, insomnia

 Increased appetite

 Hyperglycemia

 Mild fluid retention

 When IV doses are given too rapidly patient may experience

transient and intense perianal, vaginal, or anal burning

(51)

AJ…

 Presents to clinic 5 days after her first

cycle of cisplatin and etoposide. She states that she had continuous nausea with several episodes of emesis and is considering no further therapy.

 She has been using prochlorperazine

(Compazine) without significant benefit.

What would be a reasonable

recommendation now ?

(52)

Breakthrough Considerations…

 If patient has no N/V – don’t change anything

 If patient has N/V, choose an agent with a different

mechanism of action and add ‘PRN’ to current regimen  Take patient-specific characteristics into consideration

 Anxiety, depression, concurrent medications, dyspepsia

 Multiple concurrent medications may be required

 If N/V controlled, continue breakthrough medication(s) on

scheduled basis

(53)

Breakthrough Considerations…

If N/V uncontrolled:

 Consider changing antiemetic therapy to higher-level primary

treatment

 Consider adding aprepitant/fosaprepitant

 Add other antiemetics, such a dopamine antagonists, butyrophenones

 Adjust intensity or frequency of 5-HT3

 Changing to a different 5-HT3 may be of questionable benefit  If treatment goal is non-curative, consider different

chemotherapy regimen

 Adding an anxiolytic to combination antiemetics

 Consider antacid, H2 antagonist or PPI therapy in patients

with dyspepsia NCCN Guidelines. Antiemesis. Version 1.2012.

(54)
(55)

Dopamine Antagonists

Phenothiazines – effective with moderately and mildly

emetogenic agents; delayed N/V

 Prochlorperazine (Compazine)

 Dose: 10mg PO/IV/IM every six hours (max of 40mg/day); 25mg Supp PR

Q12hr

 Promethazine (Phenergan)

 Not a very potent antiemetic for cancer patients

 Recent shortages of Compazine IV have increased use

 12.5-25mg PO every 4 hours

 25mg PO Phenergan ~ = 6.25mg IV Q 4-6 hours

 Strong vein irritant with possible tissue damage on extravasation; give IV via

central line

Adverse effects (class)

 Sedation (especially with IV Phenergan and in elderly)

 Hypotension

(56)

Dopamine Antagonists

Metoclopramide (Reglan)

 Dopamine antagonist at lower doses; serotonin antagonist at

high doses

 Use in breakthrough N/V

 Dosing: 10-20mg PO/IV Q6hr PRN

 Most common adverse effects – diarrhea, dystonia

Haloperidol (Haldol)

 Used in breakthrough N/V

 Dosing: 0.5-1mg PO/IV/IM Q6hr PRN

 Most common adverse effects – drowsiness, dystonia, dry

(57)

AJ…

 The addition of metoclopramide is a

very reasonable choice.  10-20mg PO Q6hr

 If she responds favorably, this should

be added as a scheduled med to her regimen with the next cycle.

 If not, consider haloperidol or

(58)

Refractory Nausea & Vomiting

Olanzapine (Zyprexa)

 An antipsychotic that blocks multiple neurotransmitters in the CNS

including dopamine, serotonin, acetylcholine and histamine

 When compared with aprepitant-based regimens in moderately and

highly emetogenic chemotherapy it is at least as effective in acute N/V control and more effective in controlling delayed symptoms

 Dosing:

 2.5-10mg/day starting day (HS) before or day of chemotherapy and continue

for 5-10 days

 Adverse effects:

 Sedation or sleep disturbance, fatigue, dizziness, dry mouth and weight

gain

 Cautions:

 Use in elderly

 Hyperglycemia; an association with onset of diabetes mellitus  QT prolongation

Navari,RM., et al. Olanzapine Versus Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Randomized Phase III Trial. J Support Oncol 2011;9:188-195.

(59)

Cannabinoids

Approved by FDA for the treatment of CINV in patients

who fail to respond adequately to conventional

antiemetics.

 Dronabinol (Marinol) – 5-10mg PO every 3-6 hours  Nabilone (Cesamet) – 1-2mg PO BID

Recommend starting with low

dose to minimize toxicity

Common adverse effects

 Dizziness  Drowsiness  Dysphoria  Dry mouth

(60)

Other Possibilities…

In addition to the four primary neurotransmitters,

GABA and histamine receptors may also play a role

in CINV

Gabapentin (Neurontin)

 Antiemetic action noted in patients with breast cancer who

received gabapentin to help relieve hot flashes

Antihistamines

 Antiemetic effect may be related to blocking histamine

receptors or by inducing sedation

Lohr,L., Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. J Hematol Oncol Pharm. 2011;1(4):13-21.

(61)

Refractory Nausea & Vomiting

Patients with persistent N/V after chemotherapy

should be evaluated for other possible causes:

Brain metastases

Electrolyte abnormalities

Tumor infiltration of bowel or

other GI abnormalities

(62)
(63)
(64)

Risk Factors for Anticipatory N/V

Age < 50 years

N/V after last chemotherapy administration described

as “moderate, severe or intolerable”

Feeling “warm or hot all over” after last chemotherapy

administration

Susceptibility to motion sickness

History of anxiety or depression

 Anticipatory anxiety (also a conditioned response to adverse

stimuli) is more prevalent than ANV

Experiencing “sweating” and/or “generalized

weakness” after last chemotherapy administration

(65)

Anticipatory Nausea & Vomiting

Not typically associated with stimulation of

neuroreceptors

 Stimuli most frequently associated with ANV were olfactory

(smell) and cognitive

Most literature describes observational

versus experimental studies

Good News ~ there is much less observed

ANV now than in older studies!

Treatment includes pharmacologic

and non-pharmacologic methods

(66)
(67)

Benzodiazepines

Antianxiety agents may be helpful in ANV or used to

treat breakthrough CINV

 They may delay the onset of ANV and help to control sleep

disturbances related to diagnosis and chemotherapy

Affect the limbic system and cortical input into the

medulla

Agents commonly recommended:

 Lorazepam  Alprazolam

Adverse effects

 Sedation, dizziness, amnesia,

respiratory depression

(68)

Important Principles

Evaluate each patient individually

Evaluate the emetogenic potential and pattern of

the chemotherapeutic regimen to be given

Antiemetics are most effective when given

prophylactically

(69)
(70)
(71)
(72)
(73)
(74)

References

 1. Gralla RJ, et al. Recommendations for the use of antiemetics: Evidence-based clinical practice guidelines. J Clin Oncol

1999;17:2971-16.

 2. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J

Clin Oncol. 2011;29:4189-4198.

 3. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of

chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 2010;21 (Suppl 5):v232-v243.

 4. NCCN Guidelines Version 1.2012. Antiemesis. National Comprehensive Cancer Network.

 5. Hesketh, PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008; 358:2482-94.

 6. The Chemotherapy Source Book, 4th Ed., M.C. Perry. Lippincott 2008.

 7. Lohr, LK, Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. J

Hematol Oncol Pharm. 2011;1(4):13-21.

 8. T. Mays. Gastrointestinal Toxicities: Nausea and Vomiting in Oncology Pharmacy Preparatory Review Course, Volume

2. ACCP, ASHP 2011

 9. Lohr, L., Chemotherapy-Induced Nausea and Vomiting. The Cancer Journal. Vol 144, No 2, March/April 2008.

 10. Roscoe, JA, et al. Prevention of Delayed Nausea: A University of Rochester Cancer Center Community Clinical Oncology

Program Study of Patients Receiving Chemotherapy. J Clin Oncol August 20, 2012. Abstract.

 11. Navari, RM et al. Olanzapine Versus Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A

Randomized Phase III Trial. J Supportive Oncol 2011;9:188-195.

 12. U.S. Food and Drug Administration. Alert for Ondansetron and QT Prolongation. September 2011.  13. Aapro, MS, et al. Anticipatory Nausea and Vomiting. Support Care Cancer 2005;13:117-21.

 14. Roila,F., Hesketh, PJ, Herrstadt, J. Prevention of chemotherapy- and radiotherapy- induced emesis: results of the 2004

Perugia International Antiemetic Consensus Conference. Ann Oncol 2006;17:20-28.

 15. U.S. Food and Drug Administration. FDA Issues Update on QT Prolongation Risk With Ondansetron. June 29, 2012.

 16. Jarkowski, A., et al. The Risk of Neurotoxicity with Concomitant Use of Aprepitant and Ifosfamide. The Oncology Pharmacist;

April 2011.

 17. Merck & Co., Inc. Fosaprepitant, Aprepitant Product Information.

Figure

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References