J.J., a 69-year-old woman, is a former smoker of 60 pack-years who presents with a stage IIIA (T2N2M0) primary lung adenocarcinoma. She was not considered a surgical candidate. The final treatment recommendation was definitive chemoradiation therapy, with plans for two cycles of neoadjuvant chemotherapy prior to the start of radiation because of the large lung mass and inability to deliver safe radiation doses. The initial chemotherapy plan included a combination of cisplatin (75 mg/m 2 ) and pemetrexed (500 mg/m 2 ) every 21 days.
On further discussion of potential chemotherapy side effects, Mrs. J. expresses concern regarding the potential for severe nausea and vomiting associated with the treatment, as she suffers from severe motion sickness and remembers having had significant nausea with her two pregnancies. She asks whether anything can be done to prevent and treat chemotherapy-associated nausea and vomiting.
Nausea and vomiting are two of the most feared and most commonly reported symptoms in patients with cancer, and can occur either as a result of the malignancy itself or from antineoplastic treatment. Over the last few decades, significant progress has been made in the development of more potent and effective chemotherapeutic agents. However, there is a significant cost in term of toxicity and the side effects of treatment, which often limit management options. Among the cancer treatment-related side effects, chemotherapy-induced nausea and vomiting (CINV) are, historically, two of the most common ; they can significantly affect patients’ quality of life, functional ability, and adherence to potentially useful and curative anticancer therapy.
Pathophysiology of Nausea and Vomiting
The vomiting reflex is triggered by afferent impulses to the vomiting center from vagus nerve terminals in the wall of the small bowel, the chemoreceptor trigger zone, or the cerebral cortex; the act of vomiting occurs when efferent impulses are sent to a number of organs and tissues such as the abdominal muscles, salivary glands, cranial nerves, and respiratory center. It is now thought that the central site of the emetic reflex, previously referred to as the “vomiting center” and most recently named the “central pattern generator,” is not an isolated area within the central nervous system but rather a group of loosely organized neurons throughout the medulla that interact through various pathways to coordinate the sequence of behaviors during vomiting. The primary sources of afferent input to the central pattern generator include the area postrema (commonly referred to as the “chemoreceptor trigger zone”) and the gastrointestinal tract through vagal and splanchnic afferents, which terminate primarily in the nucleus tractus solitarius and, to a lesser extent, the area postrema. These two central nervous system centers are collectively referred to as the dorsal vagal complex. The area postrema is located at the caudal end of the fourth ventricle, on the dorsal surface of the medulla oblongata where the blood-brain barrier is relatively permeable, and is therefore positioned to detect emetic stimuli in either the blood or the cerebrospinal fluid.
The main neurotransmitters implicated in the pathogenesis of acute and delayed CINV include serotonin (5-HT), substance P, and dopamine, which bind to 5-HT 3 , neurokinin-1 (NK1), and dopamine D 2 receptors, respectively.
- •
The 5-HT 3 receptors are found on the terminal ends of the vagal afferent nerves, as well as in key areas of the human brain stem, including the area postrema and the nucleus tractus solitarius. Preliminary evidence suggests that the selective 5-HT 3 receptor antagonists exert their action mainly by antagonizing the action of serotonin at the 5-HT 3 receptors on the peripheral vagal afferent terminals.
- •
The tachykinin NK1 receptors are widely distributed throughout the central and peripheral nervous system, as well as the respiratory, cardiovascular, genitourinary, and gastrointestinal tracts. It is currently thought that the NK1 receptor antagonists exert their action at a central level and that penetration of the blood-brain barrier is essential for their ability to prevent cisplatin-induced emesis.
Types of Chemotherapy-Induced Nausea and Vomiting Syndromes
Three distinct chemotherapy-induced nausea and/or vomiting syndromes have been described: acute, delayed, and anticipatory. Although the exact mechanism behind each syndrome is unclear, this classification has important implications for both prevention and management of CINV. Acute CINV occurs within 24 hours of chemotherapy administration; it may occur within 1 to 2 hours, with a peak incidence at 4 to 6 hours.
Delayed CINV is arbitrarily defined as occurring more than 24 hours after chemotherapy. Although it is most common after high-dose cisplatin, it has been associated with other agents as well, such as carboplatin, oxaliplatin, or the combination of cyclophosphamide with an anthracycline. For cisplatin, nausea and vomiting typically reach maximal intensity at 48 to 72 hours, and can last up to 5 or more days.
Anticipatory CINV is a conditioned response that tends to occur when nausea and vomiting have been poorly controlled with previous cycles of chemotherapy. Previous neutral stimuli become conditioned stimuli that elicit anticipatory nausea and/or vomiting, which can then be brought on by the smell of the hospital, the sight of the clinic, the treating physician, or the chemotherapy suite. Although usually associated with negative past experiences, anticipatory nausea and/or vomiting has also been described in patients who have a high expectancy of developing nausea despite never having received any cancer treatment. The incidence of anticipatory CINV can be as high as 57%, with nausea occurring more commonly than vomiting. Risk factors associated with the development of anticipatory nausea and/or vomiting include previous history of motion sickness, age younger than 50 years, past history of anxiety or depression, uncontrolled acute or delayed CINV with previous cycles, or chemotherapy extended over a prolonged period of time.
Emetogenicity of Chemotherapeutic agents
The most important factor in predicting CINV is the emetogenicity of the chemotherapeutic agent(s) used. Several classification schemes have been proposed that reflect the likelihood of emesis with both single agents and combination chemotherapy. The development of such algorithms has been of great value in providing a framework for the management of CINV and for the development of antiemetic treatment guidelines. In 2004, the Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC) held a consensus conference whereby a modification of the original schema of Hesketh et al. was proposed. This classification, utilized by both MASCC and the American Society of Clinical Oncology updated guidelines, divides intravenous chemotherapeutic agents into four categories on the basis of risk (incidence) of emesis in the absence of prophylaxis ( Table 18-1 ):
- •
High: greater than 90% emetic risk
- •
Moderate: 30% to 90% emetic risk
- •
Low: 10% to 30% emetic risk
- •
Minimal: less than 10% emetic risk
| Emetic Risk (incidence of emesis without antiemetics) | Agent |
|---|---|
| High (> 90%) |
|
| Moderate (30% to 90%) |
|
| Low (10% to 30%) |
|
| Minimal (< 10%) |
|
A new problem with utilizing this classification system is the growing use of oral chemotherapeutic agents, which tend to be prescribed over a period of several days to weeks. This makes it difficult to assess the contribution of acute versus delayed CINV and, as a result, antiemetic regimes recommended for single-dose intravenous agents may not apply to oral cytotoxic or targeted agents. The 2004 MASCC updated guidelines include a separate listing of the estimated emetic risk of the most commonly used oral antineoplastic agents.
Identifying Patients at Increased Risk for Development of CINV
In addition to the emetogenic potential of chemotherapy drugs, there are also well-described patient factors predisposing for more or less emetic trouble with specific regimes, which have been supported in multiple studies. The patient characteristics predicting development of more severe CINV include:
- •
Poor emetic control with prior chemotherapy
- •
Younger age (less than 65 years) ; increasing evidence indicates that older patients tend to tolerate chemotherapy better than younger patients
- •
Female gender ; in addition, emesis during pregnancy seems to be associated with an increased risk of developing CINV
- •
Low alcohol intake (10 or less alcoholic drinks per week in one study)
- •
Low social functioning or high fatigue scores
- •
Tumor burden – in one ovarian cancer study, patients 55 years or older with large (greater than 2 cm) tumors had more acute and delayed CINV
- •
Poor control of acute CINV increases the risk of delayed nausea and vomiting
- •
Presence of other causes of nausea and vomiting including constipation, which may be more frequent in elderly patients
Increased use of medications (polypharmacy) resulting from the presence of various comorbid conditions in older individuals may result in an increased risk of side effects and nausea.
Differential Diagnosis of Nausea and Vomiting in Patients with Cancer
In addition to chemotherapy and radiation therapy, many other factors can contribute to the development of nausea and vomiting in patients with advanced cancer. While it may be difficult to distinguish among the various causes, most patients will have additional signs, symptoms, or test abnormalities that can be helpful in pointing to the correct etiology. A thorough history and physical examination, as well as guided laboratory and imaging evaluation, may be critical steps in the assessment of nausea and vomiting in this patient population. The list is comprehensive, but most patients will have one or more of the contributing factors:
- •
Medications (most importantly narcotics, nonsteroidal anti-inflammatory drugs, antibiotics); a careful medication history, including nonprescription drugs is essential
- •
Postoperative nausea and vomiting following general anesthesia
- •
Gastroesophageal reflux disease (GERD) or peptic ulcer disease; absence of typical reflux symptoms does not rule out GERD
- •
Gastric outlet obstruction from malignancy or peptic ulcer disease
- •
Gastroparesis resulting from tumor involvement of the vagus nerve or lower thoracic spinal sympathetic plexus, paraneoplastic gastrointestinal dysmotility (described with small cell lung cancer and rarely other malignancies, and associated with antineuronal nuclear [ANNA-1, anti-Hu] or other antibodies ), and medications (i.e., anticholinergic drugs); patients usually complain of vomiting food eaten several hours earlier, and a succussion splash may be detected on physical examination
- •
Pancreatitis
- •
Cholecystitis
- •
Constipation
- •
Bowel obstruction; feculent vomiting suggests advanced obstruction or a gastrocolic fistula
- •
Peritoneal metastases and malignant ascites
- •
Mesenteric ischemia
- •
Increased intracranial pressure; vomiting may be projectile, and is usually associated with other focal neurologic signs or symptoms
- •
Metabolic causes (hyponatremia or hypernatremia, hyperglycemia, renal or hepatic insufficiency)
Types of Antiemetic Agents
Serotonin (5-HT 3 ) Receptor Antagonists
The successful development of 5-HT 3 -receptor antagonists, a drug class that has a high therapeutic index for prevention of CINV, was a major breakthrough in the management of this clinical problem. A large number of clinical trials have since been conducted, proving their efficacy and safety. As of this date, five such 5-HT 3 -receptor–selective antagonists have found their way in clinical practice: four first-generation agents (granisetron, ondansetron, dolasetron, and tropisetron) and one second-generation agent (palonosetron).
First-Generation 5-HT 3 Receptor Antagonists
- •
Numerous clinical trials using various doses, routes, and schedules of administration have demonstrated that first-generation 5-HT 3 antagonists are equally effective in preventing acute CINV. This was further supported by the results of two large meta-analyses.
- •
5-HT 3 first-generation agents share similar low side-effect profiles, which most often include headache, constipation, transient asymptomatic elevation in liver transaminases, and reversible clinically insignificant ECG changes (including prolongation of the QTc-interval). ECG changes are most prominent 1 to 2 hours after the drug administration and return to baseline within 24 hours. Although clinically important adverse cardiovascular events associated with these changes are excitingly rare, particular care should be taken in elderly patients who are more likely to use other cardiovascular medications, therefore increasing the risk of drug-drug interactions and side-effects.
- •
A single daily dose of a 5-HT 3 receptor antagonist prechemotherapy seems to be as effective as multiple daily doses or a continuous intravenous infusion, offering both convenience and potential cost savings. In addition, each drug has a plateau in therapeutic efficacy at a definable dose level, above which further dose escalation does not improve symptom control.
- •
Oral administration is equally efficacious as the intravenous route, even with highly emetogenic therapy. An orally disintegrating ondansetron tablet is also available for patients with dysphagia or anorexia and provides equivalent treatment to the oral swallowed formulation. In addition, a granisetron transdermal patch was recently approved by the Food and Drug Administration (FDA) and has been proven to be no less effective than oral granisetron when applied 24 to 48 hours prior to the first dose of chemotherapy
- •
Combining 5-HT 3 antagonists with dexamethasone further improves their efficacy.
- •
The role of first-generation 5-HT 3 receptor antagonists in preventing delayed CINV is less clear. A meta-analysis found that adding a 5-HT 3 antagonist to dexamethasone does not improve its effectiveness in preventing delayed emesis. Similarly, a recent randomized study found that first-generation agents were not better than prochlorperazine in controlling delayed doxorubicin-induced nausea and that the proportion of patients reporting delayed nausea exceeded 70% in both groups.
A Second-Generation 5-HT 3 Receptor Antagonist (Palonosetron)
- •
Palonosetron has a significantly higher binding affinity for the 5-HT 3 receptor and a longer half-life (approximately 40 hours) compared to first-generation agents.
- •
A single intravenous dose of palonosetron was shown to be as effective as a comparable dose of dolasetron in preventing acute CINV and superior in preventing delayed emesis.
- •
The safety profile of palonosetron is similar to first-generation 5-HT 3 antagonists.
- •
No dose adjustments or special monitoring are required for geriatric patients.
- •
Intravenous palonosetron is FDA-approved for prevention of acute and delayed nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy as a single dose on day 1; repeat dosing in the days after chemotherapy or in the setting of multiday regimens has not been well studied.
Neurokinin-1-Receptor Antagonists (Aprepitant)
The implication of substance P in the pathogenesis of acute and delayed CINV has led to the development of aprepitant, a novel neurokinin-1 antagonist; preliminary trials conducted in late 1990s demonstrated the high clinical efficacy of neurokinin receptor blockage for the prophylaxis of acute and delayed emesis associated with highly emetogenic chemotherapy. Subsequently, the approval of aprepitant for general use significantly improved the ability to prevent CINV in patients receiving moderately and highly emetogenic chemotherapy.
- •
Two phase III clinical trials, including a total of 1,043 patients receiving chemotherapy of high emetic risk (cisplatin), demonstrated a significantly improved control of acute and delayed CINV with the three-drug regimen of oral aprepitant (125 mg on day 1; 80 mg on days 2 and 3), ondansetron (32 mg intravenously on day 1), and dexamethasone (12 mg orally on day 1; 8 mg/d on days 2-4) over the standard combination of ondansetron (32 mg intravenously on day 1) and dexamethasone (20 mg orally on day 1; 8 mg twice daily on days 2-4).
- •
Similarly, aprepitant was shown to be more effective in preventing emesis when added to a standard regimen of ondansetron and dexamethasone versus the standard regimen of ondansetron and dexamethasone in 866 patients with breast cancer undergoing moderately emetogenic chemotherapy (cyclophosphamide alone or in combination with doxorubicin or epirubicin).
- •
Aprepitant plus dexamethasone alone does not seem to be as effective as the three-drug combination regimen including a 5-HT 3 receptor antagonist.
- •
Aprepitant is FDA-approved for use, in combination with other antiemetic agents, for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy.
- •
Chronic continuous use of aprepitant for prevention of nausea and vomiting has not been studied and is not recommended.
- •
An intravenous version of aprepitant (fosaprepitant dimeglumine) has been recently approved for use in the United States as a 115 mg infusion 30 minutes prior to chemotherapy on day 1, followed by standard dose oral aprepitant (80 mg) on days 2 and 3. Efficacy is thought to be similar to the oral regimen, although data are limited.
- •
Aprepitant is both a moderate inducer and moderate inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4) and a moderate inducer of CYP2C9 and therefore can alter the metabolism of certain drugs. Aprepitant should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4, as it could result in elevated plasma levels of these medications. Induction of warfarin metabolism may lead to clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time and therefore increased monitoring may be required in the 2-week period following administration of aprepitant with each chemotherapy cycle.
- •
The oral dose of dexamethasone (a CYP3A4 substrate) should be reduced by approximately 50% when coadministered with aprepitant, in order to achieve exposures of dexamethasone similar to those obtained when it is used without aprepitant. Nonetheless, these recommendations do not apply when corticosteroids are used as anticancer therapy (i.e., part of a combination chemotherapy regimen).
Dopamine Receptor Antagonists
Benzamides
Metoclopramide is the most commonly used drug in this class. It blocks type 2 dopamine receptors and 5-HT 3 serotonin receptors (when used in higher doses used to prevent CINV) in the chemoreceptor trigger zone, increases lower esophageal sphincter tone, and enhances bowel and gastric motility. The usual recommended doses are 20 to 40 mg orally every 4 to 6 hours (conventional dose) or 2 to 3 mg/kg (high dose). Metoclopramide crosses the blood-brain barrier, and side effects include extrapyramidal reactions such as acute dystonia, akathisia, and possible irreversible tardive dyskinesia, especially with prolonged use of high doses and in the elderly. Diphenhydramine or hydroxyzine can be used to antagonize the dopaminergic toxicity of metoclopramide. In addition, metoclopramide can lower the seizure threshold and increase the risk of convulsions in patients with epilepsy. In the past, metoclopramide combined with dexamethasone was the antiemetic regimen of choice for preventing delayed CINV, but it has largely been replaced by the use of 5-HT antagonists and aprepitant.
Phenothiazines
Phenothiazines, such as prochlorperazine (Compazine), thiethylperazine (Torecan), promethazine (Phenergan), and chlorpromazine (Thorazine) act predominantly as dopamine receptor antagonists, but they also have anticholinergic and antihistaminic blocking effects. Phenothiazines are useful in the treatment of nausea and vomiting caused by various gastrointestinal disorders, but their role in prevention of highly-emetogenic CINV is limited. However, they still play a role in the treatment of mild CINV, as well as breakthrough nausea and vomiting. Phenothiazines can be given intravenously, intramuscularly, orally, or rectally, making them very useful in patients who have difficulties with intravenous access or are unable to tolerate oral intake. Side effects include extrapyramidal symptoms (acute dystonia, akathisia, tardive dyskinesia), anticholinergic effects (dry mouth, urinary retention, tachycardia, drowsiness), and sedation. Acute dystonia is more common in younger, than in older, patients and, as with metoclopramide, diphenhydramine or hydroxyzine can be used to antagonize extrapyramidal system receptors. Intravenous administration of prochlorperazine can cause marked hypotension, especially in the elderly and especially if administered too rapidly.
Butyrophenones
The two drugs in this class, droperidol (Inapsine) and haloperidol (Haldol) are type 2 dopamine receptor antagonists. Although they have stronger antiemetic effects than phenothiazines, the incidence of extrapyramidal side effects is higher. Other side effects include sedation, hypotension, and clinically significant QTc prolongation associated with an increased risk of sudden death. Droperidol is currently rarely, if ever, used for the prevention of CINV. Haloperidol can be administered intramuscularly, intravenously, or orally; however, its prolonged half-life (18 hours) often limits its use. Before the introduction of 5-HT 3 receptor antagonists, butyrophenones were used as an alternative to high-dose metoclopramide ; however, their utilization has markedly decreased in recent years.
Atypical Antipsychotics
Olanzapine is a new atypical antipsychotic drug which blocks dopaminergic, serotoninergic, antihistaminic, muscarinic, and dopaminergic receptors. Olanzapine was initially found to be effective in patients with advanced cancer who required opioid analgesics for pain. In a recently published small phase I study, Passik and colleagues used olanzapine for prevention of moderate and highly-emetogenic CINV in a dose of 5 mg daily for 2 days prior to chemotherapy and 10 mg daily for the subsequent 8 days (days 0-7). Four of six patients receiving highly emetogenic chemotherapy and nine of nine patients receiving moderately emetogenic regimens achieved complete control of delayed nausea, with the main side effect being grade 3 depressed level of consciousness in 3 of 15 patients treated. A similarly high complete response rate and an acceptable toxicity profile were achieved in two subsequent phase II trials when olanzapine and dexamethasone were combined with granisetron and palonosetron, respectively. Olanzapine is available in oral and injectable (intramuscular) formulations. The main side effects are extrapyramidal and anticholinergic reactions, sedation, as well as weight gain and an associated risk of diabetes when used for a prolonged period of time.
Corticosteroids
Corticosteroids are among the most commonly used antiemetics because of their low cost, efficacy, and wide availability. At equivalent doses, all corticosteroids appear to have comparable efficacy and can be used interchangeably. Dexamethasone and methylprednisolone are the most thoroughly studied; dexamethasone is used most often because of its availability in generic forms and the variety of dosage formulations. The efficacy of oral and intravenous formulations appears to be equivalent; therefore oral formulations are usually recommended because of ease of administration and low cost. The mechanism of action has not been fully elucidated and there is no clear evidence to support central neurotransmitter blockade with corticosteroid use. The main side effects include insomnia, agitation, mood changes, indigestion/epigastric discomfort, increased appetite, weight gain, and hyperglycemia. Therefore, patients with a prior history of diabetes or those receiving NSAIDs should be closely monitored when corticosteroids are administered. Adrenal insufficiency has not been described with the short courses of corticosteroids (2 to 4 days) used in the prevention or treatment of CINV.
Single-agent corticosteroid treatment, such as dexamethasone (8 mg), is currently recommended for the prophylaxis of acute emesis with low-emetogenic chemotherapy. Corticosteroids are most useful, however, when used in combination with aprepitant and 5-HT 3 serotonin receptor antagonists in patients receiving chemotherapy of moderate or high emetogenic potential. For prevention of acute CINV induced by highly emetogenic chemotherapy, a dose of 20 mg of dexamethasone is recommended before chemotherapy, when given in combination with a 5-HT 3 serotonin antagonist, but the dose should be decreased to 12 mg when aprepitant is added to the regimen. For patients receiving moderately emetogenic chemotherapy, a single dose of 8 mg of dexamethasone is currently recommended before chemotherapy. The recommended dexamethasone dose for prevention of delayed nausea is 8 mg daily for 2 to 3 days following chemotherapy.
Other Agents
Benzodiazepines
Benzodiazepines are weak antiemetic agents and their use as single agents to prevent CINV is not recommended. Benzodiazepines are mainly used as adjunctive agents to reduce anxiety, anticipatory nausea and vomiting, and refractory emesis occurring despite adequate prophylaxis regimens. Lorazepam (Ativan) and alprazolam (Xanax) are the most commonly used drugs in this class. The main side effect of benzodiazepines is sedation; therefore elderly patients and patients receiving medications with additional central nervous system depressant activity (e.g., phenothiazines, opioids) should be carefully monitored.
Antihistamines
Antihistamines do not have significant antiemetic activity and should not be used as single agents in the prevention or treatment of CINV. Antihistamines are mainly used as adjunctive agents to prevent dystonic reactions with dopamine receptor blockers, or for treatment of nausea in patients with advanced cancer when the nausea is thought to be mediated by the vestibular system.
Cannabinoids
Despite the controversy that surrounds the use of cannabinoids for CINV, several studies using delta-9-tetrahydrocannabinol (THC) have shown this agent to be an effective antiemetic, compared to placebo and even prochlorperazine. Drugs in this class are available as plant extracts (dronabinol or tetrahydrocannabinol) and semisynthetic substances (nabilone, levonantradol). The most frequently used doses are 5 to 10 mg orally every 6 to 8 hours for dronabinol and 1 to 2 mg orally every 12 hours for nabilone. In a systematic review of efficacy and adverse effects of cannabinoids in the prevention of CINV, it was found that they were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride. However, cannabinoids have not been proven to be more effective in patients receiving mildly or very highly emetogenic chemotherapy. Side effects occurred more frequently with cannabinoids and included dizziness, dysphoria, depression, hallucinations, paranoia, and hypotension. Some potentially “beneficial” side effects include euphoria and sedation. As with other agents having a lower therapeutic index, cannabinoids should be reserved for patients who are intolerant of or refractory to 5-HT 3 serotonin receptor antagonists, aprepitant, or dexamethasone.
Treatment Recommendations General Principles Regarding Emesis Control in Patients Receiving Chemotherapy
- •
The main goal of antiemetic therapy in patients with cancer undergoing chemotherapy is prevention of nausea and/or vomiting. Patients who experience acute nausea or emesis are also much more likely to develop these complications 24 hours or more after treatment.
- •
Therapy should start before the administration of chemotherapy and cover at least the first 3 days for agents with high emetic risk.
- •
Oral administration of antiemetic agents is equally efficacious as the intravenous route, even with highly emetogenic therapy, and therefore the oral route is preferred unless the patient is unable to tolerate or swallow oral medications.
- •
The choice of the antiemetic regimen should be based upon the emetogenic potential of the chemotherapeutic agent(s) used, side-effect profiles, and patient-specific factors including previous experience with antiemetics.
- •
For multidrug chemotherapeutic regimens, the choice of antiemetics should be on the basis of the drug with the highest emetogenic potential, although adding low- or moderate-risk agents usually increases emetogenicity by one level.
- •
For multiday chemotherapy regimens, it has been recommended that antiemetics appropriate for the emetogenic risk of chemotherapy should be administered during each day of treatment. Nonetheless, there is a lack of formal guidelines for this situation.
- •
The best management of anticipatory nausea and/or vomiting is adequate control of acute and delayed CINV, use of anxiolytics (although the response is usually not maintained as chemotherapy treatment continues), and use of behavioral therapies involving desensitization.
- •
Other potential causes of nausea and vomiting should be excluded and treated, if possible.
Serotonin (5-HT 3 ) Receptor Antagonists
The successful development of 5-HT 3 -receptor antagonists, a drug class that has a high therapeutic index for prevention of CINV, was a major breakthrough in the management of this clinical problem. A large number of clinical trials have since been conducted, proving their efficacy and safety. As of this date, five such 5-HT 3 -receptor–selective antagonists have found their way in clinical practice: four first-generation agents (granisetron, ondansetron, dolasetron, and tropisetron) and one second-generation agent (palonosetron).
First-Generation 5-HT 3 Receptor Antagonists
- •
Numerous clinical trials using various doses, routes, and schedules of administration have demonstrated that first-generation 5-HT 3 antagonists are equally effective in preventing acute CINV. This was further supported by the results of two large meta-analyses.
- •
5-HT 3 first-generation agents share similar low side-effect profiles, which most often include headache, constipation, transient asymptomatic elevation in liver transaminases, and reversible clinically insignificant ECG changes (including prolongation of the QTc-interval). ECG changes are most prominent 1 to 2 hours after the drug administration and return to baseline within 24 hours. Although clinically important adverse cardiovascular events associated with these changes are excitingly rare, particular care should be taken in elderly patients who are more likely to use other cardiovascular medications, therefore increasing the risk of drug-drug interactions and side-effects.
- •
A single daily dose of a 5-HT 3 receptor antagonist prechemotherapy seems to be as effective as multiple daily doses or a continuous intravenous infusion, offering both convenience and potential cost savings. In addition, each drug has a plateau in therapeutic efficacy at a definable dose level, above which further dose escalation does not improve symptom control.
- •
Oral administration is equally efficacious as the intravenous route, even with highly emetogenic therapy. An orally disintegrating ondansetron tablet is also available for patients with dysphagia or anorexia and provides equivalent treatment to the oral swallowed formulation. In addition, a granisetron transdermal patch was recently approved by the Food and Drug Administration (FDA) and has been proven to be no less effective than oral granisetron when applied 24 to 48 hours prior to the first dose of chemotherapy
- •
Combining 5-HT 3 antagonists with dexamethasone further improves their efficacy.
- •
The role of first-generation 5-HT 3 receptor antagonists in preventing delayed CINV is less clear. A meta-analysis found that adding a 5-HT 3 antagonist to dexamethasone does not improve its effectiveness in preventing delayed emesis. Similarly, a recent randomized study found that first-generation agents were not better than prochlorperazine in controlling delayed doxorubicin-induced nausea and that the proportion of patients reporting delayed nausea exceeded 70% in both groups.
A Second-Generation 5-HT 3 Receptor Antagonist (Palonosetron)
- •
Palonosetron has a significantly higher binding affinity for the 5-HT 3 receptor and a longer half-life (approximately 40 hours) compared to first-generation agents.
- •
A single intravenous dose of palonosetron was shown to be as effective as a comparable dose of dolasetron in preventing acute CINV and superior in preventing delayed emesis.
- •
The safety profile of palonosetron is similar to first-generation 5-HT 3 antagonists.
- •
No dose adjustments or special monitoring are required for geriatric patients.
- •
Intravenous palonosetron is FDA-approved for prevention of acute and delayed nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy as a single dose on day 1; repeat dosing in the days after chemotherapy or in the setting of multiday regimens has not been well studied.
First-Generation 5-HT 3 Receptor Antagonists
- •
Numerous clinical trials using various doses, routes, and schedules of administration have demonstrated that first-generation 5-HT 3 antagonists are equally effective in preventing acute CINV. This was further supported by the results of two large meta-analyses.
- •
5-HT 3 first-generation agents share similar low side-effect profiles, which most often include headache, constipation, transient asymptomatic elevation in liver transaminases, and reversible clinically insignificant ECG changes (including prolongation of the QTc-interval). ECG changes are most prominent 1 to 2 hours after the drug administration and return to baseline within 24 hours. Although clinically important adverse cardiovascular events associated with these changes are excitingly rare, particular care should be taken in elderly patients who are more likely to use other cardiovascular medications, therefore increasing the risk of drug-drug interactions and side-effects.
- •
A single daily dose of a 5-HT 3 receptor antagonist prechemotherapy seems to be as effective as multiple daily doses or a continuous intravenous infusion, offering both convenience and potential cost savings. In addition, each drug has a plateau in therapeutic efficacy at a definable dose level, above which further dose escalation does not improve symptom control.
- •
Oral administration is equally efficacious as the intravenous route, even with highly emetogenic therapy. An orally disintegrating ondansetron tablet is also available for patients with dysphagia or anorexia and provides equivalent treatment to the oral swallowed formulation. In addition, a granisetron transdermal patch was recently approved by the Food and Drug Administration (FDA) and has been proven to be no less effective than oral granisetron when applied 24 to 48 hours prior to the first dose of chemotherapy
- •
Combining 5-HT 3 antagonists with dexamethasone further improves their efficacy.
- •
The role of first-generation 5-HT 3 receptor antagonists in preventing delayed CINV is less clear. A meta-analysis found that adding a 5-HT 3 antagonist to dexamethasone does not improve its effectiveness in preventing delayed emesis. Similarly, a recent randomized study found that first-generation agents were not better than prochlorperazine in controlling delayed doxorubicin-induced nausea and that the proportion of patients reporting delayed nausea exceeded 70% in both groups.
A Second-Generation 5-HT 3 Receptor Antagonist (Palonosetron)
- •
Palonosetron has a significantly higher binding affinity for the 5-HT 3 receptor and a longer half-life (approximately 40 hours) compared to first-generation agents.
- •
A single intravenous dose of palonosetron was shown to be as effective as a comparable dose of dolasetron in preventing acute CINV and superior in preventing delayed emesis.
- •
The safety profile of palonosetron is similar to first-generation 5-HT 3 antagonists.
- •
No dose adjustments or special monitoring are required for geriatric patients.
- •
Intravenous palonosetron is FDA-approved for prevention of acute and delayed nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy as a single dose on day 1; repeat dosing in the days after chemotherapy or in the setting of multiday regimens has not been well studied.
Neurokinin-1-Receptor Antagonists (Aprepitant)
The implication of substance P in the pathogenesis of acute and delayed CINV has led to the development of aprepitant, a novel neurokinin-1 antagonist; preliminary trials conducted in late 1990s demonstrated the high clinical efficacy of neurokinin receptor blockage for the prophylaxis of acute and delayed emesis associated with highly emetogenic chemotherapy. Subsequently, the approval of aprepitant for general use significantly improved the ability to prevent CINV in patients receiving moderately and highly emetogenic chemotherapy.
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Two phase III clinical trials, including a total of 1,043 patients receiving chemotherapy of high emetic risk (cisplatin), demonstrated a significantly improved control of acute and delayed CINV with the three-drug regimen of oral aprepitant (125 mg on day 1; 80 mg on days 2 and 3), ondansetron (32 mg intravenously on day 1), and dexamethasone (12 mg orally on day 1; 8 mg/d on days 2-4) over the standard combination of ondansetron (32 mg intravenously on day 1) and dexamethasone (20 mg orally on day 1; 8 mg twice daily on days 2-4).
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Similarly, aprepitant was shown to be more effective in preventing emesis when added to a standard regimen of ondansetron and dexamethasone versus the standard regimen of ondansetron and dexamethasone in 866 patients with breast cancer undergoing moderately emetogenic chemotherapy (cyclophosphamide alone or in combination with doxorubicin or epirubicin).
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Aprepitant plus dexamethasone alone does not seem to be as effective as the three-drug combination regimen including a 5-HT 3 receptor antagonist.
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Aprepitant is FDA-approved for use, in combination with other antiemetic agents, for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy.
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Chronic continuous use of aprepitant for prevention of nausea and vomiting has not been studied and is not recommended.
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An intravenous version of aprepitant (fosaprepitant dimeglumine) has been recently approved for use in the United States as a 115 mg infusion 30 minutes prior to chemotherapy on day 1, followed by standard dose oral aprepitant (80 mg) on days 2 and 3. Efficacy is thought to be similar to the oral regimen, although data are limited.
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Aprepitant is both a moderate inducer and moderate inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4) and a moderate inducer of CYP2C9 and therefore can alter the metabolism of certain drugs. Aprepitant should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4, as it could result in elevated plasma levels of these medications. Induction of warfarin metabolism may lead to clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time and therefore increased monitoring may be required in the 2-week period following administration of aprepitant with each chemotherapy cycle.
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The oral dose of dexamethasone (a CYP3A4 substrate) should be reduced by approximately 50% when coadministered with aprepitant, in order to achieve exposures of dexamethasone similar to those obtained when it is used without aprepitant. Nonetheless, these recommendations do not apply when corticosteroids are used as anticancer therapy (i.e., part of a combination chemotherapy regimen).
Dopamine Receptor Antagonists
Benzamides
Metoclopramide is the most commonly used drug in this class. It blocks type 2 dopamine receptors and 5-HT 3 serotonin receptors (when used in higher doses used to prevent CINV) in the chemoreceptor trigger zone, increases lower esophageal sphincter tone, and enhances bowel and gastric motility. The usual recommended doses are 20 to 40 mg orally every 4 to 6 hours (conventional dose) or 2 to 3 mg/kg (high dose). Metoclopramide crosses the blood-brain barrier, and side effects include extrapyramidal reactions such as acute dystonia, akathisia, and possible irreversible tardive dyskinesia, especially with prolonged use of high doses and in the elderly. Diphenhydramine or hydroxyzine can be used to antagonize the dopaminergic toxicity of metoclopramide. In addition, metoclopramide can lower the seizure threshold and increase the risk of convulsions in patients with epilepsy. In the past, metoclopramide combined with dexamethasone was the antiemetic regimen of choice for preventing delayed CINV, but it has largely been replaced by the use of 5-HT antagonists and aprepitant.
Phenothiazines
Phenothiazines, such as prochlorperazine (Compazine), thiethylperazine (Torecan), promethazine (Phenergan), and chlorpromazine (Thorazine) act predominantly as dopamine receptor antagonists, but they also have anticholinergic and antihistaminic blocking effects. Phenothiazines are useful in the treatment of nausea and vomiting caused by various gastrointestinal disorders, but their role in prevention of highly-emetogenic CINV is limited. However, they still play a role in the treatment of mild CINV, as well as breakthrough nausea and vomiting. Phenothiazines can be given intravenously, intramuscularly, orally, or rectally, making them very useful in patients who have difficulties with intravenous access or are unable to tolerate oral intake. Side effects include extrapyramidal symptoms (acute dystonia, akathisia, tardive dyskinesia), anticholinergic effects (dry mouth, urinary retention, tachycardia, drowsiness), and sedation. Acute dystonia is more common in younger, than in older, patients and, as with metoclopramide, diphenhydramine or hydroxyzine can be used to antagonize extrapyramidal system receptors. Intravenous administration of prochlorperazine can cause marked hypotension, especially in the elderly and especially if administered too rapidly.
Butyrophenones
The two drugs in this class, droperidol (Inapsine) and haloperidol (Haldol) are type 2 dopamine receptor antagonists. Although they have stronger antiemetic effects than phenothiazines, the incidence of extrapyramidal side effects is higher. Other side effects include sedation, hypotension, and clinically significant QTc prolongation associated with an increased risk of sudden death. Droperidol is currently rarely, if ever, used for the prevention of CINV. Haloperidol can be administered intramuscularly, intravenously, or orally; however, its prolonged half-life (18 hours) often limits its use. Before the introduction of 5-HT 3 receptor antagonists, butyrophenones were used as an alternative to high-dose metoclopramide ; however, their utilization has markedly decreased in recent years.
Atypical Antipsychotics
Olanzapine is a new atypical antipsychotic drug which blocks dopaminergic, serotoninergic, antihistaminic, muscarinic, and dopaminergic receptors. Olanzapine was initially found to be effective in patients with advanced cancer who required opioid analgesics for pain. In a recently published small phase I study, Passik and colleagues used olanzapine for prevention of moderate and highly-emetogenic CINV in a dose of 5 mg daily for 2 days prior to chemotherapy and 10 mg daily for the subsequent 8 days (days 0-7). Four of six patients receiving highly emetogenic chemotherapy and nine of nine patients receiving moderately emetogenic regimens achieved complete control of delayed nausea, with the main side effect being grade 3 depressed level of consciousness in 3 of 15 patients treated. A similarly high complete response rate and an acceptable toxicity profile were achieved in two subsequent phase II trials when olanzapine and dexamethasone were combined with granisetron and palonosetron, respectively. Olanzapine is available in oral and injectable (intramuscular) formulations. The main side effects are extrapyramidal and anticholinergic reactions, sedation, as well as weight gain and an associated risk of diabetes when used for a prolonged period of time.
Benzamides
Metoclopramide is the most commonly used drug in this class. It blocks type 2 dopamine receptors and 5-HT 3 serotonin receptors (when used in higher doses used to prevent CINV) in the chemoreceptor trigger zone, increases lower esophageal sphincter tone, and enhances bowel and gastric motility. The usual recommended doses are 20 to 40 mg orally every 4 to 6 hours (conventional dose) or 2 to 3 mg/kg (high dose). Metoclopramide crosses the blood-brain barrier, and side effects include extrapyramidal reactions such as acute dystonia, akathisia, and possible irreversible tardive dyskinesia, especially with prolonged use of high doses and in the elderly. Diphenhydramine or hydroxyzine can be used to antagonize the dopaminergic toxicity of metoclopramide. In addition, metoclopramide can lower the seizure threshold and increase the risk of convulsions in patients with epilepsy. In the past, metoclopramide combined with dexamethasone was the antiemetic regimen of choice for preventing delayed CINV, but it has largely been replaced by the use of 5-HT antagonists and aprepitant.
Phenothiazines
Phenothiazines, such as prochlorperazine (Compazine), thiethylperazine (Torecan), promethazine (Phenergan), and chlorpromazine (Thorazine) act predominantly as dopamine receptor antagonists, but they also have anticholinergic and antihistaminic blocking effects. Phenothiazines are useful in the treatment of nausea and vomiting caused by various gastrointestinal disorders, but their role in prevention of highly-emetogenic CINV is limited. However, they still play a role in the treatment of mild CINV, as well as breakthrough nausea and vomiting. Phenothiazines can be given intravenously, intramuscularly, orally, or rectally, making them very useful in patients who have difficulties with intravenous access or are unable to tolerate oral intake. Side effects include extrapyramidal symptoms (acute dystonia, akathisia, tardive dyskinesia), anticholinergic effects (dry mouth, urinary retention, tachycardia, drowsiness), and sedation. Acute dystonia is more common in younger, than in older, patients and, as with metoclopramide, diphenhydramine or hydroxyzine can be used to antagonize extrapyramidal system receptors. Intravenous administration of prochlorperazine can cause marked hypotension, especially in the elderly and especially if administered too rapidly.
Butyrophenones
The two drugs in this class, droperidol (Inapsine) and haloperidol (Haldol) are type 2 dopamine receptor antagonists. Although they have stronger antiemetic effects than phenothiazines, the incidence of extrapyramidal side effects is higher. Other side effects include sedation, hypotension, and clinically significant QTc prolongation associated with an increased risk of sudden death. Droperidol is currently rarely, if ever, used for the prevention of CINV. Haloperidol can be administered intramuscularly, intravenously, or orally; however, its prolonged half-life (18 hours) often limits its use. Before the introduction of 5-HT 3 receptor antagonists, butyrophenones were used as an alternative to high-dose metoclopramide ; however, their utilization has markedly decreased in recent years.
Atypical Antipsychotics
Olanzapine is a new atypical antipsychotic drug which blocks dopaminergic, serotoninergic, antihistaminic, muscarinic, and dopaminergic receptors. Olanzapine was initially found to be effective in patients with advanced cancer who required opioid analgesics for pain. In a recently published small phase I study, Passik and colleagues used olanzapine for prevention of moderate and highly-emetogenic CINV in a dose of 5 mg daily for 2 days prior to chemotherapy and 10 mg daily for the subsequent 8 days (days 0-7). Four of six patients receiving highly emetogenic chemotherapy and nine of nine patients receiving moderately emetogenic regimens achieved complete control of delayed nausea, with the main side effect being grade 3 depressed level of consciousness in 3 of 15 patients treated. A similarly high complete response rate and an acceptable toxicity profile were achieved in two subsequent phase II trials when olanzapine and dexamethasone were combined with granisetron and palonosetron, respectively. Olanzapine is available in oral and injectable (intramuscular) formulations. The main side effects are extrapyramidal and anticholinergic reactions, sedation, as well as weight gain and an associated risk of diabetes when used for a prolonged period of time.
Corticosteroids
Corticosteroids are among the most commonly used antiemetics because of their low cost, efficacy, and wide availability. At equivalent doses, all corticosteroids appear to have comparable efficacy and can be used interchangeably. Dexamethasone and methylprednisolone are the most thoroughly studied; dexamethasone is used most often because of its availability in generic forms and the variety of dosage formulations. The efficacy of oral and intravenous formulations appears to be equivalent; therefore oral formulations are usually recommended because of ease of administration and low cost. The mechanism of action has not been fully elucidated and there is no clear evidence to support central neurotransmitter blockade with corticosteroid use. The main side effects include insomnia, agitation, mood changes, indigestion/epigastric discomfort, increased appetite, weight gain, and hyperglycemia. Therefore, patients with a prior history of diabetes or those receiving NSAIDs should be closely monitored when corticosteroids are administered. Adrenal insufficiency has not been described with the short courses of corticosteroids (2 to 4 days) used in the prevention or treatment of CINV.
Single-agent corticosteroid treatment, such as dexamethasone (8 mg), is currently recommended for the prophylaxis of acute emesis with low-emetogenic chemotherapy. Corticosteroids are most useful, however, when used in combination with aprepitant and 5-HT 3 serotonin receptor antagonists in patients receiving chemotherapy of moderate or high emetogenic potential. For prevention of acute CINV induced by highly emetogenic chemotherapy, a dose of 20 mg of dexamethasone is recommended before chemotherapy, when given in combination with a 5-HT 3 serotonin antagonist, but the dose should be decreased to 12 mg when aprepitant is added to the regimen. For patients receiving moderately emetogenic chemotherapy, a single dose of 8 mg of dexamethasone is currently recommended before chemotherapy. The recommended dexamethasone dose for prevention of delayed nausea is 8 mg daily for 2 to 3 days following chemotherapy.
Other Agents
Benzodiazepines
Benzodiazepines are weak antiemetic agents and their use as single agents to prevent CINV is not recommended. Benzodiazepines are mainly used as adjunctive agents to reduce anxiety, anticipatory nausea and vomiting, and refractory emesis occurring despite adequate prophylaxis regimens. Lorazepam (Ativan) and alprazolam (Xanax) are the most commonly used drugs in this class. The main side effect of benzodiazepines is sedation; therefore elderly patients and patients receiving medications with additional central nervous system depressant activity (e.g., phenothiazines, opioids) should be carefully monitored.
Antihistamines
Antihistamines do not have significant antiemetic activity and should not be used as single agents in the prevention or treatment of CINV. Antihistamines are mainly used as adjunctive agents to prevent dystonic reactions with dopamine receptor blockers, or for treatment of nausea in patients with advanced cancer when the nausea is thought to be mediated by the vestibular system.
Cannabinoids
Despite the controversy that surrounds the use of cannabinoids for CINV, several studies using delta-9-tetrahydrocannabinol (THC) have shown this agent to be an effective antiemetic, compared to placebo and even prochlorperazine. Drugs in this class are available as plant extracts (dronabinol or tetrahydrocannabinol) and semisynthetic substances (nabilone, levonantradol). The most frequently used doses are 5 to 10 mg orally every 6 to 8 hours for dronabinol and 1 to 2 mg orally every 12 hours for nabilone. In a systematic review of efficacy and adverse effects of cannabinoids in the prevention of CINV, it was found that they were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride. However, cannabinoids have not been proven to be more effective in patients receiving mildly or very highly emetogenic chemotherapy. Side effects occurred more frequently with cannabinoids and included dizziness, dysphoria, depression, hallucinations, paranoia, and hypotension. Some potentially “beneficial” side effects include euphoria and sedation. As with other agents having a lower therapeutic index, cannabinoids should be reserved for patients who are intolerant of or refractory to 5-HT 3 serotonin receptor antagonists, aprepitant, or dexamethasone.
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