Rx Focus: Management and Prevention of Chemotherapy-Induced Nausea and Vomiting

Although tremendous progress has been made in cancer treatment, many patients rank chemotherapy-induced nausea and vomiting (CINV) among the most disturbing and feared adverse effects of cancer therapy.^1-3 An estimated 70% to 80% of patients who receive chemotherapy experience CINV; of those patients, an estimated 46% have contemplated discontinuing their chemotherapy because of CINV.^1,3 Furthermore, an estimated 50% of cancer patients may refuse or delay chemotherapy because of fear of CINV.^1,2

If poorly controlled or uncontrolled, CINV can have a significant and negative impact on a patient’s physical, mental, and emotional well-being.^4,5 CINV also can lead to serious consequences, including anorexia, dehydration, electrolyte imbalances, malnutrition, esophageal tears, deterioration of quality of life, inadequate delivery of chemotherapy, and withdrawal or refusal of therapy.^2,4-7

Physiology of CINV

Research into the mechanism through which chemotherapeutic agents induce nausea and vomiting has revealed some of the critical pathways involved; however, much is still not known about this complex process.^2,8 CINV is thought to result from stimulation of the vomiting center by neurotransmitters released from the chemoreceptor trigger zone (CTZ), located on the dorsal surface of the medulla oblongata.^2,7-10

The enterochromaffin cells of the gastrointestinal (GI) tract also contain receptors that can trigger the afferent vagus nerve to stimulate the CTZ and initiate the emesis process.¹⁰ Multiple neurotransmitters also are involved in this complex physiologic process. The most important neuroreceptors are the 5-hydroxytryptamine 3 (5-HT₃) or serotonin receptors, the dopamine receptors, and the neurokinin-1 (NK₁) receptor.¹¹ Chemotherapeutic agents are presumed to cause a release of emetic transmitters, and these substances bind to receptors in the CTZ and probably bind to other areas of the brain and GI tract.⁸ Thus, the use of antiemetics before the administration of potentially emetogenic chemotherapy is particularly important for optimal patient care.⁸

Factors Influencing CINV

The various types of CINV are listed in the Table. The type of chemotherapeutic agent or regimen and the frequency of cycles that a patient receives are the most accurate predictors of the incidence and severity of CINV.^2,12 Chemotherapy agents are classified according to emetic risk as having high, moderate, or low potential for inducing emesis.^2,9,12 Cisplatin is one of the most emetogenic agents and is known to produce nausea and vomiting within 1 to 2 hours after receiving the drug in >99% of patients if no antiemetics are used.^2,8,12 A list of the emetogenic risk levels of several chemotherapeutic agents can be found online at www.PharmacyTimes.com/CINV.

Other factors that may affect the incidence and severity of CINV include^1,2,9,12:

• History of poorly controlled emesis

• Age (individuals <50 years of age have greater incidence of emesis)

• Gender (women have greater risk than men)

• Individuals with a history of alcohol abuse have a lower incidence of nausea and vomiting.

• Concurrent radiation therapy as well as previous exposure to chemotherapy

In addition, nonchemotherapy-related causes of emesis must be evaluated, such as bowel obstruction, renal insufficiency, brain metastases, or the use of other medications (eg, narcotic analgesics).^1,2,9,12

Pharmacologic Treatment

The classes of pharmacologic agents currently used for the prevention and management of CINV include 5-HT₃ selective serotonin receptor antagonists, NK₁ receptor antagonists, corticosteroids, and various adjunctive agents (eg, metoclopramide, phenothiazines, and benzodiazepines).

Selective serotonin receptor antagonists

The introduction of the 5-HT₃ selective serotonin receptor antagonists in the early 1990s had a significant impact on the management of CINV, and these agents are considered to be the cornerstone of prophylactic therapy for chemotherapy with moderate-to-high emetic potential.^2,12

The 5-HT₃ receptor antagonists are selective serotonin inhibitors that competitively inhibit the binding of serotonin to 5-HT₃ receptors.^2,8,12,13 Their antiemetic effects are postulated to stem from blockage of 5-HT₃ receptors located on the nerve terminals of the vagus in the periphery and centrally in the CTZ of the area postrema.^2,12-16 The agents in this drug class include ondansetron (Zofran), granisetron (Kytril), dolasetron (Anzemet), and tropisetron (Navoban). Tropisetron is currently not available in the United States. All of these agents are available in oral and injectable forms.

In 2003, the FDA approved a secondgeneration 5-HT₃ antagonist, palonosetron (Aloxi) as an injection; the drug was approved as an oral capsule in August 2008. Studies have shown that palonosetron is a highly selective second-generation 5-HT₃ receptor antagonist with demonstrated efficacy and long-lasting protection from CINV. Palonosetron differs from the older 5-HT₃ antagonists due to its prolonged half-life (approximately 40 hours) and significantly greater affinity for the 5-HT₃ receptor.^12,16,17 A study reported in the January 8, 2009, issue of Lancet Oncology concluded that a single dose of palonosetron was effective in preventing CINV and also showed some superiority over an older agent, granisetron, when both agents were administered in combination with dexamethasone.¹⁷

In September 2008, the FDA approved granisetron transdermal system (Sancuso), the first and only transdermal 5-HT₃ antagonist. The patch provides up to 5 consecutive days of control of nausea and vomiting for patients undergoing a moderately and/or highly nauseainducing chemotherapy regimen.¹⁸

The most common adverse effects associated with 5-HT₃ antagonists include headache and constipation.14-16,19

Corticosteroids

Corticosteroids, such as dexamethasone and methylprednisolone, are the second most widely used agents to prevent CINV.^2,11 They are effective for both acute and delayed emesis. Dexamethasone is especially valuable when administered in combination with 5-HT₃ serotonin receptor antagonists and the NK1 receptor antagonist aprepitant in patients receiving chemotherapy of high or moderate emetic risk.^11,12,20 According to the American Society of Clinical Oncology (ASCO) antiemetic guidelines, single- agent use of this class is appropriate in patients receiving chemotherapies of low emetic risk.²⁰

Neurokinin-1 receptor antagonists

In 2003, the FDA approved aprepitant (Emend), a NK₁ receptor antagonist representing the newest class of antiemetic agents used for the prevention of CINV. Aprepitant is an oral formulation and the first agent available in its class. The most common adverse effects associated with aprepitant include abdominal pain, constipation, dehydration, diarrhea, dizziness, fatigue, general malaise, and hiccups.^12,21,22

In January 2008, the FDA granted approval for fosaprepitant injection, an NK₁ receptor antagonist and water-soluble phosphoryl prodrug for aprepitant that is converted to aprepitant 30 minutes after intravenous administration.^21,22 This substance P and NK₁ receptor selective antagonist crosses the blood—brain barrier and binds to brain NK₁.^12,21 It inhibits emesis via central actions induced by antineoplastic agents, including highly emetogenic agents (eg, cisplatin), and augments the antiemetic activity of 5-HT₃ receptor antagonists (eg, ondansetron) and dexamethasone.^8,12,21 NK₁ receptor antagonists are administered as part of a regimen with dexamethasone and 5-HT3 receptor antagonists to prevent CINV.^8,12,21,22

Adjunctive Therapy

Agents such as metoclopramide, butyrophenones, and phenothiazines should be reserved for patients intolerant of or refractory to 5-HT₃ serotonin receptor antagonists, NK₁ receptor antagonists, and dexamethasone.^2,12,20 Lorazepam and diphenhydramine are useful adjuncts to antiemetic drugs. ^2,12,20

According to ASCO antiemetic guidelines, the combination of a 5-HT₃ antagonist, dexamethasone, and aprepitant is recommended before the administration of chemotherapeutic agents with a high risk of emesis.^12,20 A combination of a 5-HT₃ receptor serotonin antagonist, dexamethasone, and aprepitant is recommended for patients receiving an anthracycline and cyclophosphamide.^12,20 Patients receiving other chemotherapy of moderate emetic risk should receive a 5-HT₃ receptor serotonin antagonist and dexamethasone. In all patients receiving cisplatin and all other agents of high emetic risk, the 2-drug combination of dexamethasone and aprepitant is recommended for the prevention of delayed emesis.^12,20

For more information on the management and prevention of CINV, including the ASCO Recommendations for Antiemetic Therapy, visit the following Web sites: www.asco.org and www. ManageCINV.com.