Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy1,2. It is important to differentiate nausea from vomiting, as more patients experience nausea rather than vomiting3. There are 6 different categories of CINV
1. Acute CINV
2. Delayed CINV
3. Breakthrough CINV
4. Refractory CINV
5. Anticipatory CINV
6. Radiation Induced Nausea and Vomiting
ACUTE CINV: Acute CINV by definition begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment.
DELAYED CINV: This is defined as nausea and vomiting occurring more than 24 hours after chemotherapy administration and can persist for several days4. This is often underestimated, as a third of the patients receiving chemotherapy may experience delayed nausea and vomiting with out prior acute nausea or vomiting.
BREAKTHROUGH CINV: This is defined as nausea and/or vomiting experienced by patients despite prophylactic treatment with antiemetics. These patients require additional intervention with antiemetics to treat their symptoms.
REFRACTORY CINV: Patients on chemotherapy may experience nausea and vomiting following subsequent cycles of chemotherapy administration when prophylaxis/rescue for nausea and vomiting have failed in earlier cycles.
ANTICIPATORY CINV: This is a “learned conditioned response” with psychologic undertones as a result of prior experience of nausea and vomiting with chemotherapy. It usually occurs about 12 hours leading up to chemotherapy administration5,6. The incidence varies from 20%-50%. It is more often seen in younger patients and nausea is more common than vomiting. This entity is difficult to treat and may require psychologic counseling.
RADIATION INDUCED NAUSEA AND VOMITING: This is often experienced by patients undergoing Total Body Irradiation (TBI), a technique that is used prior to bone marrow transplantation7. Patients undergoing radiation to the upper abdomen will also experience nausea and vomiting8.
Pathophysiology of Nausea and Vomiting
The brain controls the multistep pathway that results in vomiting. There are two separate units in the medulla that play a vital role in the causation of nausea and vomiting.
• Chemoreceptor trigger zone (CTZ) also called Area Postrema, present on the floor of the fourth ventricle. This area is very sensitive to chemical stimuli and is easily accessible to emetogenic substances in the general circulation.
• Vomiting Center (Emetic Center) located in the reticular formation of the medulla. This center integrates the emetic response and coordinates the act of vomiting.
The neuroreceptors involved in mediating vomiting include Serotonin (5HT), Dopamine (D2), Neurokinin-1(NK-1), Cannabinoid(CB1), Opiate, Histamine(H1), Corticosteroid and Acetylcholine or Muscarinic(M) receptors. These receptors are located in the vomiting and vestibular centers of the brain9. The most important receptors involved in the emetic response however are Serotonin and Dopamine receptors10. Vomiting is triggered by the Vomiting Center after it receives impulses from CTZ, GI tract, and cerebral cortex and vestibular apparatus in the inner ear. Chemotherapeutic agents and radiation therapy generally induce vomiting by producing free radicals, which in turn act on the enterochromaffin cells, resulting in the release of Serotonin(5-hydroxytryptamine-5HT3). Serotonin activates the serotonin receptors. Activation of the receptors then activates the vagal afferent pathway, which in turn activates the vomiting center and causes an emetic response. Chemotherapeutic agents along with its metabolites also directly stimulate the CTZ by way of general circulation, triggering vomiting through the Vomiting Center.
Classification of Chemotherapeutic agents based on Emetogenicity11
High Risk: More than 90% of the patients experience acute emesis
Moderate Risk: 30-90% of the patients experience acute emesis
Low Risk: 10-30% of the patients experience acute emesis
Minimal Risk: Less than 10% of the patients experience acute emesis
Risk Factors for Nausea and Vomiting
• Emetogenic potential of the chemotherapy agent used
• Younger age
• Female gender
• History of motion sickness
• Alcohol consumption
Classification of Antiemetics
Serotonin (5-HT3) Receptor Antagonists
ZOFRAN ® (Ondansetron): This agent is the first in its class approved by the FDA in 1991 for the treatment of CINV. This first generation 5-HT3 receptor antagonist is available as an IV preparation, sublingual/chewable tablet, oral tablet and oral solution. This agent has a shorter half life than KYTRIL® and ALOXI®.
KYTRIL® (Granisetron): This first generation 5-HT3 receptor antagonist provides 24-hour protection against chemotherapy induced nausea and vomiting. It is available as a single dose Injection as well as tablets or oral solution
ALOXI ® (Palonosetron): This second generation 5-HT3 antagonist has a 100 fold higher binding affinity to 5-HT3 receptor than other 5-HT3 receptor antagonists12. This agent is effective in preventing both acute and delayed onset nausea and vomiting. This agent has to be given IV and oral administration is not feasible due to poor bioavailability, unlike the first generation 5-HT3 antagonists.
Neurokinin-1 (NK-1) Receptor Antagonist
EMEND® (Aprepitant): This agent selectively blocks the binding of substance P to the NK-1 receptor in the central nervous system and thereby complements the antiemetic activity of 5-HT3 receptor antagonists by virtue of its different mechanism of action. It is available as tablets as well as parenteral preparation. This agent can interact with several other drugs more, so when given orally because of first-pass metabolism13. It is therefore important to check the package insert for drug interactions.
Dopamine Receptor Antagonists
These agents antagonize dopamine (D2)-receptors which are involved in the emetic signaling through the chemoreceptor trigger zone. Dopamine receptor antagonists also counteract dopamine receptors in the stomach, implicated in decreasing stomach motility during nausea and vomiting. The three main classes of dopamine receptor antagonists are phenothiazines, butyrophenones, and benzamides.
Phenothiazines – PHENERGAN® (promethazine) belongs to this class. Low doses of phenothiazines antagonize interaction of dopamine with D2-receptors and thus exert an antiemetic effect.
Benzamides – Are strong central and peripheral D2-antagonists. They exert antiemetic effects by increasing lower esophageal sphincter tone and decreasing transit time through the upper gastrointestinal tract. REGLAN® (metoclopramide) belongs to this class.
Butyrophenones
HALDOL® (Haloperidol) belongs to this group of agents.
H1 Receptor Antagonists
Antihistamines antagonize the H1 receptors and inhibit the action of histamine. They also affect the vestibular system, decreasing stimulation of the vomiting center. Further, they also exhibit activity by inhibiting the muscarinic receptor. However, second generation antihistamines such as CLARITIN® (Loratidine), ALLEGRA® (Fexofenadine) and ZYRTEC® (Cetirizine) do not cross the blood brain barrier, and as such do not cause drowsiness and cannot be used as antiemetics. Some examples of H1 receptor antagonists include
• DRAMAMINE® (Dimenhydrinate)
• ANTIVERT® (Meclizine)
• BENADRYL® (Diphenhydramine)
Muscarinic Receptor Antagonists
These agents are good for motion sickness. They antagonize the acetylcholine receptors in the brain. Scopolamine transdermal belongs to this class
Cannabinoids Receptor Antagonists
These agents antagonize the CB1 receptors in the brain. The two drugs in this class
• MARINOL® (Dronabinol)
• CESAMET® (Nabilone)
Corticosteroids
The mechanism of action not clear. It may be related to the inhibition of arachidonic acid release. The agents in this class include
• DECADRON® (Dexamethasone)
• SOLUMEDROL® (Methylprednisolone)
Benzodiazepines
These agents are sometimes effective for anticipatory nausea and vomiting associated with cancer therapy. It may also be useful for vestibular disorders.
• VALIUM® (Diazepam)
• ATIVAN® (Lorazepam)
• XANAX®: (Alprazolam) Miscellaneous
• TIGAN® (Trimethobenzamide)
General Principles of treating Nausea and Vomiting
1) Prevention is better than cure. Aggressively preventing nausea and vomiting will not only improve patients quality of life but will also decrease the incidence of anticipatory nausea and vomiting.
2) The addition of DECADRON® to 5-HT3 and NK-1 receptor antagonists improves the efficacy of the antiemetic regimen.
3) The choice of an antiemetic regimen should be based on patient risk factors as well as emetogenic potential of a given chemotherapy regimen.
4) The toxicity of a given antiemetic agent and potential drug interactions should be taken into consideration before prescribing.
5) Breakthrough emesis should be aggressively managed with round the clock dosing rather than PRN dosing and a drug from a different class should be considered for treatment of this entity. Also consider rectal or IV route of administration rather than PO route.
6) Ensure patients are well hydrated and electrolyte imbalances are promptly addressed.
7) Think “outside the box” when addressing nausea and vomiting in cancer patients. Do not overlook bowel obstruction, brain metastases, uremia, nausea from pain meds such as opiates, chemo or tumor related gastroparesis and anticipatory nausea and vomiting.
8) Anticipatory nausea and vomiting can be difficult to treat and benzodiazepines (ATIVAN®, XANAX®) along with behavioral therapy may be beneficial.
Reference List
1. Morran C, Smith DC, Anderson DA, McArdle CS. Incidence of nausea and vomiting with cytotoxic chemotherapy: a prospective randomised trial of antiemetics. Br Med J 1979; 1(6174):1323-1324.
2. Jenns K. Importance of nausea. Cancer Nurs 1994; 17(6):488-493.
3. Hickok JT, Roscoe JA, Morrow GR et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol 2005; 6(10):765-772.
4. Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985; 3(10):1379-1384.
5. Moher D, Arthur AZ, Pater JL. Anticipatory nausea and/or vomiting. Cancer Treat Rev 1984; 11(3):257-264.
6. Jacobsen PB, Redd WH. The development and management of chemotherapy-related anticipatory nausea and vomiting. Cancer Invest 1988; 6(3):329-336.
7. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
8. Harding RK. Prodromal effects of radiation: pathways, models, and protection by antiemetics. Pharmacol Ther 1988; 39(1-3):335-345.
9. Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm 1985; 10(2):143-166.
10. BORISON HL, WANG SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953; 5(2):193-230.
11. Grunberg SM, Osoba D, Hesketh PJ et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–an update. Support Care Cancer 2005; 13(2):80-84.
12. Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother 2003; 4(12):2297-2303.
13. Shadle CR, Lee Y, Majumdar AK et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004; 44(3):215-223.
