Chemotherapy-induced Nausea and Vomiting

Traditionally, nausea and vomiting are among the most commonly observed, as well as feared, side effects for patients who are receiving chemotherapy.¹ Despite modern anti-emetic therapy, in patients taking highly emetogenic chemotherapy the incidence of nausea and vomiting has been reported to be up to 60 and 50%, respectively;^2,3 additionally, anticipatory symptoms may occur in up to 40% of patients.⁴ It is estimated that in 70–80% of patients, pre-medication and symptomatic treatment can avoid or ameliorate chemotherapy-induced nausea and vomiting (CINV).⁵ Prior to routine use of modern anti-emetics, up to 20% of patients were not able to complete or delayed doses of their chemotherapy program.⁶ In the 1990s, the introduction of serotonin receptor antagonists (5HT3 antagonists) and corticosteroids further improved control of nausea and emesis.⁷ Modern classes of anti-emetic include 5HT3 antagonists, substance P neurokinin 1 receptor antagonists, motility agents, phenothiazine, benzodiazepines, and corticosteroids (see Table 1). Control of CINV is important as it allows patients to complete chemotherapy protocols and enhances the quality of life of patients in therapy. Despite modern anti-emetic regimens, a significant number of patients continue to experience symptoms of nausea and vomiting, and healthcare providers have been shown to underestimate the incidence of CINV.^3,8 Seventy-five percent of patients with nausea and 50% of those with vomiting reported a negative impact on the performance of activities of daily living when queried with the Functional Living Index–Emesis (FLIE) questionnaire.⁹

Mechanisms of Chemotherapy-related Nausea and Vomiting
While the precise mechanism of CINV stimulation remains unknown, there are known anatomical zones of the central nervous system, neuronal pathways, and neurochemical mechanisms underlying the process of emesis.⁷ Mechanisms by which antineoplastic agents may induce emesis include direct actions on medullary centers, cell damage in the gastrointestinal tract, and learned cortical responses.¹⁰ The chemotherapy trigger zone (CTZ) and vomiting center (VC) are two wellknown anatomical centers in the central nervous system attributed to nausea and vomiting.¹¹ Signals in blood as well as spinal fluid can interact with the CTZ because it is a circumventricular structure in the fourth ventricle, outside of the blood–brain barrier. The VC is located in the lateral reticular formation of the medulla. Signals from the CTZ act on the VC and induce efferent impulses to the salivation center, abdominal muscles, respiratory tract, and cranial nerves, which induce emesis. The vestibular system, pharynx and gastrointestinal tract, and cortical structures may also activate the VC.⁷

Several neurotransmitters have been identified that mediate emesis including dopamine, histamine, acetylcholine, serotonin, protachykinin-1, and γ-aminobutyric acid (GABA). Dopamine receptors have been found mainly in the area postrema that act primarily as emesis-inducing transmitters.¹² High concentrations of histamine and cholinergic receptors have been identified in neural networks associated with emesis such as the nucleus tractus solitarius.¹³ Serotonin receptors, found on the vagal afferent and other neurons of the gastrointestinal tract, have been theorized to modulate emesis outside of central nervous system stimuli.¹⁴ In animal models, cisplatin has been shown to cause release of serotonin from small intestinal mucosa that binds to splanchnic and vagal 5HT3 receptors or 5HT3 receptors in the brainstem to stimulate emesis.¹⁵ Protachykinin-1 is one of the most recently investigated neurotransmitters. It acts on central brain areas involved in control of vomiting including the brainstem, nucleus tractus solitarius, and area postrema.¹⁶ Understanding of the neuronal pathways and neurotransmitter functions has led to the development of several classes of neurotransmitter-receptor-targeted anti-emetic agents. Definitions of Chemotherapy-related Nausea and Vomiting
When recommending anti-emetic regimens, most guidelines take into account the emetogenicity of the antineoplastic agent being used, as well as the type of nausea and vomiting being treated. Three commonly referenced guidelines have been published by the Multinational Association of Supportive Care in Cancer (MASCC), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN).^17–19 Antineoplastic agents are classified into four emetogenic risk groups: high, moderate, low, and minimal (see Table 2). Each risk group has been defined by the percentage of patients having emetic episodes when given an antineoplastic agent without anti emetic prophylaxis. Correspondingly, high, moderate, low, and minimally emetic agents produce emesis in 90, 30–90, 10–30, and fewer than 10% of patients, respectively. As emesis potential has been stringently tested in only a few agents, difficulty arises in assigning data-supported risk categorization to all antineoplastic agents; therefore, categorization of some agents has been by experience rather than by data.^20–22

Patterns of CINV have also been defined based on symptom onset and duration, and include acute, delayed, breakthrough, refractory, and anticipatory CINV. Acute CINV begins within the first 24 hours after chemotherapy has started. Acute CINV can be further subdivided into nausea and vomiting occurring within the first 12 hours, and delayed acute nausea and vomiting occurring from 12 to 24 hours.²³ Peak acuity usually occurs within six to seven hours of initiation of chemotherapy. Delayed nausea and vomiting develops more than 24 hours after chemotherapy initiation and may last for six to seven days.²⁴ Carboplatin, cisplatin, cyclophosphamide, and doxorubicin are often associated with delayed nausea and vomiting.²⁵ The most important risk factor for delayed nausea and vomiting is the presence of acute nausea and vomiting; however, the incidence of delayed nausea and vomiting in the absence of acute nausea and vomiting has been reported to be 18–36% after receiving highly emetogenic chemotherapy.^2,8 Due to the delay in symptoms from the time of chemotherapy infusion, delayed nausea and vomiting may be under-recognized. In a study of perceptions among physicians and nurses, 75% of providers underestimated the incidence of delayed nausea and vomiting.² Breakthrough nausea and vomiting occurs despite anti-emetic prophylaxis and requires rescue medication. Refractory nausea and vomiting refers to symptoms that occur during subsequent treatment cycles after incomplete control in earlier cycles.²³Patients experiencing breakthrough nausea and vomiting are at risk for refractory nausea and vomiting and anticipatory nausea and vomiting.^20,26 Anticipatory nausea and vomiting begins before chemotherapy, and is often associated with a history of poorly controlled acute and delayed CINV. Symptoms of anticipatory nausea and vomiting can be precipitated by taste, odor, sight, and anxiety, and this type of nausea may be difficult to treat. Up to 20% of patients may develop anticipatory nausea and vomiting by the fourth cycle of chemotherapy.²⁷ It may respond to prophylactic use of anti-anxiety agents, such as alprazolam and lorazepam; however, there are limited data from prospective trials.²⁸ Current recommendations for treatment also include behavioral interventions (i.e. medications, relaxation), systematic desensitization, and aggressive control of acute and delayed nausea and vomiting.¹⁸

Classes of Anti-emetic
5-HT3 Antagonists
Introduced in the 1990s, 5-HT3 antagonists are considered to be highly effective in prophylaxis of acute CINV. Almost all anti-emetic regimens of at least moderately emetogenic chemotherapies include 5-HT3 antagonists.²⁹ These agents are well-established in the management of acute emesis; however, their role is less clear in the management of delayed emesis.³⁰ 5-HT3 antagonists have been identified to prevent 50–70% of acute CINV.³¹ This class includes dolasetron, granisetron, ondansetron, palonosetron, and tropisetron. None of the 5-HT3 antagonists is identified as preferentially recommended by MASCC, NCCN, or ASCO guidelines.

Palonosetron, the newest 5-HT3 antagonist, was introduced in 1993. It has a higher binding activity, estimated to be 100-fold stronger than other 5-HT3 antagonists, and a longer half-life of approximately 40 hours.³² Palonosetron is available in intravenous preparations only. It is approved by the US Food and Drug Agency (FDA) for preventing acute CINV associated with moderately and highly emetogenic chemotherapy and for the prevention of delayed CINV associated with moderately emetogenic chemotherapy. A randomized double blind trial of palonosetron versus ondansetron showed higher efficacy rates for palonosetron in controlling both acute (81 versus 69%) and delayed (48 versus 31%) emesis.³³ In a trial against dolansetron, palonosetron was equivalent in preventing acute CINV and superior in preventing delayed CINV after moderately emetogenic chemotherapy.³² Trials comparing traditional 5-HT3 antagonists with palonosetron have been criticized for not routinely including corticosteroids with traditional 5-HT3s for prevention of delayed CINV.³⁴ Common side effects of 5-HT3 antagonists include dizziness, headache, and diarrhea or constipation. They are not associated with sedation or extrapyramidal symptoms (EPS). 5-HT3 may also cause asymptomatic electrocardiogram changes including prolonged PT and QTc intervals.Corticosteroids
Methylprednisone (MP) and dexamethasone are recommended for prevention of acute CINV for low and moderately emetogenic chemotherapy.³⁵ The mechanism underlying corticosteroid efficacy is unknown; however, it is hypothesized that MP decreases cisplatininduced 5-HT release from peripheral blood mononuclear cells.³⁶ In early studies, dexamethasone was shown to be superior to metoclopramide in patients receiving non-platinum based regimens.³⁷ Previously, 5HT3 antagonists—metoclopramide and dexamethasone combinations— were considered standard of care. Multiple studies with 5-HT3 antagonists have demonstrated improved control with the addition of corticosteroids. Study of the addition of aprepitant to standard ondansetron and dexamethasone in highly emetogenic cisplatin therapy showed superior control to the standard therapy, with complete protection of 82.8 versus 68.4%.³⁸ If given in combination with aprepitant, the dose of the steroid should be decreased as dexamethasone is a sensitive substrate for the cytochrome P450 (CYP P450) 3A4 enzyme. Corticosteroids may cause hyperglycemia in patients with diabetes and may cause changes in mental status.

Substance P Inhibitors
Aprepitant is an oral regimen for the prevention of acute and delayed nausea and vomiting that works by binding to the protachykinin-1 receptor. Protachykinin-1, a mediator of pain, inflammation, nausea, and vomiting, cannot bind to aprepitant-occupied receptors.³⁹ Other protachykinin-1 receptor antagonists include L-758,298, vofopitant,CP-122,721, and CJ-11,974; however, aprepitant is the only clinically available drug. Aprepitant is an oral regimen that is recommended for a three-day course, and has been shown to control cisplatin CINV in the acute and delayed phase in two randomized, placebo-controlled phase III studies.^40,41 These trials studied 1,099 patients who received 70mg/m² cisplatin and who were randomized to receive ondansetron and oral dexamethasone followed by oral dexamethasone twice daily on days two to four after chemotherapy versus aprepitant before chemotherapy followed by aprepitant and dexamethasone daily on days two and three followed by dexamethasone on day four. The aprepitant groups performed better in controlling overall emetic response: 63 and 73% versus 43 and 52% for the control groups.

Data exist that support the notion that aprepitant is effective in controlling nausea and vomiting from moderately emetogenic chemotherapy.⁴² MASCC and NCCN guidelines recommend aprepitant as an additional component to corticosteroids and 5HT3 antagonists for prophylaxis against CINV of highly emetogenic chemotherapies.¹⁸

Recently, fosaprepitant, an intravenous neurokinin-1 receptor antagonist, has been submitted to the FDA as a parenteral alternative to aprepitant.⁴³ Dizziness, constipation or diarrhea, headache, and weakness are side effects of aprepitant. There exists potential for rug–drug interactions as aprepitant may effect the metabolism of medications cleared by the CYP3A4 and CYP2c9 enzymatic pathways.⁴⁴ Commonly used medications that may be rendered less effective include oral contraceptives and coumadin. The areas under the curve of oral dexamethasone and intravenous methylprednisolone have been shown to be increased with use of aprepitant, and steroid doses should be reduced.⁴⁵

Substituted Benzamides
Metoclopramide was developed for the treatment of diabetic gastroperesis and it acts as a prokinetic agent. High-dose regimens have been shown to reduce and prevent cisplatin-related emesis.⁴⁶ Side effects of EPS, anxiety, and depression limit the use of high-dose metoclopramide. Although metoclopramide has been shown to be as effective as 5HT3 antagonists in combination with steroids for prevention of delayed CINV, it is recommended to be used only in special circumstances of steroid or 5-HT3 antagonist intolerance.^47,48
Cannabanoids
Cannabanoids are controversial, and guidelines recommend their use only in patients intolerant of 5HT3 antagonists or steroids and aprepitant. Cannabinoids should be used with caution because of side effects of sedation, dysphoria, depression, hallucinations, and euphoria. Several small trials and reviews have attempted to discern the effectiveness of cannabinoids; however, their effectiveness in controlling CINV remains questionable.^49–51
Benzodiazepines
Benzodiazepines can be useful to reduce anxiety and risk of anticipatory CINV. The anti-emetic potential of lorazepam and alprazolam is low; however, they are recommended by MASCC guidelines as they may decrease anticipatory nausea and vomiting. Benzodiazipines have been shown to decrease anticipatory nausea and vomiting from 18 to 0% in a double-blind, placebo-controlled study of women with breast cancer.²⁸
Antihistamines
Antihistamines such as diphenhydramine or hydroxyzine have been used to treat emesis related to motion sickness. High levels of H1 and muscarinic receptors in neuronal pathways associated with CINV suggest that antihistamines may be effective; however, their role is poorly defined in treating CINV.⁷

Phenothiazines
Prochlorperazine and thiopropanate were the first drugs found to be superior to placebo in reducing CINV.⁵² The effectiveness of phenothiazines is dose-related, and this class of anti-emetic is limited by antidopaminergic side effects of hypotension, restlessness, EPS, and sedation. Concurrent use of phenothiazine, substituted benzamide, and butyrophenone is advised against because of increased risk for movement disorders, including akathisia and EPS. Butyrophenones
Haloperidol, droperidol, and domperidone have anti-emetic activity by blocking dopamine receptors. The butyrophenones are considered relatively ineffective in treating CINV.^53,54

Atypical Antipsychotics
Olanzapine, an atypical antipsychotic, has activity at many receptor sites related to CINV including dopamine, serotonin, histaminergic, adrenergic, and muscarinic receptors.⁵⁵ Oral as well as sublingual preparations are available. Olanzapine combined with a 5HT3 antagonist and steroids was shown be effective in prevention of acute and delayed CINV in a phase II study.⁵⁶ MASCC guidelines suggest olanzapine for refractory and breakthrough emesis.¹⁸ Adverse effects include somnolence, postural hypotension, constipation, dizziness, restlessness, weight gain, hyperglycemia, EPS, and tardive dyskinesia.

Guidelines for the Adminstration and Classification of Anti-emetics
Prophylactic and treatment recommendations have been developed and recently updated by the MASCC, ASCO, and NCCN.^17,18,19 Several general principles apply to anti emetic use. As dose, route, frequency, and combinations of antineoplastics may affect the degree of symptoms, anti-emetic regimens should be tailored to each chemotherapeutic regimen. Most chemotherapeutic agents produce less nausea and vomiting when given by continuous infusion. Combination anti-emetic regimens may provide greater protection against nausea then single agents.

In general, two agents of the same class should not be used in combination as this can increase side effects and not increase efficacy. Oral anti-emetics are safe, convenient, and cost-efficient compared with other regimens; however, some patients may not be able to swallow or absorb medications through the gastrointestinal tract.¹⁷

However, patient risk factors that have been identified are currently not incorporated into decision-making guidelines. Patients who are under 50 years of age and have a history of anxiety or of motion sickness are at increased risk for CINV.^57,58 Incidence of CINV has been found to be lower in patients with a history of alcohol use.²¹ Female gender is associated with a higher rate of CINV in patients taking cisplatin and 5-fluorouracil.⁵⁹ Females with a history of hyperemesisgravidarum or emesis during previous chemotherapy also carry a higher risk for CINV.^21,22

Highly Emetogenic Chemotherapy
ASCO, NCCN, and MASCC guidelines all recommend 5HT3-antagonist, dexamethasone, and aprepitant within the first 24 hours for prevention of acute CINV caused by highly emetogenic chemotherapy.^17–19 Recommendation for treatment of delayed CINV caused by highly emetogenic chemotherapy includes dexamethasone and aprepitant. In a meta-analysis, which did not include palonosetron, 5HT3 antagonists were not cost-effective in preventing delayed CINV from highly emetogenic chemotherapy.⁶⁰

Moderately Emetogenic Chemotherapy
5-HT3-antagonists with dexamethasone are recommended for acute CINV with moderately emetogenic chemotherapy.^17–19A doubleblind study of addition of aprepitant to regimens containing cyclophosphamide with doxorubicin or epirubicin has shown benefit for the addition of aprepitant to prevention of acute emesis caused by moderate emetic risk agents.⁶¹Therefore, ASCO and MASCC suggest the addition of aprepitant to regimens containing anthracycline and cyclophosphamide, while NCCN guidelines suggest aprepitant even more broadly. According to ASCO and MASCC guidelines, for patients with significant probability of suffering delayed emesis with moderately emetogenic chemotherapy, oral dexamethasone, a 5HT3 antagonist, or both should be used.¹⁸ ASCO and MASCC recommend aprepitant for a three-day course if it was used on day one.

Mildly Emetogenic Chemotherapy
Single-agent anti-emetics may be used for prophylaxis of mildly emetogenic chemotherapies. MASCC and ASCO guidelines advise single-agent dexamethasone, while NCCN also recommends prochloperazine or metoclopramide as alternatives.Treatment of Breakthrough and Refractory Nausea and Vomiting
Strategies to treat breakthrough and refractory nausea and vomiting include an assessment of the previous anti-emetic regimen, chemotherapy regimen, and tumor status. Anti-emetic agents should be reviewed for appropriate dose and schedule. Attention should be focused on whether the appropriate anti-emetic regimen was used for the antineoplastic emetogenic potential. ASCO recommendations do not recommend substituting a different serotonin agonist if another has failed. However, there are randomized double-blind studies supporting change from one 5HT3 antagonist to another.⁶² Addition of benzodiazepines (lorazepam or alprazolam), substituting high-dose intravenous metoclopramide for the 5HT3 antagonist, or adding dopamine-receptor antagonists or neuroleptics have been suggested.¹⁸ MASCC and NCCN guidelines suggest the atypical neuroleptic olanzapine.⁵ Consideration of tumor response and goals of care have been advocated by ASCO, with emphasis on quality of life while continuing chemotherapies that have the greatest efficacy.¹⁷ If CINV symptoms present in atypical patterns, investigation of other causes should be made, including brain metastases, intestinal obstruction, and other medications (i.e. opioids, bronchodilators).
Innovations in Treatment Delivery
Barriers to prevention of CINV, including the impracticality of oral medication for a patient who is already nauseated, difficulty swallowing, and polypharmacy have led to the development of depot transdermal delivery of the 5-HT3 antagonist granisetron. NCCN guidelines advocate the utilization of this transdermal patch 24–48 hours before initiation of moderate- to high-emetic-risk chemotherapy. Subcutaneous administration of granisetron resulted in 27% higher area under the curve levels for 0–12 hours, with similar values at 0–24 hours to intravenous granisetron in a study of 31 patients receiving platinum based chemotherapy. Further trials are necessary to confirm biological equivalence; however, preliminary results suggest equivalent bioavailability.
Alternative Therapies
Randomized trials have attempted to explore non-pharmacological interventions for CINV. Yoga, hypnosis, acupressure, acupuncture-point stimulation, and massage therapy have been shown to have some benefit.^63–67 Although pre-chemotherapy patient education can reduce nausea expectancy, it has no effect on the occurrence of nausea.⁶⁸
Anti-emetics in Children
There are limited data regarding utilization, timing, and dosages appropriate for prophylaxis of CINV in children. 5HT3 antagonists have been shown to be more effective than metoclopramide, phenothiazone, and cannabinoids.⁶⁹ The few studies that examine anti-emetics in children receiving chemotherapy have small numbers and suboptimal design.
Future Research Directions
Many research questions remain. Future directions of anti-emetic research should focus on improved understanding of the mechanisms of nausea and vomiting, optimal dosing regimens, and newer, more efficacious, and hopefully less expensive alternatives. ■