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 Compazine & Phenergan Centrally acting non-phenothiazines Tigan Vestibular disturbances Antivert Motion sickness Dramamine & Scopolamine Pregnancy 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(5- HT3,D2,NK1 ) Cerebral cortex (sensory) Vestibular system (H!, muscarinic )

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: 1790-1796.

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 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.1.2004 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.1.2004. Available at http://www.nccn.org.

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. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298. 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;56:729-764. 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;54:273-298.

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 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;56:729-764.

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 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;56:729-764. 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;39:1074-1080.

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 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.

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) 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

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;56:729-764. 2. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest. 2000;18:163-173. 3. Lindley CM, Hirsch JD, O’Neill CV et al. Quality of life consequences of chemotherapy-induced emesis. Qual Life Res. 1992;1:331-340. 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;149:296-302. 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;80:864-868.

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

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