1. CHEMOTHERAPY INDUCED NAUSEA AND VOMITING
Dr. Rotich Julius (BPharm)
Pharmacist, MTRH
1/11/2016

2. Outline Definitions General overview of N/V Pathophysiology of CINV
Types of CINV
Drugs used in management of CINV
Summary

3. 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

4. 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

5. History and PE Timing of symptoms Relation to meals
Associated symptoms
Last menstrual period
Comorbid conditions
Epidemiologic data
Drug history
Physical Examination

6. Laboratory Rule out obstruction and peritonitis HCG Urinalysis
Electrolytes, BUN, creatinine, glucose
Transaminases, amylase
EKG, head CT, upper GI &/or endoscopy

7. General Management Phenothiazines Centrally acting non-phenothiazines
Compazine & Phenergan
Centrally acting non-phenothiazines
Tigan
Vestibular disturbances
Antivert
Motion sickness
Dramamine & Scopolamine
Pregnancy
No approved
Others
Marinol, Zofran, Kytril

8. 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:

9. 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:

10. Pathophysiology ctd’
Nausea & vomiting are complex interaction from different systems
Central vomiting center (medulla) CTZ (5-HT3 ,D2,NK1 )
Gastrointestinal(visceral afferents(5- HT3,D2,NK1 )
Cerebral cortex (sensory)
Vestibular system (H!, muscarinic )

11. Pathophysiology of Chemotherapy-Induced Emesis
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.1
1. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993;329:

12. 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

13. 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
Emetogenic Potential of Single Antineoplastic Agents
Shown are agents of moderate to high emetic risk. Low emetic risk (Level 2; 10-30% frequency of emesis) and minimal emetic risk (Level 1; <10% frequency of emesis) agents are also detailed in NCCN guidelines v but not shown here.
Frequency of emesis shown are proportions of patients who experience emesis in the absence of effective antiemetic prophylaxis.
1NCCN guidelines v Available at

16. 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
Individuals bring to chemotherapy a unique set of characteristics that moderate their responses—positive and negative—to treatment.
Patient risk factors that increase the likelihood of developing CINV are listed on the slide.
Age <50 years
Women more likely than men to develop CINV
History of light alcohol use; people who drink more heavily are less likely to develop CINV
History of nausea or vomiting associated with pregnancy or motion sickness
History of CINV associated with prior exposure to chemotherapeutic agents
Patients who have a tendency to be anxious are at increased risk
ASHP. Am J Health Syst Pharm. 1999:56: ; Balfour and Goa. Drugs. 1997:54:
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs. 1997;54:

17. 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
Chemotherapy-induced nausea and vomiting (CINV) falls into 3 distinct phases. Familiarity with these is useful for planning prophylactic treatment.
Acute CINV is defined as nausea and/or vomiting that occurs within 24 hours of the administration of cancer chemotherapy.
Delayed CINV is defined as nausea and vomiting that occurs after the first 24 hours. It may last for as long as 120 hours after administration of cancer chemotherapy.
Anticipatory CINV is nausea and vomiting that occurs as a learned response or conditioning. It generally occurs during subsequent cycles of chemotherapeutic treatment when CINV has been poorly managed following previous cycles of chemotherapy. Anticipatory CINV occurs before, during, or after chemotherapy, but usually earlier than an episode of acute CINV would be expected to occur.
Anticipatory CINV does not respond to antiemetic agents or other pharmacologic interventions, but has been shown to respond to behavioral modifications or nonpharmacologic approaches. It is preferable to preempt anticipatory CINV by ensuring adequate control of CINV with the first course of emesis-producing chemotherapy.
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:

18. Chemotherapy-Induced Emesis: Key Treatment Milestones
Aprepitant, March 2003
Palonosetron July, 2003

19. Pharmacologic Agents Corticosteroids Dopamine antagonists
Serotonin (5-HT3) antagonists
NK-1 receptor antagonists
Cannabinoids
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.
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:

20. 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%)

21. 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

22. 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

23. 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.

24. 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 .

25. Cannabinoids
Cannabinoids (e.g. dronabinol and nabilone) possess weak antiemetic efficacy combined 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.

26. 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% ( ) NNT 12.2 Number of doses per protected pt: HT3 RA as adjunct to dexamethasone Absolute RR (95% CI) 2.6% ( ) NNT 38.8 Number of doses per protected pt: 423
Geling and Eichler, JCO 23:

27. ASCO 2006/NCCN 2009 Recommendations by Risk Category
High (>90% emetic risk)
Including AC containing regimens
Three-drug combination of a HT3 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

28. How Can We Improve the Value of Care in CINV?
Value = Quality
 Cost
Direct
Indirect
 Cure Rate
 Nausea or Emesis  Functioning
 Side Effects
 Compliance or  Patient Inconvenience
 Access to Care
Chemotherapy-induced nausea and vomiting may be classified as acute (beginning within the first 24 hours after chemotherapy), delayed (beginning more than 24 hours after chemotherapy), or anticipatory (beginning before acute chemotherapy-related symptoms would be expected to occur).
Some data suggest the delayed phase may begin as early as 16 hours.
Although mild nausea and vomiting may be discomforting, more severe cases of nausea and vomiting may result in dehydration, malnutrition, and electrolyte imbalance. These conditions can affect quality of life, the desire to continue with antitumor therapy, and survival.1,2 Studies have demonstrated that nausea and vomiting secondary to chemotherapy impair a patient’s ability to complete household tasks, enjoy meals, and maintain activities of daily living and recreation.3,4
1. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
2. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest. 2000;18:
3. Lindley CM, Hirsch JD, O’Neill CV et al. Quality of life consequences of chemotherapy-induced emesis. Qual Life Res. 1992;1:
4. O’Brien BJ, Rusthoven J, Rocchi A et al. Impact of chemotherapy-associated nausea and vomiting on patients’ functional status and on costs: survey of five Canadian centres. Can Med Assoc J. 1993;149:
5. Grunberg SM, Ehler E, McDermed JE et al. Oral metoclopramide with or without diphenhydramine: potential for prevention of late nausea and vomiting induced by cisplatin. J Natl Cancer Inst. 1988;80:

29. 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

30. THANK YOU!!