Nausea And Vomiting In Cancer Patients – Causes, Prevention, Treatment (Antiemetic Drugs)

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In this article, we will explain how to treat nausea and vomiting in cancer patients.

Nausea is an unpleasant feeling or urge to vomit. Nausea is a symptom, which is experienced by a person and not visible to other.

Vomiting can be described as “throwing up” the content of the stomach due to abrupt contraction of stomach muscles that push the stomach contents out through mouth via esophagus (food pipe). Vomiting is a sign, that is it is visible to others. Vomiting may or may not be preceded by nausea.

Nausea and/or vomiting (N/V) are 2 of the most common and distressing side effects associated with cancer or its treatment. The N/V mostly occur simultaneously, but these are considered as 2 different problems in medical science. It is important to control both N/V in cancer patients so that they can remain compliant with their cancer treatment. Thus, cancer patients generally receive medicines that help in controlling N/V, also known as anti-emetics.

Types of Nausea and Vomiting in Cancer patients

The N/V are side effects that are subjective in nature and each individual’s experience of N/V is unique. With the same type and severity of disease, and with the same treatment, N/V may occur in an individual while it may not for the others due to different threshold levels of activation for vomiting center among different individuals.

It can vary in intensity, duration, pattern, and response to treatment with anti-emetics.

Based on such characteristics, N/V can be divided into the following types:

Acute Nausea/Vomiting

This type of N/V is usually intense and short-lived. Treatment-related acute N/V generally happen within a few minutes to hours after cancer treatment is administered or during the treatment administration.

Delayed Nausea/Vomiting

Delayed N/V happen more than 24 hours to few days after cancer treatment administration. This type of N/V is usually mild to moderate in intensity and take more time than acute N/V to resolve.

Anticipatory Nausea/Vomiting

This type of N/V occurs prior to a cancer-treatment administration. Patients usually experience this due to prior experience with the same kind of treatment that led to N/V. Experts believe that the brain pairs the cancer treatment’s taste, smell, sight, sound, or pain with the N/V. Anticipatory N/V is more common among children.

Breakthrough Nausea/Vomiting

This type of N/V is usually intense and short-lived. It happens even when a patient is receiving anti-emetic treatment to prevent it. Higher dose or a different type of anti-emetic is generally required for the management of this type of N/V.

Refractory Nausea/Vomiting

This is the most severe type of N/V that do not respond to anti-emetics being used for preventing it. It is usually intense and long-lived. Higher dose or a different type of anti-emetic is generally required for a longer duration of time for the management of this type of N/V.

Causes of Nausea and Vomiting in cancer patients

Vomiting is a reflex action that is triggered upon activation of the vomiting center, a part of the brain. It may occur as a result of many unpleasant things related to the disease or its treatment, for example, foul smell or taste of the drug used, patient experiencing anxiety or pain due to disease or treatment administration, disease/treatment-related inflammation, poor blood flow, or irritation in the upper GIT.

Following are the factors that can induce nausea or vomiting in cancer patients:

Cancer – The disease (cancer) itself can cause N/V if it involves the brain, upper GIT, or liver, and pancreas. Large tumors that are present in nearby organs but press on the brain or GIT organs may also cause vomiting. Also, cancer affecting the liver or pancreas can cause N/V.

Surgery – Patients who undergo surgery, depending upon the extent of the procedure, may report N/V due to the tissue damage caused by the surgery or due to the side effects of anesthesia or other intervention during the surgery. The risk of developing N/V further increases if surgery is carried out on the brain or on organs directly linked with the brain.

Chemotherapy – Chemotherapy is frequently employed as a primary treatment in cancer patients with advanced-stage disease. It involves treatment with cytotoxic agents that kill the cancer cells. Many chemotherapeutic agents are emetogenic (that means they are very likely to cause N/V).

Radiation therapy – Radiotherapy is another common treatment modality employed for cancer treatment. Radiations also cause tissue damage and have the potential to cause N/V.

Concomitant medicines/procedure – Sometimes, the supportive treatment used beside the primary treatment may cause N/V. For example, biopsy procedure or pain medicines may cause N/V in cancer patients.

Constipation – Cancer patients who have the problem of constipation are prone to N/V. Constipation may occur due to a side-effect of a medicine or may occur naturally. To avoid nausea vomiting in such patients, constipation must be treated.

Electrolytes Imbalance – An imbalance of electrolytes (minerals and salts) in the blood may cause N/V in cancer patients.

Anxiety – Some cancer patients have severe anxiety due to the disease they have or due to other disease-related factors. The anxiety increases the probability of cancer treatment causing N/V. Thus, cancer patients with severe anxiety should receive supportive care for anxiety besides the primary cancer treatment.

Intense pain – Cancer patients usually deal with the pain that may couple with the induction of N/V if not controlled properly. Thus, it is recommended that such patients should also receive pain treatment along with cancer therapy.

Past experience – Some patients may have an experience of N/V with certain chemotherapy drug(s). Such patients are prone to have N/V when they undergo similar treatment in future. In such cases, pre-treatment with anti-emetic medicine is usually recommended.

Predisposing Factors

The likelihood that a patient will have cancer-related N/V depends on many factors as detailed below:

      • Type of disease – Cancer involving brain or associated structures or those that affect upper GIT usually cause N/V more commonly.
      • Severity of disease – The advanced disease is more likely to cause N/V compared to the less advanced disease. Also, the disease that has spread to brain or GIT organs usually cause N/V.
      • Type of treatment – Certain type of surgery, chemotherapy, and/or radiotherapy are more likely to cause N/V.
      • Treatment regimen – Higher dose or higher dosing frequency of chemotherapy is more likely to cause N/V.
      • Age of patient – Younger patients are more likely to have N/V compared to old-age individuals.
      • Gender of the patient – Females are more prone to N/V compared to male counterparts.
      • Anxiety or Depression – Patients who have anxiety or depression are at higher risk of developing N/V.
      • Motion sickness – Patients with motion sickness usually have a lower threshold for N/V.
      • Prior Treatment – Patients who have received chemotherapy in past are usually more prone to N/V.
      • Drinking habit – It has been reported that patients who have never drunk are more prone to N/V.

Emetogenicity of Chemotherapeutic Agents

High (>90%)

      • cisplatin,
      • dacarbazine,
      • high dose cyclophosphamide,
      • carmustine,
      • mechlorethamine,
      • streptozotocin

Moderate (30-90%)

      • Carboplatin,
      • Ifosfamide,
      • Cyclophosphamide,
      • Doxorubicin,
      • Epirubicin,
      • Daunorubicin,
      • oxaliplatin,
      • AraC,
      • irinotecan,
      • bendamustine

Low (10-30%)

      • Topotecan,
      • Gemcitabine,
      • Paclitaxel,
      • Etoposide,
      • Methotrexate,
      • Mitomycin,
      • Fluorouracil,
      • Trastuzumab,
      • docetaxel,
      • mitoxantrone,
      • ixabepilone,
      • pemetrexed,
      • bortezomib,
      • cetuximab,
      • trastuzumab

Minimal(<10%)

      • Bleomycin,
      • Busulfan,
      • Vincristine,
      • Vinblastine,
      • Chlorambucil,
      • Hydroxyurea, 
      • bevacizumab,
      • rituximab

Antiemetic Agents Used for Chemotherapy Induced Nausea/Vomiting

  • Dopamine (DA) Antagonists
      • metoclopramide
      • promethazine
      • prochlorperazine
  • Serotonin (5HT-3) Antagonists
      • ondansetron
      • granisetron
      • dolasetron
      • palonosetron
  • Substance P (NK-1) inhibitors
      • Aprepitant
      • Fosaprepitant
  • Corticosteroids: Dexamethasone
  • Benzodiazepines: Lorazepam
  • Cannabinoids
      • Marinol (delta-9-THC)
      • nabilone

5HT-3 Antagonists

Mechanism of Action

  • Competitive, highly selective antagonist of type 3, 5-HT3 receptors present centrally, in the area postrema of brain, and peripherally, on vagal nerve terminals.
  • Antiemetic action mediated centrally, peripherally, or at both sites.
  • Effective in acute nausea and vomiting but plays only a limited role in delayed emesis.

Indications

  • Prevention of acute nausea and vomiting associated with initial and repeat courses of moderately or highly emetogenic cancer chemotherapy.
  • Prevention of nausea and vomiting associated with radiation, including TBI and fractionated abdominal radiation.
  • Prevention of postoperative nausea and vomiting.

Adverse Effects

  • Headache
  • Constipation, diarrhea, and/or abdominal pain.
  • Asthenia, fatigue, malaise
  • Transient elevations in LFTs. Usually clinically asymptomatic.
  • Hypersensitivity reactions with dyspnea, skin rash, urticaria, bronchospasm, and hypotension have been reported in rare instances

Special Considerations

  • No dose adjustment is required in hepatic and/or renal impairment.
  • Use with caution in pts with cardiac conduction abnormalities, including prolonged PR and QT intervals.
  • Use with caution in patients who are receiving antiarrhythmic agents or other drugs that can prolong the PR, QRS, and QT intervals.
  • Careful monitoring of electrolytes, including potassium and magnesium, is required to reduce the occurrence of arrhythmias.

ondansetron

24mg PO

8mg PO bid

8mg or 0.15mg/kg IV

8 mg bid D2 and 3

granisetron

2mg PO

1mg or 0.01mg/kg IV

 

tropisetron

5mg PO /IV

 

dolasetron

100mg PO

100mg or 1.8mg/kg IV

 

palonosetron

0.25mg IV

0.5mg PO

 

Substance-P Inhibitors (Aprepitant/Fosaprepitant)

Mechanism of Action

  • Selective , Neurokinin type 1 (NK 1) receptors antagonist
  • Block substance P from binding to NK1 receptor
  • Augment the antiemetic activity of 5HT3 antagonists and dexamethasone
  • Inhibit both acute and delayed CINV

Indications

  • Prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer CT.
  • Prevention of postoperative nausea and vomiting

Dosage

  • Aprepitant
      • 125 mg PO, D1
      • 80 mg PO on d 2 and 3
      • PONV: 40 mg PO within 3 hours prior to induction of anesthesia.
  • Fosaprepitant
      • IV: 115 mg IV 30 mins before CT on day 1 only.

Toxicities/Adverse Effects

  • Fatigue is most common side effect.
  • CNS effects include headache and insomnia.
  • GI side effects include constipation and/or diarrhea.
  • Hiccups observed in 10% of patients.

Corticosteroids

Mechanism of Action

  • Precise mechanism of action is not known.
  • Suppresses prostaglandin release from hypothalamus, which may then inhibit the subsequent process of nausea and vomiting.
  • Anti-inflammatory.

Indications

  • Prevention of nausea and vomiting associated with cancer CT in combination with other antiemetics, including 5-HT3 receptor antagonists, metoclopramide, and lorazepam.

Dosage

  • With aprepitant
    • 12mg PO or IV D1,
    • 8mg D2-4
  • Without aprepitant
    • 20mg PO orIV, 8mg bid D2-4
    • 8mg PO or IV D1 8mg D2,3              

Dopamine Antagonists

Metoclopramide

Mechanism of Action
  • Acts centrally by directly blocking the dopamine receptors in CTZ of the area postrema of brain.
  • Acts peripherally to enhance the action of acetylcholine at muscarinic synapses.
  • Stimulates GI motility through increasing gastric emptying via cholinergic excitatory processes.
  • Inhibits 5-HT3 receptors at high doses.
Indications
  • Prevention and/or treatment of nausea and vomiting associated with cancer chemotherapy.
  • Prevention of postoperative nausea and vomiting.
  • Treatment of GI motility disorders, diabetic gastroparesis, and/or gastroesophageal reflux.
Dosage
  • Oral: Recommended dose is 10–40 mg PO every 4–6 hours as needed.
  • IV: Recommended dose is 1–2 mg/kg IV administered 30 minutes before CT and repeated every 4–6 hours as needed.
Special Considerations
  • Contraindicated in pheochromocytoma as it may induce a hypertensive crisis.
  • Contraindicated in pts with seizure disorders because the frequency and severity of seizures may be increased.
  • Use with caution in pts with renal impairment. Dose adjustment is required in pts with decreased renal function.
  • Use with caution in pts with Parkinson’s disease as symptoms may be worsened
  • Extrapyramidal symptoms typically occur within 24–48 hrs of metoclopramide treatment. Most commonly seen with high-dose therapy and in pediatric pts and young adults.
  • Diphenhydramine 50 mg IV or IM can provide immediate relief.
  • Use with caution in pts with a history of mental depression and/or suicidal tendencies as exacerbation or worsening of underlying depression may occur.
Adverse Effects
  • Headache, fatigue, drowsiness, restlessness, and insomnia are the most common side effects (10%–15%).
  • Diarrhea and/or abdominal pain.
  • Dry mouth.
  • Hypersensitivity reactions with dyspnea, skin rash, urticaria, bronchospasm, and hypotension.
  • Extrapyramidal reactions with motor restlessness, tremor, akathesia, dystonia, and tardive dyskinesia.

Prochlorperazine

Mechanism of Action
  • Phenothiazine
  • Precise mechanism is unclear.
  • Blocks dopamine receptors in the CTZ.
  • Inhibits vagal stimulation of the vomiting center by peripheral afferents.
Indications
  • Control of nausea and vomiting of various etiologies.
  • Management of manifestations of psychotic disorders.
  • Acute treatment of generalized nonpsychotic anxiety
Dosage
  • Oral: 10 mg PO every 4–6 hours.
  • Rectal: 25 mg per rectum every 12 hours.
  • IM: 10–25 mg IM every 4–6 hours.
  • IV: 10–25 mg IV every 4–6 hours.
Precautions
  • Contraindicated in pts with known hypersensitivity to phenothiazines.

Use with caution in patients-

  • Who are on CNS depressants, in elderly pts, pts with glaucoma, pts under the age of 35 years as there is an increased risk of dystonic reactions
  • Pts should be advised to avoid heat exposure as prochlorperazine may interfere with thermoregulatory mechanisms.
  • Pts should be advised to avoid sun exposure to prevent photosensitivity reactions.
Adverse Effects
  • Drowsiness, sedation, insomnia, dizziness, and blurred vision.
  • Extrapyramidal reactions in the form of motor restlessness, tremor, akathisia, dystonia, pseudoparkinsonism, and tardive dyskinesia.
  • Dry mouth, constipation.
  • Orthostatic hypotension.
  • Mild photosensitivity, skin rash, and urticaria

Cannabinoids

  • CB agonists act as Omnineuromodulators
    —a term that describes their role in activating CB1 endocannabinoid receptors, which are present throughout the CNS and modulate neuronal signaling
  • Evidence shows that Omnineuromodulation underlies the therapeutic role of CB agents in the treatment of CINV, Cachexia, and Neuropathic Pain

Dronabinol

  • Use with caution
    • in elderly pts due to an increased risk of neuropsychoactive effects.
    • in patients with a history of alcohol and/or substance abuse.
    • in patients with underlying psychiatric disorders, including mania, depression, or schizophrenia.
  • Pts should be cautioned about possible neuropsychiatric side effects, including mood changes, euphoria, depression, insomnia, and, in extreme cases, psychosis.
  • Prescriptions should be limited to only one course of chemotherapy.

Side Effects

  • Mood changes, drowsiness, confusion, and dizziness.
  • Impairment in perception, coordination, and sensory function.
  • Visual distortions, nightmares, hallucinations, and depersonalization are also observed.
  • Orthostatic hypotension, tachycardia, facial flush, conjunctival injection, and palpitations.
  • Dry mouth, abdominal pain, and diarrhea occur in less than 10% of patients

Lorazepam (Benzodiazepines)

Mechanism of Action

  • Interacts with GABA-benzodiazepine receptor complex, which is widely expressed in the brain.
  • Exhibits high affinity for GABA recognition site and enhances the binding affinity of GABA for its receptor site on the same receptor complex.
  • Intensity of action, including antianxiety effects, sedation, and reduction of seizure activity, appears to be directly related to the occupancy status of the receptor.

Indications

  • Management of nausea and vomiting associated with emetogenic cancer CT either alone or in combination with other drugs, such as 5-HT3 antagonists and/or corticosteroids.
  • Management of anxiety disorders and acute relief of symptoms of anxiety and/or anxiety associated with depressive symptoms.
  • Management of preoperative anxiety.
  • Management of status epilepticus.

Side Effects

  • Sedation, depression, headache, sleep disturbance, dizziness, weakness, and unsteadiness are most commonly observed.
  • Changes in appetite, nausea, and GI symptoms may occur infrequently.
  • Transient amnesia or memory impairment.

Dose : 0.5 -2mg PO/IV/SL 4-6hrly   D1-4

What are the implications of cancer-related Nausea and Vomiting (N/V)?

Cancer-related N/V are 2 of the most common side effects observed in cancer patients.

  • makes it difficult for the patient to receive sufficient nutrition for body needs.
  • prevent the patient to stick to the treatment schedule and may lead to missed doses or drug elimination via vomiting.
  • dehydration and lack of essential minerals that body requires for its normal functioning
  • tiredness, fatigue
  • weight loss, loss of appetite,
  • trouble in concentrating, loss of interest in daily activities,

Overall, the nausea and vomiting have a detrimental effect on the quality of life of the cancer patient.

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