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Overview of Chemotherapy-Induced Nausea and Vomiting and Evidence-Based Therapies
Nelly Adel, PharmD, BCOP, BCPS
Participating Faculty
Managed Care Considerations in Chemotherapy-Induced Nausea and Vomiting

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

Nelly Adel, PharmD, BCOP, BCPS
Among patients with cancer, chemotherapy-induced nausea and vomiting (CINV) is a common adverse effect that not only impacts quality of life, but also treatment outcomes. It is important to address these issues from both prevention and treatment standpoints so that patients remain adherent to their regimens. With CINV being classified into 5 different types, the primary medication options for prevention and treatment include 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids. Other medications used, but to a lesser extent, include dopamine antagonists, benzodiazepines, cannabinoids, and olanzapine. In addition, those patients who express interest in alternative or nonpharmacologic therapies may have options as well. With the array of medications available for patients with cancer, pharmacists play an integral role in optimizing patient outcomes. Therefore, it is important that pharmacists stay up-to-date on the most current guidelines available for CINV treatment.

Am J Manag Care. 2017;23:-S0
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

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

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