Download Chemotherapy induced Nausea and vomiting

CHEMOTHERAPY
INDUCED
NAUSEA AND
VOMITING
Dr. Rotich Julius (BPharm)
Pharmacist, MTRH
1/11/2016
OUTLINE
Definitions
 General overview of N/V
 Pathophysiology of CINV
 Types of CINV
 Drugs used in management of CINV
 Summary

DEFINITIONS






Nausea is usually defined as the inclination to vomit
or as a feeling in the throat or epigastric region
alerting an individual that vomiting is imminent (
subjective ).
Nausea ---Autonomic symptoms
Vomiting is defined as the ejection or expulsion of
gastric contents through the mouth, often requiring a
forceful event (reflexive )
Vomiting. Contraction + forced expel of GI content
Retching is the contraction of the abdominal
wall,diaphragm &thoracic muscles without expulsion.
Retching---- Contractions of muscles
CAUSES OF NAUSEA/ VOMITING
Early pregnancy
 Psychogenic vomiting
 Bulemia
 Pyloric channel ulcer
 Acute gastritis
 Gastric retention
 Viral gastroenteritis
 Acute gastroenteritis

Myocardial infarction
 Peritonitis
 Acute obstruction
 Neurologic emergency
 Drug toxicity
 Cancer therapy
 Drug withdrawal

HISTORY AND PE
Timing of symptoms
 Relation to meals
 Associated symptoms
 Last menstrual period
 Comorbid conditions
 Epidemiologic data
 Drug history
 Physical Examination

LABORATORY
Rule out obstruction and peritonitis
 HCG
 Urinalysis
 Electrolytes, BUN, creatinine, glucose
 Transaminases, amylase
 EKG, head CT, upper GI &/or endoscopy

GENERAL MANAGEMENT

Phenothiazines


Centrally acting non-phenothiazines


Dramamine & Scopolamine
Pregnancy


Antivert
Motion sickness


Tigan
Vestibular disturbances


Compazine & Phenergan
No approved
Others

Marinol, Zofran, Kytril
PATHOPHYSIOLOGY
•
Two sites in the brainstem—
--the vomiting center and the chemoreceptor trigger zone—are important
to emesis control.
The vomiting center(VC) consists of an intertwined neural network in
the nucleus tractus solitarius that controls patterns of motor activity.
The chemoreceptor trigger zone (CTZ), located in the area postrema, is
the entry point for emetogenic stimuli.
•
Enterochromaffin cells in the gastrointestinal tract respond to
chemotherapy by releasing serotonin. Serotonin binds to 5-HT3
receptors, which are located not only in the gastrointestinal tract, but
also on vagal afferent neurons and in the nucleus tractus solitarius
and the area postrema.
Grunberg SM, Hesketh PJ. Control of chemotherapy-induced
emesis. N Engl J Med. 1993;329:
1790-1796.
PATHOPHYSIOLOGY CTD’
• The
activated 5-HT3 receptors signal the
chemoreceptor trigger zone via pathways that may
include the afferent fibers of the vagus nerve.
• Serotonin
also may bind with 5-HT3 receptors in the
brainstem.
• Other
neurotransmitters, including dopamine and
substance P, also influence the chemoreceptor trigger
zone.
• Afferent
impulses from the chemoreceptor trigger zone
stimulate the vomiting center, which initiates emesis.1
Grunberg SM, Hesketh PJ. Control of chemotherapy-induced
emesis. N Engl J Med. 1993;329:
1790-1796.
PATHOPHYSIOLOGY CTD’
Nausea & vomiting are complex interaction from
different systems
 Central vomiting center (medulla) CTZ (5-HT3
,D2,NK1 )
 Gastrointestinal(visceral afferents(5HT3,D2,NK1 )
 Cerebral cortex (sensory)
 Vestibular system (H!, muscarinic )

PATHOPHYSIOLOGY OF
CHEMOTHERAPY-INDUCED EMESIS
CHEMOTHERAPY-INDUCED
NAUSEA AND VOMITING
AN UNMET MEDICAL NEED

Over one million cancer patients receive chemotherapy
each year


20% highly emetogenic chemotherapy (HEC)
Chemotherapy-induced nausea and vomiting (CINV)
Among the most distressing side effects of chemotherapy
 Disrupt patients’ daily lives
 Patients may even delay scheduled chemotherapy

J Clin Oncol 1997;15(1):103-9
American Cancer Society. Cancer Facts & Figures 2001
EMETOGENIC POTENTIAL OF SINGLE
ANTINEOPLASTIC AGENTS
HIGH
Risk in nearly all patients (> 90%)
MODERATE
Risk in 30% to 90% of patients
LOW
Risk in 10% to 30% of patients
MINIMAL
Fewer than 10% at risk
PATIENT-SPECIFIC RISK FACTORS FOR
CINV
Age <50 years
 Women > men
 History of light alcohol use
 History of vomiting with prior exposure
to chemotherapeutic agents
 Other risks

History of motion sickness
 History of nausea or vomiting during pregnancy
 History of anxiety

ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298.
TYPES OF CINV: DEFINITIONS

Acute (post-treatment)


Delayed



Learned or conditioned response from poorly controlled
nausea and vomiting associated with previous
chemotherapy
Breakthrough


CINV that begins after first 24 hours
May last for 120 hours
Anticipatory


Occurs within first 24 hours after administration of cancer
chemotherapy
CINV that occurs despite prophylaxis and requires rescue
Refractory

Occurs during subsequent treatment cycles when
prophylaxis and/or rescue has failed in previous cycles
CHEMOTHERAPY-INDUCED EMESIS:
KEY TREATMENT MILESTONES
Aprepitant, March 2003
Palonosetron July, 2003
PHARMACOLOGIC AGENTS

Corticosteroids

Dopamine antagonists

Serotonin (5-HT3) antagonists

NK-1 receptor antagonists

Cannabinoids
STEROIDS








Corticosteroids are an integral part of antiemetic therapy
for acute and delayed CINV.
When used in combination with other antiemetics,
corticosteroids exert a booster effect, raising the emetic
threshold.
Dexamethasone is the most frequently used corticosteriod.
Steroids are sometimes underutilised, owing to concerns
regarding potential adverse events . Usually, when used in
the short term as antiemetic therapy, corticosteroids are
well tolerated.
Adverse events include
moderate-to-severe insomnia (45%),
indigestion/epigastric discomfort (27%), agitation (27%),
increased appetite (19%), weight gain (16%) and acne (15%)
DOPAMINE ANTAGONISTS
These agents include phenothiazines,
butyrophenones and substituted benzamides.
 One of the most frequently used benzamides is
metoclopramide.
 However, in patients receiving cisplatin-based
chemotherapy,the effects of conventional doses of
metoclopramide are not significantly different
from placebo.
 Although not effective in the acute phase,
metoclopramide in combination with
corticosteroids has proven efficacy in the
prevention of delayed CINV

SEROTONIN ANTAGONISTS





Generation 1/2
Ondansetron, granisetron, tropisetron, dolasetron
and,more recently, palonosetron.
When given at equivalent doses for the prevention of
acute emesis, 5-HT3-RAs have equivalent efficacy and
safety and can be used interchangeably .
Single-dose daily schedules have similar efficacy to
multiple dose daily schedules, and oral forms have
been shown to be as effective as I.V. forms
. As a class, 5-HT3-RAs are well tolerated; common
adverse events include mild headache,transient
elevation of hepatic enzymes and constipation
BENZODIAZEPINES
Benzodiazepines can be useful additions to
antiemetic regimens in certain circumstances.
 They are often used to treat anxiety and reduce
the risk of anticipatory CINV.
 Benzodiazepines are also used in patients with
refractory and breakthrough emesis
 Olanzapine, an atypical antipsychotic drug, has
potential antiemetic properties due to its ability
to bind at several receptors involved in the CINV
pathways.

NK-1 RECEPTOR ANTAGONISTS
They exert their antiemetic action through the
inhibition of substance P in the emetic pathways
in both the central and peripheral nervous
systems.
 Aprepitant , casopitant,, netupitant and
rolapitant, are agents in this class.
 Aprepitant is available for oral and as
fosaprepitant in the i.v. administration form.
 It is recommended for use in the acute phase in
combination with a 5-HT3-RA plus
dexamethasone .

CANNABINOIDS




Cannabinoids (e.g. dronabinol and nabilone) possess weak
combined
antiemetic efficacy
with potentially
beneficial sideeffects, including sedation and euphoria.
This makes them a useful adjunctive therapy in selected
patients; in the ASCO and NCCN guidelines, cannabinoids
are recommended for patients intolerant of or refractory to
5-HT3-RA or steroids andaprepitant.
In a systematic review of the efficacy of oral cannabinoids
in the prevention of nausea and vomiting, cannabinoids
were found to be slightly better than dopamine receptor
antagonists,including phenothiazines, haloperidol and
metoclopramide.
Despite this, their clinical utility was found to be generally
limited by the high incidence of adverse events, such as
dizziness, dysphoria and hallucinations.
META-ANALYSIS OF EFFICACY OF 5-HT3RA IN
PREVENTION OF DELAYED EMESIS FROM
CHEMOTHERAPY
Reviewed 5 studies, 1,716 pts comparing 5-HT3 RA to placebo,
5 studies, 2,240 pts comparing 5-HT3 RA + dexamethasone to
dexamethasone alone
5-HT3 RA as monotherapy
Absolute RR (95% CI)
8.2% (3.0-13.4)
NNT 12.2 Number of doses per protected pt: 74.4
5-HT3 RA as adjunct to dexamethasone
Absolute RR (95% CI)
2.6% (-0.6-5.8)
NNT 38.8
Number of doses per protected pt: 423
Geling and Eichler, JCO 23:1289-1294
ASCO 2006/NCCN 2009
RECOMMENDATIONS BY RISK CATEGORY
High (>90% emetic risk)
Three-drug combination of a HT3
Including AC containing regimens serotonin receptor antagonist,
dexamethasone, and aprepitant
Moderate (>30% to 90% emetic
risk)
Two-drug combination of a HT3
serotonin receptor antagonist
and dexamethasone (+/aprepitant for selected patients)
Low (10% to 30% emetic risk)
Dexamethasone 8-12 mg
Minimal (<10% emetic risk
No antiemetic routinely
HOW CAN WE IMPROVE THE VALUE OF
CARE IN CINV?
 Cost
Value = Quality
 Cure Rate
 Nausea or Emesis 
Functioning
 Side Effects
 Compliance or  Patient
Inconvenience
• Direct
• Indirect
SUMMARY
5HT3 RA’s are therapeutically good & major advance in
supportive care for control of acute emesis
 Treatment guidelines have changed over time

Degree of nausea incurred has been refined for many
agents
 Delayed CINV recommendations are updated


Prevention of CINV has improved, but challenges remain
Improving detection of CINV, especially after 24 hours
 Educating patients and oncology healthcare givers
 The development and evaluation of clinically useful
assessment tools
 Further development of regimens to treat delayed CINV
