Chemotherapy Induced Nausea and Vomiting

Dr. Mohammad Aljawadi PharmD, Msc, PhD

Jamilah Alsaidan Msc

PHCL 477

Clinical Pharmacy Department

College of Pharmacy

King Saud University

March 2015

The three consecutive phases of emesis are:

Chemotherapy Induced Nausea and Vomiting

Emesis

Nausea Retching Vomiting

• Inclination to vomit• Feeling in throat or epigastric region

alerting individual vomiting is imminent. Nausea

• Is the labored movement of the abdominal and thoracic muscles before vomitingRetching

• The forceful expulsion of gastric contents through the mouth due to GI retro-peristalsis

Vomiting

Chemotherapy Induced Nausea and Vomiting

Vomiting is triggered by afferent impulses to the vomiting center, a nucleus of cells in the medulla

Impulses are received from sensory centers, such as:◦ The chemoreceptor trigger zone (CTZ)◦Cerebral cortex◦Visceral afferents from the pharynx and GI tract

Etiology

Visceral afferents from the pharynx and GI tract

Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract

Cholinergic, histaminic, dopaminergic, opiate, serotonergic, neurokinin, and benzodiazepine receptors

Three main causes of vomiting ◦ Stimulation of chemoreceptor trigger zone in the 4th ventricle◦ Stimulation of the GI tract◦ Sensory input and memory

Etiology

Nausea and or / vomiting may be part of the symptom complex for a variety of gastrointestinal, cardiovascular, infectious, neurologic, metabolic or psychogenic processes

Chemotherapy Induced Nausea and Vomiting

N & V may be a feature of such conditions as pregnancy, may follow ◦ operative procedures◦ administration of certain medications such as those used in

cancer chemotherapy or inhalation of noxious odors

Chemotherapy Induced Nausea and Vomiting

Gastrointestinal mechanisms◦ Mechanical obstruction:

e.g. Gastric outlet obstruction, Small bowel obstruction

◦ Functional gastrointestinal disorders: e.g.Gastroparesis, Non-ulcer dyspepsia, Chronic intestinal pseudo-obstruction, Irritable bowel syndrome

◦ Organic gastrointestinal disorders e.g Peptic ulcer disease, Pancreatitis, Pyelonephritis, Cholecystitis ,Cholangitis, Hepatitis

◦ Acute gastroenteritis ( Viral, Bacterial)

Specific etiologies

Cardiovascular diseases◦Acute myocardial infarction 

Miscellaneous causes◦   Pregnancy◦Noxious odors ◦Operative procedures

Neurologic processes◦Migraine headache◦Vestibular disorders

Specific etiologies

Specific etiologies

Metabolic disorders◦ Diabetes mellitus (diabetic

ketoacidosis)◦ Renal disease (uremia)

Psychiatric causes◦ Anxiety disorders◦ Anorexia nervosa

Drug withdrawal◦ Opiates◦ Benzodiazepines

Therapy-induced causes◦ Cytotoxic chemotherapy◦ Radiation therapy◦ Anticonvulsant preparations◦ Opiates◦ Antibiotics

Depending on severity of symptoms, patients may present in mild to severe distress

Symptoms◦ Simple: Self-limiting, resolves spontaneously and requires only

symptomatic therapy

◦Complex: Not relieved after administration of antiemetics; progressive deterioration of patient secondary to fluid-electrolyte imbalances; usually associated with noxious agents or psychogenic events

Clinical Presentation

Signs◦ Simple: Patient complaint of queasiness or discomfort◦Complex: Weight loss; fever; abdominal pain

Laboratory tests◦ Simple: None◦Complex: Serum electrolyte concentrations; upper/lower GI

evaluation

Clinical Presentation

Clinical Presentation

Other information◦ Fluid input and output◦Medication history◦Recent history of behavioral or visual changes, headache, pain,

or stress ◦ Family history positive for psychogenic vomiting

Specific etiologies

Metabolic disorders◦ Diabetes mellitus (diabetic

ketoacidosis)◦ Renal disease (uremia)

Psychiatric causes◦ Anxiety disorders◦ Anorexia nervosa

Drug withdrawal◦ Opiates◦ Benzodiazepines

Therapy-induced causes◦ Cytotoxic chemotherapy◦ Radiation therapy◦ Anticonvulsant preparations◦ Opiates◦ Antibiotics

Emetogenic potential of chemotherapy agents

HighModerateLowMinimal

Chemotherapy Induced Nausea and Vomiting- Emetogenic potential of some cytotoxic agents

High (>90%) Carmustine   Cisplatin   Cyclophosphamide ≥1,500

mg/m2 Dacarbazine   Dactinomycin   Mechlorethamine   Streptozotocin  

Moderate (30–90%) Carboplatin   Cytarabine >1 g/m2

Cyclophosphamide <1,500 mg/m2

Daunorubicin   Doxorubicin   Epirubicin   Idarubicin   Ifosfamide   Irinotecan   Oxaliplatin

Chemotherapy Induced Nausea and Vomiting- Emetogenic potential of some cytotoxic agents Low (10–30%) Bortezomib   Cetuximab   Cytarabine ≤1 g/m2   Docetaxel   Etoposide   Fluorouracil   Gemcitabine   Methotrexate   Mitomycin   Mitoxantrone   Paclitaxel   Pemetrexed   Topotecan   Trastuzumab

Minimal (<10%) Bevacizumab   Bleomycin   Busulfan   2-Chlorodeoxyadenosine

Fludarabine   Rituximab   Vinblastine   Vincristine   Vinorelbine

Non-Chemotherapy Etiologies of Nausea and vomiting in cancer patients◦ Fluid and electrolyte abnormalities

Hypercalcemia

◦ Volume depletion

◦ Adrenocortical insufficiency

◦ Drug Induced Opiates Antifungals Antibiotics

Chemotherapy Induced Nausea and Vomiting

Other◦Uremia◦Metastases◦Gastrointestinal obstruction◦ Increased intracranial pressure◦ Peritonitis◦Radiation Therapy

Chemotherapy Induced Nausea and Vomiting

The overall goal of antiemetic therapy is to prevent or eliminate nausea and vomiting◦ This should be accomplished without adverse events or with

clinically acceptable adverse effects◦ Simple nausea and vomiting prevention is achieved easily with

treatment◦ Patients with more complex problems require greater

assistance

Desired outcome of treatment

General Approach to Treatment

Non drug Modalities Medication

Treatment Modalities

The treatment choice depends on severity of the NV and associated conditions

The management of psychogenic vomiting is greatly dependent on psychological intervention

Underlying problems are complex and must be addressed

Treatment of underlying psychological disorder with its appropriate medications

E.g. Bulimia nervosa

Chemotherapy Induced Nausea and Vomiting

Non drug modalities include Dietary, Psychological, or physical changes

Simple complaints- Avoid or intake in moderation troublesome food, beverage or odor

Behavioral interventions include relaxation biofeedback, self hypnosis, cognitive distraction, guided imagery, and systematic desensitization

Chemotherapy Induced Nausea and Vomiting- Non Drug Modalities

Antiemetic drugs- both non-prescription and prescription are recommended

The treatment of simple nausea and vomiting usually requires minimal therapy. Drugs are usually effective in small, infrequently administered doses.

The management of complex nausea and vomiting, for example, in patients who are receiving cytotoxic chemotherapy, may require combination therapy.

Pharmacologic Therapy

Many treatment options for clinician to choose from Factors that enable a clinician to discriminate between

medication options:◦ The suspected etiology of the symptoms◦ The frequency, duration, and severity of the episodes◦ The ability of the patient to use oral, rectal, injectable, or

transdermal medications◦ The success of previous antiemetic medication

Pharmacologic Therapy

In relation to chemotherapy administration; Nausea or vomiting that occurs:

within 24 hours: Acute◦ Intensity peaks after 5-6 hours

after 24 hours: Delayed before chemo given: Anticipatory

Chemotherapy Induced Nausea and Vomiting

The distinction between acute and delayed symptoms becomes blurred with respect to time of onset after several doses and for several consecutive days

Delayed symptoms are best described with cisplatin

Chemotherapy Induced Nausea and Vomiting

Breakthrough vomiting occurs despite prophylactic treatment and /or requires additional rescue medications

Refractory emesis refers to emesis that occurs during treatment cycles when antiemetic prophylaxis and / or rescue therapy has failed in previous cycles

Chemotherapy Induced Nausea and Vomiting

Factors to consider when selecting an antiemetic for CINV include the following:

1) The emetic risk of the chemotherapy agent or regimen

2) Patient specific factors3) Patterns of emesis after administration of specific

chemotherapy agents or regimens

Chemotherapy Induced Nausea and Vomiting- Factors to consider

The emetic risk of the agent is the most important and primary factor to consider when deciding IF you will administer prophylactic agents and WHICH antiemetic agent to select

The combination of metoclopramide and dexamethasone was the most common regimen to prevent delayed nausea and vomiting before the availability of aprepitant

The combination is still used when aprepitant has not been incorporated into the initial regimen for CINV

Single agent phenothiazaine, butyrophenone, or steroids are used for mildly to moderately emetogenic regimens and for “as needed” use for prolonged symptoms (breakthrough symptoms)

Factors to consider

Patients receiving chemotherapy classified to be high risk should receive a combination antiemetic regimen containing three drugs on the day of chemotherapy administration (Day one)

A serotonin 5-HT3 inhibitor (e.g. Dolasetron, Granisetron, Ondansetron, Palonosetron )

+ dexamethasone +NK1 inhibitor ( e.g. aprepitant)

Chemotherapy Induced Nausea and Vomiting

Patients receiving regimens that are classified as being of moderate emetic risk should receive a combination antiemetic regimen containing an serotonin 5-HT3 inhibitor plus dexamethasone on day 1. The exception to this is patients receiving an anthracycline and

cyclophosphamide should receive the triple regimen described for high emetic risk regimens

For prophylaxis prior to administration of regimens classified as low emetogenic risk dexamethasone alone is recommended

Chemotherapy Induced Nausea and Vomiting

High Emetic risk Serotonin 5-HT3 inhibitor + dexamethasone + aprepitant

Moderate Emetic risk Anthracycline + cyclophosphamide:Serotonin 5-HT3 inhibitor + dexamethasone + aprepitant All other regimens of moderate emetic risk:Serotonin 5-HT3 inhibitor + dexamethasone

Low Emetic Risk DexamethasoneMinimal riskNo medication

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Acute Phase of CINV on Day of Chemotherapy Administration (Day 1)

High Emetic Risk◦ Serotonin 5-HT3 inhibitor :

Dolasetron 100 mg po or 100 mg IV or 1.8 mg/kg IV Granisetron 2 mg po or 1 mg IV or 0.01 mg/kg IV Ondansetron 24 mg po or 8 mg IV or 0.15 mg/kg IV Palonosetron 0.25 mg IV

◦AND Dexamethasone 12 mg po ◦ AND Aprepitant 125 mg po

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Acute Phase of CINV on Day of Chemotherapy Administration (Day 1) DOSES

Moderate emetic risk◦Anthracycline and cyclophosphamide

as before, as high emetic risk

◦All other regimens of moderate emetic risk: Dolasetron 100 mg po or 100 mg IV or 1.8 mg/kg IV Granisetron 2 mg po or 1 mg IV or 0.01 mg/kg IV Ondansetron 24 mg po or 8 mg IV or 0.15 mg/kg IV Palonosetron 0.25 mg IV AND Dexamethasone 8mg IV

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Acute Phase of CINV on Day of Chemotherapy Administration (Day 1)

Low Risk◦Dexamethasone 8mg IV

Minimal Risk◦None

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Acute Phase of CINV on Day of Chemotherapy Administration (Day 1)

High Emetic Risk Days 2 and 3 after chemotherapy: dexamethasone (8mg IV) + aprepitant

(80mg PO)

Moderate Emetic risk◦ Anthracycline + cyclophosphamide:

Days 2 and 3 after chemotherapy: aprepitant ( 80mg PO)

All other regimens of moderate emetic risk:Days 2–4 after chemotherapy: dexamethasone 8mg PO daily or Serotonin 5-HT3 inhibitor:

Ondansetron 8mg PO daily or twice dailyGranisetron 1mg PO dailyDolasetron 100mg PO daily

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Delayed Phase of CINV

Low Emetic Risk- None

Minimal Emetic Risk- None

Chemotherapy Induced Nausea and Vomiting- Prophylaxis of Delayed Phase of CINV

The best strategy to prevent delayed CINV is to control acute CINV

Aprepitant, dexamethasone and metoclopramide have demonstrated efficacy in preventing delayed CINV

Patients receiving cisplatin and other agents are at highest risk to experience delayed NV

The management of delayed CINV caused by high risk emetogenic regimens is more well defined than moderate emetic risk regimens

Chemotherapy Induced Nausea and Vomiting

Cannabinoids are used after the failure of other regimens or to stimulate appetite

Consider using an H2 blocker or proton pump inhibitor to prevent dyspepsia ( may mimic nausea)

Not FDA approved indications therefore doses not recommended

Chemotherapy Induced Nausea and Vomiting