Overview of Chemotherapy-Induced Nausea and Vomiting and Evidence-Based Therapies

Nelly Adel, PharmD, BCOP, BCPS

Patients with cancer often fearfully anticipate the prospect of many potential negative consequences resulting from antineoplastic chemotherapy. At or near the top of their concerns is the common adverse effect (AE) of chemotherapy-induced nausea and vomiting (CINV).1-3 When CINV goes untreated, it affects upwards of 60% to 80% of patients with cancer.4 CINV not only negatively impacts the quality of life (QOL) of the patient,4-6 but also the QOL of the patient’s family.7 Without prevention and control of CINV, patients may experience many undesirable events that can affect their QOL and/or treatment outcomes,8-10 including discontinuation of chemotherapy,3 which highlights the need for adequate prevention and control measures.

CINV is a substantial issue in oncology that requires active management for both prevention and treatment. In CINV, the focus is clearly on prevention to avoid clinical, QOL, and economic issues that arise when CINV is not well controlled. With updated antiemesis protocols and newer antiemetic agents, healthcare providers and pharmacists can be ready to implement the most appropriate prevention and treatment strategies.

Definition and Classifications of CINV
Definition of CINV
Although nausea and vomiting are grouped together in CINV and they often do occur together, the symptoms can occur independently.11 Nausea occurs more frequently in cancer chemotherapy11 and is described as the subjective sensation or feeling of unsettled stomach in the epigastrium and/or throat, coupled with a sensation that vomiting is impending. Vomiting, as a separate effect, is the physical expulsion of stomach contents via the mouth.12,13 Despite progress in controlling emesis, nausea remains a problem for many patients. In this activity, the sequelae of nausea and vomiting will be discussed together unless otherwise noted.

Classifications of CINV
CINV can be classified into 5 types (Table 114-19): acute, delayed, anticipatory, breakthrough, and refractory. Acute CINV occurs within 24 hours of the initial administration of an antineoplastic agent, while delayed CINV occurs after 24 hours and may peak 2 to 3 days post administration.14-16 Once a patient experiences CINV, he or she may then experience anticipatory CINV, which occurs when a sensory experience (eg, smell, sound, taste) triggers an episode of nausea and/or vomiting prior to subsequent administration of a chemotherapy regimen.16-18 Breakthrough CINV can be defined as nausea and/or vomiting that occurs within 5 days of chemotherapy treatment despite the use of a guideline-recommended antiemetic protocol, which requires the addition of more agents referred to as “rescue medications.”17,19 Refractory CINV can be described as nausea and/or vomiting that consistently occurs in subsequent chemotherapy cycles despite the use of a guideline-recommended antiemetic regimen.19

Pathophysiology
The pathophysiology of CINV includes both peripheral and central nervous system (CNS) pathways with different mechanisms involved in acute CINV and delayed CINV.10,20,21 In acute CINV, free radicals generated by toxic chemotherapeutic agents stimulate enterochromaffin cells in the gastrointestinal tract, causing the release of serotonin.10,22 Subsequently, serotonin binds to intestinal vagal afferent nerves via 5-HT3 receptors, which trigger the vomiting reflex via the nucleus of the solitary tract (NTS) and chemoreceptor trigger zone (CTZ) in the CNS.10,22 5-HT3 receptor signaling may also play a role in delayed CINV, but to a lesser extent than in acute CINV.10 Substance P is considered to be the principal neurotransmitter involved in delayed CINV. Chemotherapy drugs trigger the release of substance P from neurons in the central and peripheral nervous systems, which then binds to neurokinin-1 (NK1) receptors mainly in the NTS to induce vomiting.10,22 In both acute and delayed CINV, coordination of nausea and vomiting occurs in the vomiting center in the medulla oblongata via signals from the NTS, CTZ, or afferent vagal nerves.10 The recommended antiemetic agents for acute and delayed CINV flow from the differences in pathophysiology. However, there is evidence of “cross-talk” between 5-HT3 and NK1 pathways that may guide treatment and prevention strategies.10

Anticipatory CINV is generally regarded as a conditioned response to a prior episode of CINV.16-18 A sensory stimulus (eg, sight, sound, smell) present at the time of an episode of CINV conditions the patient to associate the stimulus with nausea and vomiting. Subsequent exposure to the stimulus then triggers the conditioned response of nausea and vomiting.13,23 The classic example is the patient who becomes nauseated simply upon arriving in the chemotherapy infusion suite. Prevention of acute and delayed CINV is the best approach to anticipatory CINV so that a sensory stimulus is not established.

Risk Factors
The risk factors for developing CINV can be categorized as patient-related or treatment-related.24 While there may be some variability in patient risk factors based on chemotherapy regimen, the common patient factors include age, gender, history of motion sickness and/or pregnancy-related nausea and vomiting, a history of alcohol use, and emesis with prior chemotherapy. Patients who are younger than 50 years have a higher risk for CINV.15,24,25 Gender appears to be a factor with a higher risk generally associated with females15,24; however, a recent multivariate analysis suggests a less prominent role of gender on CINV risk.25 Patients who have a history of motion sickness and/or pregnancy-related nausea and vomiting have a higher risk of developing CINV. A history of high alcohol intake (eg, ≥5 drinks per week) tends to lower the risk of CINV,15,24 possibly because of desensitization of the CTZ.15 The bases for some risk factors span patient and treatment elements. A risk factor that can be mitigated through preventive measures is previous episodes of CINV, and this is particularly true of anticipatory CINV.15,24,25 Related to previous episodes of CINV, another risk factor is failure to adhere to antiemetic treatment guidelines,25 a factor that is clearly dependent on healthcare providers.

Emetogenic Risk
One of the most reliable risk factors for CINV is the type of antineoplastic regimen that is being administered. Along with varying mechanisms of action, chemotherapy agents also vary with respect to their relative ability to incite emesis, ie, the emetogenic risk, which is influenced by the drug, dose, route, schedule, and the combination with other chemotherapy agents.26,27 For the purposes of this activity, the focus will be on the treatment of CINV in the high and moderate emetic risk groups. In the high-risk category, the drug has the potential to elicit CINV in >90% of patients in the absence of antiemetic prophylaxis, while in the moderate-risk category, the potential to elicit CINV ranges from 30% to 90% of patients.26 In Table 226, single therapy agents, whether administered intravenously or orally, are categorized with their relative emetogenic risk potential.26

Pharmacologic and Integrative Medical Therapies for CINV
Pharmacologic Therapies
Prevention and treatment of CINV is based on its underlying subtype. The primary goal is to prevent CINV from occurring so that subsequent episodes of nausea and vomiting and the potential for anticipatory CINV are avoided. Uncontrolled nausea and vomiting have potential effects on the patient’s QOL and adherence to chemotherapy. The various antiemetic guidelines available for CINV describe in detail the numerous options for crafting a regimen to fit a patient’s needs.17,27,28 When devising an antiemetic regimen, the level of treatment is based on the chemotherapy drug with the highest potential for emesis. Therefore, if a chemotherapy regimen includes drugs with low or minimal emetic risks, as well as a drug with high emetic risk, such as anthracyclines, the antiemetic regimen should be tailored to the drug with the highest emetic risk. Emesis control should be individualized to patient need and, depending on the chemotherapeutic agents used, duration of regimen, the route of administration for the antiemetic, and considerations regarding the AEs of the antiemetic agents.

The main pharmacologic classes of drugs used in preventing and treating CINV (Table 327) are 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids; they also include, to a lesser extent, dopamine antagonists, benzodiazepines, cannabinoids, and the atypical antipsychotic, olanzapine. With different mechanisms of action, the agents are typically administered in combination protocols to provide maximum antiemetic control, particularly when patients are undergoing high or moderate emetic risk chemotherapy regimens.

5-HT3 Receptor Antagonists
The 5-HT3 receptor antagonists act on serotonin receptors both peripherally in the intestine and centrally in the CTZ.29 This class includes the first-generation 5-HT3 receptor antagonists, ondansetron, dolasetron, and granisetron, with half-lives between 3 and 9 hours. The second-generation compound in this class, palonosetron, has a half-life of approximately 40 hours.29 The differences in half-lives influence dosing and possibly indication. Ondansetron, dolasetron, and granisetron are most commonly used in acute CINV.30,31 Palonosetron demonstrates efficacy in delayed CINV as well.32-35 Common AEs for 5-HT3 antagonists include headache and gastrointestinal effects such as constipation, as well as elevation of liver aminotransferase levels.36-39 Of particular note, ondansetron and dolasetron should be given with caution in patients with long QT syndrome.36,38

NK1 Receptor Antagonists
The NK1 receptor antagonists act peripherally and centrally by blocking the binding of substance P at the NK1 receptor.40 The approved drugs in this class include aprepitant, fosaprepitant (a prodrug of aprepitant for injection), and rolapitant.41,42 Another NK1 receptor antagonist, netupitant, is formulated with the 5-HT3 receptor antagonist, palonosetron, in a fixed-dose combination product for acute and delayed CINV.43 The NK1 antagonists are not used as sole antiemetic agents in acute CINV, but rather typically in combination with a 5-HT3 antagonist and dexamethasone. Aprepitant may also be used in delayed CINV.17,27,28 AEs of NK1 receptor antagonists are generally limited to diarrhea, fatigue, and nausea,44-48 but individual agents have specialized AEs of note. Aprepitant is metabolized by and is a moderate inhibitor of CYP3A4, which may lead to drug-drug interactions. Of particular importance in CINV, aprepitant causes an increase in plasma dexamethasone levels; therefore, reduction in dexamethasone doses are necessary when used in combination antiemetic regimens.29,49-51 Aprepitant and fosaprepitant are also contraindicated in patients receiving pimozide because inhibition of metabolism can lead to increased pimozide levels that can cause severe or life-threatening reactions, including QT prolongation.41 In addition, aprepitant and fosaprepitant should be used with caution in patients receiving warfarin, due to a potential decrease in the international normalized ratio; drug-drug interactions are possible with CYP3A4 substrates, CYP3A4 inhibitors, and CYP3A4 inducers.41

Rolapitant is generally well tolerated, with fewer than 10% of patients experiencing treatment-related AEs.44,45 The most common AEs with rolapitant were similar to those of control groups and include neutropenia, hiccups, and dizziness.42 Although rolapitant is not an inhibitor or inducer of CYP3A4,52 it is metabolized by the enzyme, and CYP3A4 inducers, such as rifampin, can reduce rolapitant blood levels and efficacy.42 As a CYP2D6 inhibitor, rolapitant is contraindicated in patients receiving thioridazine and concomitant administration should be avoided with other CYP2D6 substrates, such as pimozide, but no dose adjustment is needed with dexamethasone.42

For the netupitant/palonosetron (NEPA) combination product, AEs include asthenia, dyspepsia, fatigue, hiccups, and erythema, and severe AEs reported in clinical trials include neutropenia and leukopenia.53,54 Netupitant is a moderate inhibitor of CYP3A4 and drug interactions are possible in patients receiving drugs that are metabolized by CYP3A4, but no contraindications are listed.43 NEPA, however, should be avoided in patients with severe renal or hepatic impairment.43

Corticosteroids
While the mechanism of action of corticosteroids as antiemetics is not entirely clear, their use in CINV dates to the 1980s.29 Dexamethasone is the corticosteroid of choice for CINV, and it is often used in combination with other agents to increase antiemetic efficacy in acute and delayed CINV. Dexamethasone may also be used as monotherapy in low–emetic risk chemotherapy regimens.17,27,28

Other Agents
Dopamine receptor antagonists (eg, metoclopramide, prochlorperazine) were used in early attempts to alleviate CINV. These drugs still have their place in current CINV treatment regimens.17,27,28 It is important to emphasize that these agents are used in breakthrough CINV, and as a rescue medication, they exhibit many AEs, with the most worrisome being extrapyramidal symptoms. Although an off-label use, the atypical antipsychotic, olanzapine, has gained a role for its antiemetic effects, particularly for breakthrough CINV.17,27,28 Common AEs associated with olanzapine include sedation, fatigue, headache, dry mouth, hyperglycemia, and diarrhea.55-57 Olanzapine can also increase the risk of extrapyramidal symptoms.57 Benzodiazepines are most often used in treating anticipatory CINV, but may also be included in regimens to treat breakthrough or refractory CINV.17,27,28

Antiemetic guidelines are published by several major cancer organizations, including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and jointly by the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC).17,27,28 One notable difference among the guidelines is the consideration of cannabinoids. In the ASCO and MASCC/ESMO guidelines, cannabinoids are not listed as antiemetic alternatives, while the NCCN guidelines list cannabinoids as options for breakthrough/refractory CINV.17,27,28 Also, in the ASCO and NCCN guidelines, palonosetron is considered the preferred 5-HT3 antagonist for moderate emetogenic chemotherapy regimens, while the MASCC/ESMO guidelines do not specify any particular 5-HT3 antagonist.17,27,28,58 A generalized scheme for antiemetic protocols from the various guidelines can be found in Table 4.10,17,22,27,28,59

Integrative Medical Treatments
Given the increasing preferences for integrative medicine using complementary and alternative therapies, patients may express an interest in alternatives to standard pharmacologic treatments for CINV. Pharmacists and other healthcare providers should be aware of nonpharmacologic or alternative treatments so they can provide the proper counsel to patients. As is common with alternative medical treatments, there tends to be a dearth of well-controlled trials to properly evaluate such alternative treatments. Pharmacists and other healthcare providers may find it helpful to engage their patients in conversations regarding nonpharmacologic or alternative treatments. Even if the clinical evidence is lacking, patients may derive other benefits from such treatments. Pharmacists should also ensure that the nonpharmacologic or alternative treatments do not interact with pharmacologic therapies in a negative manner.

Behavioral Treatments
Anticipatory CINV, as a learned response to a stimulus, may respond to nonpharmacologic treatments, particularly behavioral modification approaches.10,13,23,60 Antiemetic therapies may actually exacerbate nausea and vomiting in anticipatory CINV.61 Behavioral approaches to anticipatory CINV may be preferable; they include hypnosis, muscle relaxation with guided imagery, music therapy, systematic desensitization, and biofeedback.13,27 Particularly for anticipatory CINV, patients and healthcare providers may also opt for the use of acupuncture or acupressure, in which needles or external pressure are placed at critical pressure points of the body to relieve the symptoms of nausea and vomiting.27,62

Alternative Treatments
Two of the most common alternative CINV treatments are ginger and cannabis, including its various forms and synthetic derivatives. Ginger (Zingiber officinale) has a long history as an agent to treat gastrointestinal ailments and it is a relatively popular home remedy for nausea and vomiting. Studies suggest that ginger contains bioactive compounds that bind to 5-HT3 receptors and thus may alleviate symptoms of nausea and vomiting.62,63 While controlled clinical trials studying ginger for CINV have produced mixed results, ginger, at doses up to 4 grams per day, is classified in the “generally regarded as safe” category by the FDA. Patients should discuss with their physician the doses of ginger they are taking, especially for the potential risk of bleeding in patients with thrombocytopenia.62 Most clinical success appears to be seen when ginger is used as a supplemental treatment along with standard antiemetic protocols.62

Cannabinoids for CINV
With increasing public debate on medicinal cannabis and legalized cannabis, patients may express interest in its use for CINV. A commercial form of the synthetic cannabinoid, dronabinol, has been on the market since 1985, and in 2016, a newer, oral solution formulation was approved that includes CINV as an indication.64 In addition, the FDA approved the capsule formulation of another synthetic cannabinoid, nabilone, in 1985.65 After the original nabilone manufacturer withdrew it from the market, a different manufacturer received marketing approval again in 2005.65 The synthetic cannabinoids, dronabinol and nabilone, are generally accepted for the treatment of CINV, particularly breakthrough or refractory types.27 It is important to note that dronabinol is a schedule III drug and nabilone is a schedule II drug.66-68

Role of Pharmacists
Antiemetic drugs are often used to prevent CINV caused by chemotherapy regimens that frequently include multiple drugs. With the polypharmacy typically required in chemotherapy and CINV, pharmacists can become crucial partners with other healthcare professionals and patients to optimize clinical outcomes. Pharmacists can assist with adherence to standard CINV guidelines, which can greatly assist with preventing CINV in the first place. Eligible pharmacists can also aspire to board certification in oncology,69 which can enhance their ability to provide advanced clinical expertise to patients and the medical team.

Summary
CINV remains a common AE of chemotherapy that can profoundly impact the lives of patients with cancer. Diligent adherence to antiemetic guidelines can reduce the incidence of CINV. Even with firm adherence, breakthrough or refractory CINV can occur that will require additional clinical evaluation. Pharmacists knowledgeable in CINV treatment guidelines are an important resource for patients, caregivers, and other healthcare professionals. 
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