Chemotherapy induced nausea and vomiting (CINV) can be acute, delayed, anticipatory, or refractory. The emetogenic potential of chemotherapy agents ranges from high to minimal risk. Key treatment milestones included the approval of aprepitant in 2003 and palonosetron in 2003. Current guidelines recommend three-drug combinations for high risk chemotherapy, two-drug combinations for moderate risk, and dexamethasone alone for low risk. Advances in antiemetic treatments have improved control of acute CINV but challenges remain in preventing delayed CINV.
Chemotherapy induced nausea and vomiting (CINV) can be acute, delayed, anticipatory, or refractory. The emetogenic potential of chemotherapy agents ranges from high to minimal risk. Key treatment milestones included the approval of aprepitant in 2003 and palonosetron in 2003. Current guidelines recommend three-drug combinations for high risk chemotherapy, two-drug combinations for moderate risk, and dexamethasone alone for low risk. Advances in antiemetic treatments have improved control of acute CINV but challenges remain in preventing delayed CINV.
Chemotherapy induced nausea and vomiting (CINV) can be acute, delayed, anticipatory, or refractory. The emetogenic potential of chemotherapy agents ranges from high to minimal risk. Key treatment milestones included the approval of aprepitant in 2003 and palonosetron in 2003. Current guidelines recommend three-drug combinations for high risk chemotherapy, two-drug combinations for moderate risk, and dexamethasone alone for low risk. Advances in antiemetic treatments have improved control of acute CINV but challenges remain in preventing delayed CINV.
Chemotherapy induced nausea and vomiting (CINV) can be acute, delayed, anticipatory, or refractory. The emetogenic potential of chemotherapy agents ranges from high to minimal risk. Key treatment milestones included the approval of aprepitant in 2003 and palonosetron in 2003. Current guidelines recommend three-drug combinations for high risk chemotherapy, two-drug combinations for moderate risk, and dexamethasone alone for low risk. Advances in antiemetic treatments have improved control of acute CINV but challenges remain in preventing delayed CINV.
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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
► 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
