Chemotherapy Induced Nausea

and Vomiting (CINV)

 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)
● Occurs within first 24 hours after administration of cancer
chemotherapy
► Delayed
● CINV that begins after first 24 hours
● May last for 120 hours
► Anticipatory
● Learned or conditioned response from poorly controlled nausea
and vomiting associated with previous chemotherapy
► Breakthrough
● CINV that occurs despite prophylaxis and requires rescue
► Refractory
● Occurs during subsequent treatment cycles when prophylaxis
and/or rescue has failed in previous cycles
► Two sites in the brainstem—the vomiting center and the chemoreceptor
trigger zone—are important to emesis control.
 The vomiting center consists of an intertwined neural network in the
nucleus tractus solitarius that controls patterns of motor activity. The
chemoreceptor trigger zone, 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.
► 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.
 Pathophysiology of
Chemotherapy-Induced Emesis
 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
 Pharmacologic Agents

► Four classes of drugs are commonly used to treat CINV:

corticosteroids, dopamine antagonists, serotonin antagonists,
and NK-1 receptor antagonists.

► Corticosteroids and 5-HT3 receptor antagonists, alone or in

combination, are recommended for treatment of acute CINV.

► The newest class of drugs approved to treat CINV is the NK-1

receptor antagonist.
 1st Generation 5HT3 RAs
Are Therapeutically Equivalent

 1st Generation Agents are

 Therapeutically Equivalent

Dolasetron

Ondansetron

Granisetron
 1st Generation oral and IV
 doses equally effective
 Palonosetron

► Second generation 5-HT3 antagonist

► Pharmacologic differences from older 5-HT 3 antagonists
● prolonged half-life (~40 hours)
● enhanced receptor binding affinity (30-fold)

► FDA approved
● IV formulation July 25, 2003
● Oral formulation August 22, 2008

► Regimens
● IV 0.25 mg pre chemotherapy acute/delayed HEC/MEC
● PO 0.50 mg pre chemotherapy

acute MEC
 Palonosetron: 5-HT3 Antagonist of Choice?

► Palonosetron is a 5-HT3 antagonist with strong receptor binding affinity and an

extended half-life

► Compared with other 5-HT3 receptor antagonists, palonosetron demonstrates a

strong receptor binding affinity and an extended half-life.

► Compared with dolasetron, palonosetron achieved a better CR rate in preventing

acute emesis induced by moderately emetogenic chemotherapy.

► Efficacy of palonosetron persists throughout the period of major risk for delayed
emesis, without repeated dosing.

► Definitive proof of superiority to first generation 5-HT 3 antagonists would require

trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive

dosing of the first generation agents
 Aprepitant

► Selective antagonist of the binding of Substance P to the

neurokinin 1 (NK1) receptor
► FDA approved
● Oral formulation: March 26, 2003

● IV formulation (fosaprepitant): January 31, 2008

► Regimen
● 125 mg PO day 1, 80 mg PO days 2-3 acute/delayed
HEC/MEC
● 115 mg IV day 1, 80 mg PO days 2-3 acute/delayed
HEC/MEC
 1st Generation Oral 5HT3 RAs
Not Effective for Delayed CINV
► Vomiting
● Significantly more patients vomited at least once during the
delayed period (34%) than on the day of treatment (19%) p
<0.01
► Nausea
● Nausea severity was significantly greater during the
delayed period than on the day of treatment p < 0.01
● More patients getting oral 5HT3 RAs required rescue
medications (45%) than patients getting Compazine® (27-
30%) p=0.002

Hickock et al ASCO 2005 Final Results URCC-CCOP

 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,
(palonosetron preferred-NCCN)
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

 Summary
► 1st generation 5HT3 RA’s therapeutically equivalent & major
advance in supportive care for control of acute emesis
► No major progress in CINV for ~ 10+ yrs until aprepitant &
palonosetron
► Treatment guidelines have changed
 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